Preclinical Development of Antisense Oligonucleotides to Rescue Aberrant Splicing Caused by an Ultrarare ABCA4 Variant in a Child with Early-Onset Stargardt Disease
PMID: 38607040
Gene: ABCA4
HGNC ID: 34
540 Matching Annotations
- Last 7 days
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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10-year-old girl
Case#: Patient female, 10y, ethnicity not reported
DiseaseAssertion: Stargardt disease (STGD1), early onset
FamilyInfo: autosomal recessive inheritance; co-segregation of variants in parents (each heterozygous). Pedigree shown in Figure 1A. One unaffected sibling reported.
CasePresentingHPOs: HP:0007663, HP:0007754, HP:0002587, HP:0030636, HP:0000548
CaseHPOFreeText: early-onset visual decline (age 7), symmetric disease in both eyes, hyperautofluorescent ring surrounding macular atrophy, lipofuscin accumulation, photoreceptor degeneration.
CaseNotHPOs: HP:0007707
CaseNotHPOFreeText: normal anterior segment on slit lamp exam; no external ocular abnormalities reported.
Genotyping Method: Sanger sequencing confirmation; variant identification likely via next-generation sequencing (not explicitly stated).
PreviouslyPublished: n/a
Variant: ABCA4 NM_000350.2: c.6817-713A>G; c.3259G>A (p.Glu1087Lys)
ClinVar: n/a
CAID: CA2837995439, CA227097
SupplementalData: phenotype and validation data in Figures 1–5 and Supplemental Figures S1–S5
Tags
- Scotoma
- CAID:2837995439
- General
- Zygosity:CompoundHeterozygous
- automated_hgnc_source:Gene_Name
- Gene:ABCA4
- DecreasedCentralVA
- Clin Gen
- CAID:227097
- DiseaseEntity:STGD1
- InheritancePattern:AutosomalRecessive
- MacularAtrophy
- automated_hgnc_source:CAID
- FundusAutofluorescence
- HGNC: 34
- ClinGen ABCA4 Annotations
- AlleleOrigin:Germline
- automated_hgnc:34
Annotators
URL
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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V1 H1 Exon 36.1–3 G>A chr1:94,484,001 c.5196+1137G>A 4 4 0 0
Case#: Braun Family 2 Proband (from left to right, top to bottom of available pedigrees), female
DiseaseAssertion: Stargardt
FamilyInfo: Both parents are unaffected carriers. c.1622T>C (p.L541P) and c.3113C>T (p.A1038V) complex variants were paternally inherited, c.5196+1137G>A maternally inherited.
CasePresentingHPOs:
CaseHPOFreeText: "five or more of the following features of ABCA4-associated retinal disease: decreased visual acuity before age 20, decreased visual acuity as the first visual symptom, symmetrical fundus findings, pisciform flecks, beaten metal macular atrophy, bulls-eye maculopathy, peripapillary sparing, vermillion fundus, masked choroid on fluorescein angiography, nummular pigment overlying extensive macular atrophy, central outer retinal atrophy on optical coherence tomography and central scotomas on Goldmann perimetry."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: one plausible disease-causing mutation detected in ABCA4 after assessing the entire coding sequence and canonical retinal splice junctions with automated bidirectional Sanger sequencing using an ABI 3730 sequencer
PreviouslyPublished: n/a
Variant: c.5196+1137G>A; c.1622T>C (p.L541P) and c.3113C>T (p.A1038V) complex variant
ClinVar: 438100
CAID: CA26843511
SupplementalData: pedigree in fig s2
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V1 H1 Exon 36.1–3 G>A chr1:94,484,001 c.5196+1137G>A 4 4 0 0
Case#: Braun Family 3 Proband (from left to right, top to bottom of available pedigrees), female
DiseaseAssertion: Stargardt
FamilyInfo: Both parents are unaffected, but only mother has genotype information available since father is deceased. c.1622T>C (p.L541P) and c.3113C>T (p.A1038V) complex variants were maternally inherited.
CasePresentingHPOs:
CaseHPOFreeText: "five or more of the following features of ABCA4-associated retinal disease: decreased visual acuity before age 20, decreased visual acuity as the first visual symptom, symmetrical fundus findings, pisciform flecks, beaten metal macular atrophy, bulls-eye maculopathy, peripapillary sparing, vermillion fundus, masked choroid on fluorescein angiography, nummular pigment overlying extensive macular atrophy, central outer retinal atrophy on optical coherence tomography and central scotomas on Goldmann perimetry."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: one plausible disease-causing mutation detected in ABCA4 after assessing the entire coding sequence and canonical retinal splice junctions with automated bidirectional Sanger sequencing using an ABI 3730 sequencer
PreviouslyPublished: n/a
Variant: c.5196+1137G>A; c.1622T>C (p.L541P) and c.3113C>T (p.A1038V) complex variant
ClinVar: 438100
CAID: CA26843511
SupplementalData: pedigree in fig s2
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V1 H1 Exon 36.1–3 G>A chr1:94,484,001 c.5196+1137G>A 4 4 0 0
Case#: Braun Family 4 Proband (from left to right, top to bottom of available pedigrees), male
DiseaseAssertion: Stargardt
FamilyInfo: Both parents are unaffected, but only mother has genotype information available since father is deceased. c.5196+1137G>A maternally inherited. c.1022-1035fs inferred to be inherited from the father since other siblings also have this variant. Proband has 1 affected sister with the same genotype, and 2 siblings that were unaffected heterozygotes
CasePresentingHPOs:
CaseHPOFreeText: "five or more of the following features of ABCA4-associated retinal disease: decreased visual acuity before age 20, decreased visual acuity as the first visual symptom, symmetrical fundus findings, pisciform flecks, beaten metal macular atrophy, bulls-eye maculopathy, peripapillary sparing, vermillion fundus, masked choroid on fluorescein angiography, nummular pigment overlying extensive macular atrophy, central outer retinal atrophy on optical coherence tomography and central scotomas on Goldmann perimetry."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: one plausible disease-causing mutation detected in ABCA4 after assessing the entire coding sequence and canonical retinal splice junctions with automated bidirectional Sanger sequencing using an ABI 3730 sequencer
PreviouslyPublished: n/a
Variant: c.5196+1137G>A; c.1022-1035fs
ClinVar: 438100
CAID: CA26843511
SupplementalData: pedigree in fig s2
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Non-exomic and synonymous variants in ABCA4 are an important cause of Stargardt disease
PMID: 23918662
Gene: ABCA4
Disease: Stargardt disease
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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ABCA4-associated retinopathy complicated by didanosine-associated retinal toxicity
PMID: 41561667
Gene: ABCA4
HGNC ID: 34
Case#: patient 66, male, Italy
DiseaseAssertion: STGD
FamilyInfo: N/A
CasePresentingHPOs: HP:0000505, HP:0000551, HP:0000546
CaseHPOFreeText: best-corrected visual acuity (BCVA) was 20/400 in both eyes, mild myopia, both eyes were pseudophakic, extensive bilateral chorioretinal atrophy involving both the posterior pole and the peripheral retina, widespread mottled hypoautofluorescence in the mid-periphery, along with pronounced macular hypoautofluorescence, significant central retinal thinning, an enlarged foveal depression, outer retinal hyper-reflectivity associated with extensive atrophy of both the RPE and the underlying choroid, dense epiretinal membrane (ERM) was also identified in the right eye, large central hypofluorescent zone involving the macular region and extending beyond the vascular arcades
CasePreviousTesting: n/a
GenotypingMethod: Next-Generation Sequencing
PreviouslyPublished: n/a
Variant: c.1714C > T p. (Arg572∗)
ClinVar: 620085 https://www.ncbi.nlm.nih.gov/clinvar/variation/620085/?term=620085%5BVariation+ID%5D
gnomAD: 0.000001859 https://gnomad.broadinstitute.org/variant/1-94063158-G-A?dataset=gnomad_r4
Variant: c.2461T > A p. (Trp821Arg)
ClinVar: 99136 https://www.ncbi.nlm.nih.gov/clinvar/variation/99136/?term=99136%5BVariation+ID%5D
gnomAD: 0.000008054 https://gnomad.broadinstitute.org/variant/1-94055237-A-T?dataset=gnomad_r4
Variant: c.4417C>А p. (Leu1473Met)
ClinVar: 546600 https://www.ncbi.nlm.nih.gov/clinvar/variation/546600/?term=546600%5BVariation+ID%5D
gnomAD: 0.00005762 https://gnomad.broadinstitute.org/variant/1-94029567-G-T?dataset=gnomad_r4
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Antioxidant Saffron and Central Retinal Function in ABCA4-Related Stargardt Macular Dystrophy
PMID: 31618812
Gene: ABCA4
HGNCID: HGNC:34
Patients: a group of 31 Stargardt disease/fundus flavimaculatus patients (14 males, 17 females) with an established ABCA4 genotype, accumulated prospectively over an interval of 12 months at the outpatient service of the Institution, were included in this study.
MonDO: MONDO:0019353
CaseInfo: Case 11, Male, 12yo. Compound het c.5882G > A; p.Gly1961glu (Pathogenic in ClinVar); c.6764G > T,p.Ser2255Ile
DiseaseAssertion: Stargardt disease/fundus flavimaculatus
FamilyInfo: Not provided
CasePresentingHPOs: HP:0007769, HP:0000608, HP:0012045 (Peripheral retinal degeneration, Macular degeneration, Retinal flecks)
CaseHPOFreeText: cone-rod pattern of retinal dysfunction
GenotypingMethod: Mutation screening was performed by single-strand conformation polymorphism (SSCP) strategy of the whole coding region of ABCA4. Direct sequencing was also performed on siblings of probands and parents, when available, to confirm segregation of alleles.
MultipleGeneVariants: (1) GeneName: ABCA4
(1)Variant: c.5882G > A; p.Gly1961glu
(1) CAID: CA119132
(1) gnomAD: 0.01250 (gnomadv4.0.0, Grpmax Filtering AF, South Asian) https://gnomad.broadinstitute.org/variant/1-94008251-C-T?dataset=gnomad_r4
(2) GeneName: ABCA4
(2) Variant: c.6764G>T (p.Ser2255Ile)
(2) CAID: CA202970
(2) gnomAD: 0.4845 (gnomadv4.0.0, Grpmax Filtering AF, African/African-American) https://gnomad.broadinstitute.org/variant/1-93996161-C-A?dataset=gnomad_r4
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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13. 34/F31.021.06OD−68.3−23.32p.Gly818Glu; p.Cys1488Arg
Case#: Pt 13, 34yo, female
DiseaseAssertion: Stargardt
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: stage 3 (resorbed flecks), logMAR acuity: OD=1.02 OS 1.06, FST Rod Blue Stimulus (dB) OD= −68.3, FST Cone Red stimulus (dB) OD=−23.3, FST Group 2 (elevated cone and normal rod FST thresholds)
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod:
PreviouslyPublished:
Variant: p.Gly818Glu; p.Cys1488Arg
ClinVar: 99135
CAID: CA227000
SupplementalData: n/a
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www.nature.com www.nature.com
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Over 200 ABCA4 sequence variants have been reported so far in patients with STGD and other retinopathies1,5,6,7,8,9,10,11,12,13,14,15,16,17. We have examined 33 missense mutations, 3 small in-frame deletions and 1 frameshift near the carboxy terminus (Table 1 and Fig. 2), including those mutations most commonly encountered in STGD patients1,5,6,7,8,9,10,11 and several that were reported in AMD patients15. As an initial step in assessing protein folding and stability, we analysed each ABCR variant by immunoblotting and azido-ATP labelling (Fig. 3). Mutations that cause small deletions (delVVAIC1681 and delPAL1761) or introduce charged amino acids into predicted transmembrane domains (G851D and G1886E) produce greatly reduced amounts of protein. Among the ABCR variants that are expressed with normal or nearly normal yield, azido-ATP labelling revealed a subset that is defective in ATP binding. A variety of mutations that lie outside of the nucleotide-binding domains (NBDs) can impair azido-ATP labelling, including L541P, predicted to reside adjacent to a transmembrane domain, and W1408R, which resides between the homologous halves of ABCR (Fig. 2). These data suggest that ATP binding to the NBDs is allosterically coupled to conformational changes in or near the transmembrane regions. Moreover, some mutations within either of the two NBDs abolish or nearly abolish all azido-ATP labelling, as seen, for example, with variants T971N, L1971R, G1977S and E2096K, implying allosteric coupling between the two NBDs, as described for P-glycoprotein22,23.Table 1 Naturally occurring ABCR variants produced in transfected 293 cellsFull size tableFigure 2: Locations of 37 naturally occurring ABCR sequence variants and 4 synthetic mutations.The predicted transmembrane topography and domain structure of ABCR is based on the hydropathy profile and sequence alignment with other ABC transporters. The cytosolic face of the membrane is downward. NBD, nucleotide binding domain; HH, highly hydrophobic domain shared with other members of the ABC1/ABCR subfamily of ABC transporters. A, B and C indicate the sequence motifs characteristic of nucleotide binding folds. Asterisks denote the four synthetic mutations.Full size imageFigure 3: Protein yield and ATP-binding capacity of 37 naturally occurring ABCR variants produced in transiently transfected 293 cells.Membranes were analysed by immunoblotting with affinity-purified anti-ABCR antibodies (top) and photoaffinity labelling with α-32P azido-ATP (bottom). We loaded 1 μg (immunoblotting) or 2.5 μg (azido-ATP labelling) of total membrane protein, as determined by Bradford assay, per track. The mutations that reside in NBD-1 and NBD-2 are indicated above the corresponding lanes. The relative levels of the different variant proteins and the extent of azido-ATP labelling were observed to be highly reproducible in multiple independent experiments. ABCR (large arrowhead); an endogenous 55-kD protein (small arrowhead) serves as an internal control for azido-ATP labelling. Molecular mass standards are shown on the left in kD.Full size imageThe combination of immunoblotting and azido-ATP labelling revealed defects in more than 75% of the variants tested. Among the variants with reduced yield and/or ATP binding are G863A and delG863, the two protein products of a guanosine2588→cytosine mutation that both generates a glycine-to-alanine substitution at codon 863 and activates a cryptic splice acceptor site in exon 17 that results in the removal of codon 863 from approximately 50% of the transcripts10. This is the most common allele among STGD patients in Northern Europe, representing roughly 20% of disease-associated alleles. It is also present at a frequency of approximately 3% in the general population in Northern Europe and approximately 1% in the United States population7,9,10. Genotype-phenotype correlations suggest that it is a mild allele and that it leads to STGD only when paired with a more severe allele10. Relative to wild type, the G863A variant is subtantially impaired and the delG863 variant is mildly impaired (Fig. 3).
This variant was transfected into HEK 293 cells and appears to show reduced expression and ATP-binding capacity, but no quantities were provided
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Biochemical defects in ABCR protein variants associated with human retinopathies
PMID: 11017087
Gene: ABCA4
Disease: retinopathies
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Towards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genes
PMID: 38540785
Gene: ABCA4
Disease: maculopathies
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Whole exome sequencing detects homozygosity for ABCA4 p.Arg602Trp missense mutation in a pediatric patient with rapidly progressive retinal dystrophy
PMID: 24444108
Gene: ABCA4
HGNC ID: 34
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Phenotypes of 16 Stargardt macular dystrophy/fundus flavimaculatus patients with known ABCA4 mutations and evaluation of genotype-phenotype correlation
PMID: 12192456
Gene: ABCA4
Disease: Stargardt macular dystrophy/fundus flavimaculatus
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Patient 4, a 30-year-old individual with the deleterious c.213dupG/p.Ile73Asnfs*26 frameshift mutation and the c.1654G>A/p.Val552Ile missense mutation, displayed mild STGD1 with stage 2 FC and 20/30 VA. The p.Ile73Asnfs*26 mutation is classified as a pathogenic mutation, whereas the p.Val552Ile mutation is classified as likely neutral. Biochemical analysis of the p.Val552Val, however, suggests that this is a mild mutation at a functional level consistent with the clinical assessment of patient 4 (see Discussion section for additional information).
Case#: Garces Patient 4, Canada
DiseaseAssertion: mild STGD1
FamilyInfo:
CasePresentingHPOs:
CaseHPOFreeText: 30yo, VA=20/30, FC=Stage 2 (flecks throughout the posterior pole, anterior to the vascular arcades and nasal to the optic disc and relatively normal ERGs but with prolonged dark adaptation)
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: screened for mutations in the ABCA4, CNGB3, and ELOVL4 genes
PreviouslyPublished: n/a
Variant: c.213dupG/p.Ile73Asnfs*26; c.1654G>A/p.Val552Ile
CAID: CA239745
SupplementalData:
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journals.healio.com journals.healio.com
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Novel Heterozygous Variant in RP1L1 Gene With Retinitis Pigmentosa Phenotype: A Case Report
PMID: 41201214
Gene: ABCA4
HGNC ID: 34
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Antisense oligonucleotide therapy corrects splicing in the common Stargardt disease type 1-causing variant ABCA4 c.5461-10T>C
PMID:36910710 Gene: ABCA4 HGNC: 34
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy
PMID: 29555955
Gene: ABCA4
Disease: macular and cone/cone-rod dystrophy
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Disease-causing mutations were identified in 74% of 251 consecutive MD/CCRD patients
Case#: Patient #9, female, 23yo at onset, 32yo at report, German
DiseaseAssertion: macular dystrophy or cone-rod dystrophy
FamilyInfo: inheritance= sporadic. phase not confirmed, but no other affected family members and no parental consanguinity
CasePresentingHPOs:
CaseHPOFreeText: reduced visual acuity, erg scotopic= reduced, erg-photopic=reduced
CaseNotHPOs:
CaseNotHPOFreeText: syndromic retinal disease, age-related macular degeneration, central serous retinopathy, autoimmune retinopathy, retinal vascular disease, achromatopsia, X-linked retinoschisis, North Carolina macular dystrophy
CasePreviousTesting: n/a
GenotypingMethod: Sanger sequencing of ABCA4
PreviouslyPublished: n/a
Variant: c.1654G>A p.Val552Ile; c.4771G>A p.Gly1591Arg; c.1622T>C p.Leu541Pro; c.3113C>T p.Ala1038Val
CAID: CA239745
SupplementalData: Supplementary table 1
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Supplementary tables (1.1MB, pdf)
Supplementary table 4 contains this variant, but this table is for single variants found in a recessive gene. Thus, PM3 would not be able to be used and neither would PP4
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Disease-causing or likely disease-causing mutations were identified in 185 out of 251 patients (74%) with MD/CCRD (Supplementary Table 1).
Case#: Patient #42, female, 31yo at onset, German
DiseaseAssertion: macular dystrophy or cone-rod dystrophy
FamilyInfo: phase not confirmed, but assumed in case of parental consanguinity or if only siblings were affected
CasePresentingHPOs: HP:0012508
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText: syndromic retinal disease, age-related macular degeneration, central serous retinopathy, autoimmune retinopathy, retinal vascular disease, achromatopsia, X-linked retinoschisis, North Carolina macular dystrophy
PreviouslyPublished: n/a
Variant: c.3468C>G (p.Tyr1156Ter); c.5059A>T (p.Ile1687Phe) Sanger sequencing of ABCA4
ClinVar: n/a
CAID: CA341290648
SupplementalData: Supplementary table 1
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Combined Genetic and High-Throughput Strategies for Molecular Diagnosis of Inherited Retinal Dystrophies
PMID: 24516651
Gene: ABCA4
Disease: Stargardt or CRD
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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The proband of family 31, F31:II.1, carries a homozygous missense variant within exon 42 of the ABCA4 gene.
This variant is well-known in exon 42, [M2]: c.5882G > A; p.(Gly1961Glu), rs1800553. The father of the affected patient was deceased; however, the mother was found to be homozygous for the wild type (WT) allele. According to the ACMG standards, M2 is likely pathogenic.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Cis-acting modifiers in the ABCA4 locus contribute to the penetrance of the major disease-causing variant in Stargardt disease
PMID: 33909047
Gene: ABCA4
HGNCID: HGNC:34
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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The plots of fluorescence anisotropy changes of 11-cis-retinal with wild type and mutant NBD1 protein titrations are shown in Fig. 6, A–C. The binding of mutant G863A was significantly attenuated as indicated by the drastic right shift of the binding isotherm as well as its inability to achieve saturation in the presence of a high concentration of protein (Fig. 6A). Nonlinear regression analysis gave Kd of 8.0 ± 1.3 × 10−8 m, 8.0 ± 2.0 × 10−6 m, and 4.0 ± 1.4 × 10−6 m for the wild type and R943Q and P940R mutations, respectively (Fig. 6 and Table 1). As a consequence of Stargardt disease mutations, 100-fold (R943Q) to 50-fold (P940R) decreases in the binding affinity of the NBD1 domain for 11-cis-retinal were observed. The retinal binding of the G863A mutant was severely attenuated, and the Kd was ≥1.0 × 10−5 m.
The effects of this variant on 11-cis-retinal interaction with the NBD1 was evaluated via fluorescence anisotropy. The binding of mutant G863A was significantly attenuated (Kd was ≥1.0 × 10−5 m) as indicated by the drastic right shift of the binding isotherm as well as its inability to achieve saturation in the presence of a high concentration of protein (Fig. 6A).
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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All reported ABCA4 variants (Supplementary Table S1) were classified as follows:
Patient 38 has this variant and also c.5882G>A p.(Gly1961Glu) (Supplement 4-supplementary table 1). Phase is unknown and more specific phenotype information is not provided.
clinical diagnosis of STGD1 was supported by the presence of ≥1 (likely) pathogenic ABCA4 variants with a follow-up data of ≥6 months on FAF imaging.
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academic-oup-com.libproxy.lib.unc.edu academic-oup-com.libproxy.lib.unc.edu
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The measurement of ATPase activity has been the only assay available to study the effects of mutations on ABCA4 function. We employed this assay to examine the effects of [L541P; A1038V], R602W and C1490Y mutations on in vitro ATP hydrolysis. Constructs containing wild-type and mutated ABCA4 cDNAs, tagged with the eight amino acid bovine opsin C-terminal epitope (1D4), were expressed in COS7 cells and proteins were purified on a 1D4 affinity column. CHAPS-solubilized ABCA4 was incubated subsequently with ATP, and the hydrolysis rate was estimated with the charcoal method (31).The rate of ATP hydrolysis of the complex allele [L541P; A1038V] was decreased to 68.1% of wild-type ABCA4 (Fig. 3).
ATPase activity in COS7 cells showed decreased activity (68.1% of wild-type), indicating that this variant impacts protein function (PS3_Supporting; PMIDs). However, this is not a cell type that is counted for PS3 evidence by the ABCA4 VCEP.
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onlinelibrary.wiley.com onlinelibrary.wiley.com
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Stargardt Disease with Preserved Central Vision: identification of a putative novel mutation in ATP-binding cassette transporter gene
PMID: 20163366
Gene: ABCA4
HGNC ID: 34
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www.sciencedirect.com www.sciencedirect.com
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Patient 2, a 46-year-old Caucasian woman, presented in July 1998 with a history of progressive decline in visual acuity since the age of 16
PMID: 10612508
Gene: ABCA4
Case#: Patient 2, 46-year-old female
DiseaseAssertion: STGD1
FamilyInfo: One of four affected siblings in a family consistent with autosomal recessive inheritance.
CasePresentingHPOs: HP:0000545 — Decreased visual acuity HP:0007754 — Macular atrophy HP:0030638 — Retinal flecks HP:0000512 — Abnormal fundus morphology
CaseHPOFreeText: Progressive visual decline since age 16. Best-corrected visual acuity 20/400 in both eyes. Fundus examination showed bilateral symmetrical central chorioretinal atrophy (~3 disc diameters) with prominent pigment deposits and numerous yellow flecks in the posterior pole. Fluorescein angiography demonstrated central hypofluorescence with surrounding hyperfluorescence and peripheral dark choroid.
CaseNotHPOs: Not reported
CaseNotHPOFreeText: Not reported
GenotypingMethod: PCR amplification and direct sequencing of ABCA4 after SSCP screening
PreviouslyPublished: Yes
Variant: NM_000350.2:c.2588G>C (p.Gly863Ala) NM_000350.2:c.161G>A (p.Cys54Tyr)
ClinVar: Not reported
CAID: Not reported
SupplementalData: Segregation and sequencing data shown in Figures 1 and 4
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Patient 3, a 37-year-old Caucasian woman, presented in July 1998 with a gradual decline in visual acuity that began at the age of 12.
Case#: Patient 3, 37-year-old female
PMID: 10612508
DiseaseAssertion: STGD1
FamilyInfo: Affected sibling in autosomal recessive family.
CasePresentingHPOs: HP:0000545 — Decreased visual acuity HP:0007754 — Macular atrophy HP:0030638 — Retinal flecks HP:0000512 — Abnormal fundus morphology
CaseHPOFreeText: Gradual visual decline beginning at age 12. Visual acuity 20/400 in both eyes. Fundus examination revealed bilateral macular atrophy with pigment deposits and numerous yellow flecks in the posterior pole and midperiphery. Fluorescein angiography showed large hypofluorescent regions with surrounding hyperfluorescence and peripheral dark choroid.
CaseNotHPOs: Not reported
CaseNotHPOFreeText: Not reported
GenotypingMethod: PCR and direct sequencing of ABCA4
PreviouslyPublished: Yes
Variant: NM_000350.2:c.2588G>C (p.Gly863Ala) NM_000350.2:c.161G>A (p.Cys54Tyr)
ClinVar: Not reported
CAID: Not reported
SupplementalData: Segregation and sequencing data (Figures 1, 4)
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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A cohort of 500 unrelated IRD patients was sequenced with the targeted NGS panel Genetic Eye Disease test (GEDi)3 and analyzed with a comprehensive approach, which included a standard NGS analysis pipeline detecting single-nucleotide variants (SNVs) and small insertions and deletions (indels),16 interrogation of sequence reads to detect the known pathogenic MAK-Alu insertion,21 and application of NGS read-depth algorithms (ExomeDepth15 and gCNV16) to detect larger deletions and duplications, or CNVs (Fig. 1). In this study we define CNVs as deletions or duplications that range from an average size of an exon (≈50–200 bp) and that are not detectable by standard NGS pipelines, to megabases of DNA.22
Case#: OGI802_001554
DiseaseAssertion: IRD
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: detection of CNVs on the panel-based NGS Genetic Eye Disease (GEDi) diagnostic test that involves sequencing the exons of all known IRD disease genes
PreviouslyPublished: n/a
Variant: c.1715G>C; c.5196+1137G>A
ClinVar: 99073
CAID: CA226919
SupplementalData: Table S2
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Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations
PMID: 32037395
Gene: ABCA4
Disease: IRD
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Genetic characterization of 1210 Japanese pedigrees with inherited retinal diseases by whole-exome sequencing
PMID: 36284460
Gene: ABCA4
Disease: inherited retinal diseases
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Table S2. ABCA4 variant categorization:
This variant was not evaluated.
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Table S2. ABCA4 variant categorization:
This variant was not evaluated.
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Table S2. ABCA4 variant categorization:
This variant was not evaluated.
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Personalized genetic counseling for Stargardt disease: Offspring risk estimates based on variant severity
PMID: 35120629
Gene: ABCA4
Disease: Stargardt disease
PAPER USED TO SCORE PS4
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onlinelibrary.wiley.com onlinelibrary.wiley.com
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two cases from two additional families (case 3, 11 years and case 4, 11 years).
Case#:two cases from two additional families (case 3, 11 years and case 4, 11 years).
DiseaseAssertion: Stargardt’s Disease
FamilyInfo: NR
ParentalTesting: NR
CasePresentingHPOs: HP:0030500, HP:0011507
CasePhenotypeFreeText: LogMAR visual acuity for the right and left eye of cases 1–4 was 0.3 and 0.2, 0.1 and 0.1, 0.5 and 0.4, and 0.3 and 0.4, respectively. Gross disruption of the outer retinal layers at the macula in all cases; in two (cases 2 and 4), the presumed external limiting membrane (ELM) peak was broadened with the inner segment ellipsoid band (ISe) missing. Subtle white-yellowish fine dots at the macula and numerous white-yellowish flecks extending anterior to the arcade are shown in the colour fundus photograph of case 1. Autofluorescence (AF) imaging of case 1 detected well-defined dots with high signal at the central macula surrounded by a ring of increased signal and numerous foci with high or low signal extending to the peripheral retina. Case 2 also had subtle white-yellowish fine dots at the central macula and numerous white-yellowish flecks extending anterior to the arcade, both associated with high signal on AF imaging. In addition, case 3 had white-yellowish fine dots at the macula and numerous white-yellowish flecks extending to the periphery, both of which had high or low signal on AF imaging. Case 4 showed subtle fine macular dots mainly in a para-foveal location, which are well-defined on AF imaging.
CaseNotHPOs: HP:0007401, HP:0000505
CaseNotPhenotypeFreeText: Most cases with STGD have central macular atrophy with numerous more peripheral flecks (Michaelides et al. 2003). Given their relatively good visual acuity, it is likely that the central macular dots observed in our cases may be an early sign of macular dysfunction before the development of macular atrophy. Similar fine macular dots or a ‘mottled macula’ have also been reported in other inherited retinal diseases
CasePreviousTesting: The age of disease onset in cases 1–4, defined as either the age at which visual loss was first noted by the subject or in the asymptomatic subjects when abnormal retinal appearance was first detected, was 5, 7, 8, and 6 years old, respectively.
GenotypingMethod: After informed consent was obtained, blood samples were taken from probands of 2/3 families for ABCA4 screening. A full medical history was obtained, and a full ophthalmologic examination was performed in all cases. Mutation screening of ABCA4 was performed in two probands of the three families, and two likely disease-causing variants were identified in each case; c.768G > T, p.V256V (a previously reported splicing-altering synonymous variant) and c.4363T > C, p.C1455R (a missense variant) in case 1, and c.1906C > T, p.Q636* (a non-sense variant) and c.5461-10 T > C (a disease-associated intronic variant with uncertain effect) in case 3. A blood sample was not available in one proband (case 4).
Variant: NM_000350.3(ABCA4):c.1906C>T (p.Gln636Ter) and NM_000350.3:c.5461-10T>C
LegacyVariant: c.1906C>T (p.Gln636Ter) and c.5461-10T>C
ClinVar: 265012 and 92870
CAID: CA10588302 and CA220687
gnomeAD: 1:94528164 G / A and 1:94476951 A / G
MultipleGeneVariants:No
PreviouslyPublished: No
AdditionalInfo: Most symptoms/diagnoses are consistent with Stargardt’s Disease 3, however the probands in the study were younger in age, so many of the symptoms hadn’t progressed much. Also, all of the cases had decent visual acuity, which contradicts a symptom of Stargardt’s Disease 3. Similar fine macular dots or a ‘mottled macula’ have also been reported in other inherited retinal diseases, for example, in those caused by mutations in RDH5 or RPE65, both of which encode proteins with known function in the visual cycle. The thickening of the ELM may be an OCT abnormality that precedes atrophy in the early stages of STGD
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two siblings were from one consanguineous family (case 1, 11 years and case 2, 9 years)
Case#: two siblings (female) were from one consanguineous family (case 1, 11 years and case 2, 9 years)
DiseaseAssertion: Stargardt’s Disease
FamilyInfo: NR
ParentalTesting: NR
CasePresentingHPOs: HP:0030500, HP:0011507
CasePhenotypeFreeText: LogMAR visual acuity for the right and left eye of cases 1–4 was 0.3 and 0.2, 0.1 and 0.1, 0.5 and 0.4, and 0.3 and 0.4, respectively. Gross disruption of the outer retinal layers at the macula in all cases; in two (cases 2 and 4), the presumed external limiting membrane (ELM) peak was broadened with the inner segment ellipsoid band (ISe) missing. Subtle white-yellowish fine dots at the macula and numerous white-yellowish flecks extending anterior to the arcade are shown in the colour fundus photograph of case 1. Autofluorescence (AF) imaging of case 1 detected well-defined dots with high signal at the central macula surrounded by a ring of increased signal and numerous foci with high or low signal extending to the peripheral retina. Case 2 also had subtle white-yellowish fine dots at the central macula and numerous white-yellowish flecks extending anterior to the arcade, both associated with high signal on AF imaging. In addition, case 3 had white-yellowish fine dots at the macula and numerous white-yellowish flecks extending to the periphery, both of which had high or low signal on AF imaging. Case 4 showed subtle fine macular dots mainly in a para-foveal location, which are well-defined on AF imaging.
CaseNotHPOs: HP:0007401, HP:0000505
CaseNotPhenotypeFreeText: Most cases with STGD have central macular atrophy with numerous more peripheral flecks (Michaelides et al. 2003). Given their relatively good visual acuity, it is likely that the central macular dots observed in our cases may be an early sign of macular dysfunction before the development of macular atrophy. Similar fine macular dots or a ‘mottled macula’ have also been reported in other inherited retinal diseases
CasePreviousTesting: The age of disease onset in cases 1–4, defined as either the age at which visual loss was first noted by the subject or in the asymptomatic subjects when abnormal retinal appearance was first detected, was 5, 7, 8, and 6 years old, respectively.
GenotypingMethod: After informed consent was obtained, blood samples were taken from probands of 2/3 families for ABCA4 screening. A full medical history was obtained, and a full ophthalmologic examination was performed in all cases. Mutation screening of ABCA4 was performed in two probands of the three families, and two likely disease-causing variants were identified in each case; c.768G > T, p.V256V (a previously reported splicing-altering synonymous variant) and c.4363T > C, p.C1455R (a missense variant) in case 1, and c.1906C > T, p.Q636* (a non-sense variant) and c.5461-10 T > C (a disease-associated intronic variant with uncertain effect) in case 3. A blood sample was not available in one proband (case 4).
Variant: NM_000350.3(ABCA4):c.768G>T (p.Val256=) and NM_000350.3(ABCA4):c.4363T>C (p.Cys1455Arg)
LegacyVariant: c.768G>T (p.Val256=) and c.4363T>C (p.Cys1455Arg)
ClinVar: 99505 and 377404
CAID: CA227458 and CA957621
gnomeAD: 1:94564350 C / A and 1:94495177 A / G
MultipleGeneVariants:No
PreviouslyPublished: No
AdditionalInfo: Some symptoms/diagnoses are consistent with Stargardt’s Disease 3, however the probands in the study were younger in age, so many of the symptoms hadn’t progressed much. Also, all of the cases had decent visual acuity, which contradicts a symptom of Stargardt’s Disease 3.
Tags
- Mutation:Nonsense
- Clinvar:377404
- InheritancePattern:NoInheritanceAssertion
- CAID:CA220687
- Mutation:InFrameIndel
- PreviousTesting
- CAID:CA957621
- D
- Mutation:Missense
- automated_hgnc_source:CAID
- DiseaseAssertion:Starghardt'sDisease
- Zygosity:Heterozygous
- ClinGen ABCA4 Annotations
- automated_hgnc:34
Annotators
URL
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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ABCA4P28592/1STGDc.6285T>Cp.D2095Drs1801555
Case#: Patient P28592/1,
DiseaseAssertion: STGD
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: Custom 300-kb retinal resequencing chip. PCR amplification, DNA fragmentation, and chip hybridization. Hybridization signals were analyzed using Sequence pilot module seq-C mutation detection software (2009). This resequencing approach was validated by Sanger sequence technology.
PreviouslyPublished: n/a
Variant: c.635G>A p.(R212H); c.6445C>T p.(R2149X); c.6285T>C p.(D2095D)
CAID: CA285825
SupplementalData: n/a
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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9369a AR 6601–6602delAG Frameshift
This patient was later phenotypically characterized in more depth (PMID: 12037008)
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Novel ABCA4 compound heterozygous mutations cause severe progressive autosomal recessive cone-rod dystrophy presenting as Stargardt disease
PMID: 19352439
Gene: ABCA4
HGNC ID: 34
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oce-ovid-com.libproxy.lib.unc.edu oce-ovid-com.libproxy.lib.unc.edu
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Seventy eyes (38 patients), of which 46 (66%) were female and 24 (34%) male, with RPE atrophy secondary to ABCA4 -related retinopathy (age [years], 45.51 ± 16.70; range 14–78) were included in the study ( Table 1 and see Table, Supplemental Digital Content 2 , http://links.lww.com/IAE/B170 , which shows the individual baseline and progression data of all included eyes).
Case#: Patient #34, female, 61yo at baseline visit, "intermediate" age of onset
DiseaseAssertion: ABCA4-related retinopathy with secondary RPE atrophy
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: Inclusion criteria were defined as 1) presence of at least one mutated allele in ABCA4 (NM_000350.2) in Sanger sequencing with multiplex ligation-dependent probe amplification analysis or next-generation sequencing 2) a compatible phenotype with flecks at the level of the RPE consistent with ABCA4 -related Stargardt disease 3) presence of RPE atrophy, and 4) serial examinations with an interval of at least 6 months. RPE atrophy to the end-stage (i.e., demarcated lesions with ≥90% darkness of the optic disc under short-wavelength excitation light, DDAF) that previously showed highest interreader agreement.7 The size of DDAF has to be at least 0.05 mm 2 (each single atrophic area in cases of multifocality), and the entire lesion must be completely visualized on the AF image at each visit to be advanced for analysis. Self-reported symptom onset into early-onset (≤10 years), intermediate-onset (11–44 years), and late-onset (≥45 years). ff-ERG based Category: Group 1 contained eyes with normal scotopic and photopic responses; Group 2, eyes with normal scotopic responses, but reduced (over 2 SDs) photopic B-wave and 30-Hz flicker amplitudes; and Group 3, eyes with impairment of both rod- and cone-driven responses. BCVA: OD=n/a, OS=1 [LogMAR] .
CaseNotHPOs:
CaseNotHPOFreeText: Insufficient pupil dilation, additional retinal pathology, previous retinal treatment, or other ocular comorbidities substantially affecting image quality led to exclusion from the study
GenotypingMethod: Sanger sequencing with multiplex ligation-dependent probe amplification analysis or next-generation sequencing
PreviouslyPublished: possible since Birtel is an author on this paper and the probands both have the same second variant as in PMID: 29555955
Variant: allele 1: c.3468C>G p.(Tyr1156*) allele 2: c.5059A>T p.(Ile1687Phe)
ClinVar: n/a
CAID: CA341290648
SupplementalData: The supplemental table linked here contains genotype and phenotype information.
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Seventy eyes (38 patients), of which 46 (66%) were female and 24 (34%) male, with RPE atrophy secondary to ABCA4 -related retinopathy (age [years], 45.51 ± 16.70; range 14–78) were included in the study ( Table 1 and see Table, Supplemental Digital Content 2 , http://links.lww.com/IAE/B170 , which shows the individual baseline and progression data of all included eyes).
Case#: Patient #32, male, 60yo at baseline visit, "late" age of onset
DiseaseAssertion: ABCA4-related retinopathy with secondary RPE atrophy
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: Inclusion criteria were defined as 1) presence of at least one mutated allele in ABCA4 (NM_000350.2) in Sanger sequencing with multiplex ligation-dependent probe amplification analysis or next-generation sequencing 2) a compatible phenotype with flecks at the level of the RPE consistent with ABCA4 -related Stargardt disease 3) presence of RPE atrophy, and 4) serial examinations with an interval of at least 6 months. RPE atrophy to the end-stage (i.e., demarcated lesions with ≥90% darkness of the optic disc under short-wavelength excitation light, DDAF) that previously showed highest interreader agreement.7 The size of DDAF has to be at least 0.05 mm 2 (each single atrophic area in cases of multifocality), and the entire lesion must be completely visualized on the AF image at each visit to be advanced for analysis. Self-reported symptom onset into early-onset (≤10 years), intermediate-onset (11–44 years), and late-onset (≥45 years). ff-ERG based Category: Group 1 contained eyes with normal scotopic and photopic responses; Group 2, eyes with normal scotopic responses, but reduced (over 2 SDs) photopic B-wave and 30-Hz flicker amplitudes; and Group 3, eyes with impairment of both rod- and cone-driven responses. BCVA: OD=0, OS=0 [LogMAR] .
CaseNotHPOs:
CaseNotHPOFreeText: Insufficient pupil dilation, additional retinal pathology, previous retinal treatment, or other ocular comorbidities substantially affecting image quality led to exclusion from the study
GenotypingMethod: Sanger sequencing with multiplex ligation-dependent probe amplification analysis or next-generation sequencing
PreviouslyPublished: n/a
Variant: allele 1: c.52C>T/p.(Arg18Trp) // c.1715G>A/p.(Arg572Gln) // c.2828G>A/p.(Arg943Gln) allele 2: c.1588G>A/p.(Gly863Ala) // c.5603A>T/p.(Asn1868Ile)
ClinVar: 7900
CAID: CA226918
SupplementalData: The supplemental table linked here contains genotype and phenotype information.
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Seventy eyes (38 patients), of which 46 (66%) were female and 24 (34%) male, with RPE atrophy secondary to ABCA4 -related retinopathy (age [years], 45.51 ± 16.70; range 14–78) were included in the study ( Table 1 and see Table, Supplemental Digital Content 2 , http://links.lww.com/IAE/B170 , which shows the individual baseline and progression data of all included eyes).
Case#: Patient #33, female, 64yo at baseline visit, "late" age of onset
DiseaseAssertion: ABCA4-related retinopathy with secondary RPE atrophy
FamilyInfo:
CasePresentingHPOs:
CaseHPOFreeText: Inclusion criteria were defined as 1) presence of at least one mutated allele in ABCA4 (NM_000350.2) in Sanger sequencing with multiplex ligation-dependent probe amplification analysis or next-generation sequencing,9 2) a compatible phenotype with flecks at the level of the RPE consistent with ABCA4 -related Stargardt disease,9 3) presence of RPE atrophy, and 4) serial examinations with an interval of at least 6 months. RPE atrophy to the end-stage (i.e., demarcated lesions with ≥90% darkness of the optic disc under short-wavelength excitation light, DDAF) that previously showed highest interreader agreement.7 The size of DDAF has to be at least 0.05 mm 2 (each single atrophic area in cases of multifocality), and the entire lesion must be completely visualized on the AF image at each visit to be advanced for analysis. Self-reported symptom onset into early-onset (≤10 years), intermediate-onset (11–44 years), and late-onset (≥45 years). ff-ERG based Category: Group 1 contained eyes with normal scotopic and photopic responses; Group 2, eyes with normal scotopic responses, but reduced (over 2 SDs) photopic B-wave and 30-Hz flicker amplitudes; and Group 3, eyes with impairment of both rod- and cone-driven responses. BCVA: OD=0.4, OS=1.1 [LogMAR] .
CaseNotHPOs:
CaseNotHPOFreeText: Insufficient pupil dilation, additional retinal pathology, previous retinal treatment, or other ocular comorbidities substantially affecting image quality led to exclusion from the study
GenotypingMethod: Sanger sequencing with multiplex ligation-dependent probe amplification analysis or next-generation sequencing
PreviouslyPublished: possible since Birtel is an author on this paper and the probands both have the same second variant as in PMID: 29555955
Variant: allele 1: c.3468C>G p.(Tyr1156*) allele 2: c.5059A>T p.(Ile1687Phe); c.4297G>A p.(Val1433Ile)
ClinVar: n/a
CAID: CA341290648
SupplementalData: The supplemental table linked here contains genotype and phenotype information.
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onlinelibrary.wiley.com onlinelibrary.wiley.com
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Different clinical expressions in two families with Stargardt’s macular dystrophy (STGD1)
PMID: 11594993
Gene: ABCA4
HGNC: 34
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8
PMID: 29925512
Gene: ABCA4
Disease: Stargardt
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Supplementary data. bjophthalmol-2018-312064supp004.pdf
This variant is found on pg 2 in proband 11019. Compound heterozygous for c.4532C>A, (p.Pro1511His). JHU institute (US). Said to have Stargardt based on the following criteria: "(1) patients (at least 6 years old) with at least two ABCA4 variants or one ABCA4 variant associated with a typical STGD1 phenotype and (2) presence of a well-defined atrophic lesion with/without flecks at the most recent visit of at least 300 µm in diameter (the total area of all lesions <12 mm2)." No additional details provided
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Supplementary data. bjophthalmol-2018-312064supp004.pdf
This variant is found on pg 21 in proband 13047. Compound heterozygous for c.5882G>A p.Gly1961Glu. Said to have Stargardt based on the following criteria: "(1) patients (at least 6 years old) with at least two ABCA4 variants or one ABCA4 variant associated with a typical STGD1 phenotype and (2) presence of a well-defined atrophic lesion with/without flecks at the most recent visit of at least 300 µm in diameter (the total area of all lesions <12 mm2)." No additional details provided
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www-sciencedirect-com.libproxy.lib.unc.edu www-sciencedirect-com.libproxy.lib.unc.edu
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Comprehensive genetic analysis reveals the mutational landscape of ABCA4-associated retinal dystrophy in a Chinese cohort
PMID: 37774808
Gene: ABCA4
Disease: Stargardt
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We identified 255 patients (87.9 %) harboring biallelic ABCA4 variants, 27 probands (9.3 %) with two or three variants but lacking familial segregation analysis, and eight patients (2.8 %) with monoallelic ABCA4 variants (Supplemental Table S4). We detected 268 distinct ABCA4 variants, consisting of 114 missense, 35 nonsense, 34 frameshift deletion or insertion, 31 canonical splice variants, 13 noncanonical splice site variants, 9 in-frame deletion or insertion, 9 DIVs, 4 structural variations, and 19 complex variants (Fig. 2).
Case#: Patient#010046, Chinese, female, 28yo at onset
DiseaseAssertion: stargardt
FamilyInfo: n/a
CasePresentingHPOs: STGD1 diagnosis based on the following criteria: "a bilateral central vision defect; fundus displaying a beaten-bronze appearance and/or orange-yellow flecks in the retina from the macula to the midperiphery; fluorescein angiography presenting with a typical dark choroid; and normal to subnormal ERG results." stage 2( numerous yellow-whitish flecks throughout the posterior pole) BCVA=0.05/ 0.05
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: PMID: 26780318
Variant: p.P2097S; p.A1773V phase unknown
ClinVar: 2202780
CAID: CA341277622
SupplementalData: supplementary table S4 has phenotype information
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We identified 255 patients (87.9 %) harboring biallelic ABCA4 variants, 27 probands (9.3 %) with two or three variants but lacking familial segregation analysis, and eight patients (2.8 %) with monoallelic ABCA4 variants (Supplemental Table S4). We detected 268 distinct ABCA4 variants, consisting of 114 missense, 35 nonsense, 34 frameshift deletion or insertion, 31 canonical splice variants, 13 noncanonical splice site variants, 9 in-frame deletion or insertion, 9 DIVs, 4 structural variations, and 19 complex variants (Fig. 2).
Case#: Patient#010633, Chinese, female, 20yo at onset
DiseaseAssertion: stargardt
FamilyInfo: n/a
CasePresentingHPOs: STGD1 diagnosis based on the following criteria: "a bilateral central vision defect; fundus displaying a beaten-bronze appearance and/or orange-yellow flecks in the retina from the macula to the midperiphery; fluorescein angiography presenting with a typical dark choroid; and normal to subnormal ERG results." BCVA=0.05/ 0.05
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: p.P2097S; c.3468C>G p.(Tyr1156*) phase unknown
ClinVar: 2202780;
CAID: CA341277622;
SupplementalData: supplementary table S4 has phenotype information
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Protein misfolding and the pathogenesis of ABCA4-associated retinal degenerations
PMID: 25712131
Gene: ABCA4
Disease: ABCA4-associated retinal degenerations
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both the P and PV ABCA4 variants exhibited a dramatically reduced basal ATPase activity (∼30% of WT ABCA4), which did not increase upon the addition of all-trans-retinal. Thus, ABCA4 variants carrying the P mutation were functionally impaired.
ATPase activity in HEK293 cells showed severely reduced basal ATPase activity, ∼30% of WT ABCA4, indicating that this variant impacts protein function (PS3_Supporting; PMIDs).
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Amounts of A2E in the eyes of Abca4PV/PV, Abca4−/− and WT mice at the ages of 1, 3, 6, 12 and 15 months were quantified by reverse-phase high-performance liquid chromatography (HPLC) (Fig. 9B). Mice were raised under a regular 12-h light (∼10 lux)/12-h dark cycle. Age-dependent A2E accumulation was noted in all genotypes, with Abca4PV/PV and Abca4−/− mice accumulating about 5-fold more A2E than WT mice. No statistically significant differences in A2E accumulation were found between Abca4PV/PV and Abca4−/− animals.
Autofluorescence and A2E production was measured in transgenic mice and showed loss of function of ABCA4 protein indicating that this variant impacts protein function (PS3; PMIDs).
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Frequency of ABCA4 mutations in 278 Spanish controls: an insight into the prevalence of autosomal recessive Stargardt disease
PMID: 18977788
Gene: ABCA4
Disease: Stargardt disease
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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MD-0324ABCA423c.3386G>Tp.Arg1129Leu1c.3G>Ap.Met1Ile ^15YesABCR400 + NGSThis study
Case#: MD-0324 Proband,
DiseaseAssertion: STGD
FamilyInfo: Family MD-0324
CasePresentingHPOs:
CaseHPOFreeText: STGD diagnosed based on "bilateral central vision loss; fundus presenting with a beaten-bronze appearance and/or the presence of orange-yellow flecks in the retina from the posterior pole to the mid-periphery; fluorescein angiography showing typical dark choroid; and normal to subnormal electroretinogram (ERGs)."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: Haplotype analysis, ABCR400, NGS
PreviouslyPublished: n/a
Variant:c.3386G>T p.Arg1129Leu; c.3G>A p.Met1Ile
ClinVar: n/a
CAID: CA341289040
SupplementalData: n/a
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MD-0247ABCA423c.3386G>Tp.Arg1129Leu47c.6410G>Ap.Cys2137Tyr12YesABCR400 + dHPLC + HRMAguirre-Lamban et al. 2009 (8); Aguirre-Lamban et al. 2010 (16)
Case#: Family MD-0247 Proband, 12yo at onset
DiseaseAssertion: AR cone rod dystrophy
FamilyInfo:
CasePresentingHPOs:
CaseHPOFreeText: STGD diagnosed based on "bilateral central vision loss; fundus presenting with a beaten-bronze appearance and/or the presence of orange-yellow flecks in the retina from the posterior pole to the mid-periphery; fluorescein angiography showing typical dark choroid; and normal to subnormal electroretinogram (ERGs)." VA loss, VF loss, BCVA=0.05/0.1, cone-pattern on ERG
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: Aguirre-Lamban et al. 2009 (8); PMID: 19959634
Variant: c.6410G>A (p.Cys2137Tyr); c.3386G>T (p.Arg1129Leu) found by ABCR400 + dHPLC + HRM
ClinVar: 2202779; 99224
CAID: CA341277358; CA227116
SupplementalData:
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Outcome of ABCA4 disease-associated alleles in autosomal recessive Retinal Dystrophies: Retrospective analysis in 420 Spanish families
PMID: 23755871
Gene: ABCA4
Disease: Retinal Dystrophies
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MD-0474 ABCA4 12 c.1622T>C p.Leu541Pro 28 c.4234C>T p.Gln1412* 9 NP ABCR400
another case with 541 variant potentially not in cis with 1038
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Peripheral venous blood was obtained from 24 clinically diagnosed Korean STGD patients, followed by extraction of genomic DNAs. Using exome sequencing we investigated gene mutations for the adenosine triphosphate-binding cassette, subfamily A, member 4 (ABCA4) elongation of very-long-chain fatty acids 4 (ELOVL4), and prominin 1 (PROM1), and confirmed gene mutations by the direct sequencing of polymerase chain reaction products.
Paper is said to contain this variant based on LOVD entry, but this paper is not publicly available. Requested from library. Annotation on stable PDF. No individual phenotype provided
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Clinical and Genetic Characteristics Analysis of Korean Patients with Stargardt Disease Using Targeted Exome Sequencing
PMID: 29975949
Gene: ABCA4
Disease: Stargardt
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Supplementary File pnas.1909378117.sd01.xlsx (5.4MB, xlsx)
This variant was listed in a supplemental table under "autosomal recessive variants" but there are no patient IDs to be able to know if the person who had this variant had another variant. There was also no phenotype information provided
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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ABCA4
Case#: 1 male, 6 years old, from Taiwanese and Korean decent.
DiseaseAssertion: ABCA4-related retinopathy Stargardt disease
FamilyInfo: Single affected individual. Paternal uncle presented with Stargart disease previously, and Taiwanese and Korean descent underwent genetic testing to identify two pathogenic variants in the ABCA4 gene. One of the variants found was the same ABCA4 variant from the originally affected individual. No additional family information is provided in text.
CasePresentingHPOs: HP:0000529 - progressive visual loss, HP:0025010 - Foveal atrophy, HP:0000603 - Central scotoma, HP:0007663 - Decreased visual acuity, HP:0030602 - Abnormal fundus autofluorescence imaging, HP:0007984 - ERG: Reduced dark-adapted b-wave amplitude, HP:0000512 - Abnormal electroretinogram, HP:0020032 - Hyperreflective retinal dots on OCT
CaseHPOFreeText: peripapillary sparing was observed on fundus autofluorescence imaging.
CaseNotHPOs: HP:0012045 - Retinal flecks
CaseNotHPOFreeText: N/A
Genotyping Method: Genetic testing was used and after sequencing two variants were found on the ABCA4 gene.
PreviouslyPublished: N/A
Variant: NM_000350.3(ABCA4):c.3523-2A>G
Variant: NM_000350.3(ABCA4):c.2249T>C (p.Leu750Pro)
ClinVar: Variation ID: 866764
ClinVar: Variation ID: 417984
CAID: N/A
SupplementalData: N/A
Tags
- Scotoma
- Zygosity:CompoundHeterozygous
- ClinVarID:866764
- Gene:ABCA4
- PeripapillarySparing
- DecreasedCentralVA
- DecreasedERGResponses
- PreviousTesting
- automated_hgnc_source:hgnc_tag
- MultipleGeneVariants
- DiseaseEntity:STGD1
- InheritancePattern:AutosomalRecessive
- ClinVarID:417984
- HGNC:34
- MacularAtrophy
- FundusAutofluorescence
- FamilyInfo
- ClinGen ABCA4 Annotations
- AlleleOrigin:Germline
- automated_hgnc:34
Annotators
URL
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Local file Local file
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stargardt Disease Caused by a Rare Combinationof Double Homozygous Mutations
PMID: 24509150
Gene: ABCA4
HGNC ID: 34
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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STGD-4F30ABCA4c.4555delAp.T1519Rfs*5HeteroARN/AN/AN/AN/AYABCA4c.6397T>Cp.C2133RHeteroD1D2D322.80Y
Case#: Sporadic Patient #4, female, Chinese, 30yo at report
DiseaseAssertion: STGD
FamilyInfo: n/a, sporadic case
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: WES with Sanger sequencing confirmation
PreviouslyPublished: no
Variant: c.4555delA p.(T1519Rfs*5); c.6397T>C p.(C2133R)
ClinVar: 2021273; 2733921
CAID: CA341277387; CA645372203
SupplementalData:
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Whole exome sequencing analysis identifies novel Stargardt disease-related gene mutations in Chinese Stargardt disease and retinitis pigmentosa patients
PMID: 33846575
Gene: ABCA4
Disease: Stargardt disease and retinitis pigmentosa
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Case 1A 55-year-old male was examined for long-standing central visual impairment since age 18. Family history was not significant for ocular disease. His best-corrected visual acuity of 20/350 OD and 20/200 OS was consistent with measurements over the last 20 years. Spherical refractive error measured −3.5 OD and −2.0 OS. Anterior segment examination was unremarkable and applanation tonometry measured 17 mmHg OD and 14 mmHg OS. Posterior segment examination and autofluorescence imaging were significant for sharply demarcated central and peripapillary zones of atrophy and the absence of fleck lesions (Figure 1, A–D). Humphrey visual fields demonstrated bilateral central scotomas with eccentric fixation at the inferior border. ERG examination was subnormal and similar to results obtained 22 years ago.Open in a separate windowFig. 1Case 1. STGD with peripapillary atrophy and mutations P1380L and IVS40 + 5G>A. A, Autofluorescence OD. B, Color Photo OD. C, Autofluorescence OS. D, Color Photo OS. All show marked peripapillary and macular atrophy with a sharply demarcated zone of sparing between them. These characteristics caused initial diagnostic confusion with choroidal sclerosis.Genetic testing was employed for further diagnostic information and two heterozygous ABCA4 mutations, P1380L and IVS40 + 5G>A, were identified and classified as disease-causing alleles, thereby confirming the diagnosis of STGD.
Case#: Hwang Case 1, US, male, 55yo at report, 18yo at onset
DiseaseAssertion: Stargardt disease
FamilyInfo: Family history was not significant for ocular disease
CasePresentingHPOs: HP:0007663, HP:0500087, HP:0000603, HP:0000512
CaseHPOFreeText: BCVA of 20/350 OD and 20/200 OS. Spherical refractive error measured −3.5 OD and −2.0 OS. Posterior segment examination and autofluorescence imaging were significant for sharply demarcated central and peripapillary zones of atrophy and the absence of fleck lesions (Figure 1, A–D). Humphrey visual fields demonstrated bilateral central scotomas with eccentric fixation at the inferior border.
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: Genotyping was performed by the ABCR400 microarray followed by direct sequencing to confirm identified variants.
PreviouslyPublished: n/a
Variant: P1380L and IVS40 + 5G>A
ClinVar: 7904
CAID: CA129033
SupplementalData: n/a
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Partial paternal uniparental disomy (UPD) of chromosome 1 in a patient with Stargardt disease
PMID: 17277736
Gene: ABCA4
HGNC ID: 34
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Molecular analysis of the ABCA4 gene for reliable detection of allelic variations in Spanish patients: identification of 21 novel variants
PMID: 19028736
Gene: ABCA4
Disease: cone rod dystrophy
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www.ajo.com www.ajo.commmc1.pdf1
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MD-0084 STGD1 47 c.6410G>A p.(Cys2137Tyr) 47 c.6410G>A p.(Cys2137Tyr) Yes 7 7 - 23y - <0.05/<0.05 Riveiro-Alvarez et al.,2013
This variant is found in homozygosity in family MD-0084 in a previous publication (PMID: 23755871)
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC)
PMID: 31456290
Gene: ABCA4
HGNCID: HGNC:34
SupplementalData: as applicable Table S2. Variant found in cohort of 2,420 families including 3,413 individuals with inherited retinal diseases in Israel. Likely, this is the same family reported in PMID 29706639.
Total number of families: 1; phenotype/s: CRD; NM_000350.2:c.4895dup, p.(Asn1632Lysfs*14)
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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ABCA4 mutations in Portuguese Stargardt patients: identification of new mutations and their phenotypic analysis
PMID: 19365591
Gene: ABCA4
Disease: Stargardt
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5137 Mo 25 3/10 / FC ND / c.32T>C(1) ND/p.Leu11Pro
Case#: Maia-Lopes Family 17 Proband 5137, Portuguese, 25yo at onset
DiseaseAssertion: STGD
FamilyInfo: Family 17
CasePresentingHPOs:
CaseHPOFreeText: moderate central fundus changes, vision: 3/10 / FC
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: ABCR400 microarray, dHPLC
PreviouslyPublished: n/a
Variant: ND / c.32T>C(1); ND/p.Leu11Pro
ClinVar: 99217
CAID: CA227106
SupplementalData: n/a
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Panel-based NGS testing was performed for all recruited patients for the identification of disease-causing variants. All patients recruited in this present cohort had two allele disease-causing ABCA4 variants confirmed according to the American College of Medical Genetics and Genomics guidelines (Supplementary Table S2).
Case#: Family F23 Patient P26, 42yo
DiseaseAssertion: MD-C
FamilyInfo: family f23
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: capture-based next-generation sequencing (NGS) testing
PreviouslyPublished: n/a
Variant: c.4555del(;)6119G>A genotype b (a patient harboring a severe/null variant and a missense or in-frame insertion/deletion variant)
CAID: CA232815
SupplementalData: table s2
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Supplement 4Click here for additional data file.(480K, pdf)Supplement 5Click here for additional data file.(460K, pdf)
This variant was found in 92 of the 670 alleles in this cohort (Supplement 4). Supplement 5 has the individuals listed with their genotypes, but only mentions variants that were classified as VUS/LP/P, so it is unknown which individuals specifically had this variant or which other variants they also had.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Functional Characterization of ABCA4 Missense Variants Linked to Stargardt Macular Degeneration
PMID: 33375396
Gene: ABCA4
Disease: Stargardt MD
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G818EER51 ± 1363 ± 5111 ± 825 ± 312 ± 32Moderate/Severe
When expressed in transfected HEK293T cells and quantified by Western blotting, this variant was in the range of 40%-52%. This variant has a basal ATPase activity of 63% ± 5% compared to WT (100%) and was categorized as class 2 (partial reduction in expression and basal ATPase activity that was modestly stimulated by N-Ret-PE) with a moderate/severe predicted severity.
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Supplementary TableS10
This variant is listed for Stargardt DNAID#070982 in trans with c.4253+43G>A. No phenotype information provided. This genotype was also reported in PMID: 32619608 and the first author of that paper is listed under authorship for this paper. Cannot confirm this isn't the same individual
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Supplementary TableS10
This variant is listed for Stargardt DNAID#067322 in trans with c.5603A>T p.(Asn1868Ile). No phenotype information provided.
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onlinelibrary.wiley.com onlinelibrary.wiley.com
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Clinical and genetic characteristics of Stargardt disease in a large Western China cohort: Report 1
PMID: 32845068
Gene: ABCA4
Disease: Stargardt
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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ABCA4 Gene Screening by Next-Generation Sequencing in a British Cohort
PMID: 23982839
Gene: ABCA4
Disease: ABCA4-associated disease
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Compound heterozygous novel frameshift variants in the PROM1 gene result in Leber congenital amaurosis
PMID:31836589
Gene: ABCA4
HGNC ID: 34
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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19 F 16 c.5714+5G>A c.4469G>A
Case#: Patient 19, female, age 16
DiseaseAssertion: STGD
FamilyInfo: diagnosis of autosomal recessive STGD based on the pedigree and clinical phenotype of fleck deposits with or without genetic testing
CasePresentingHPOs: HP:0000608, HP:0000007, HP:0030610, HP:0030500
CaseHPOFreeText: Macular degeneration. autosomal recessive, Photoreceptor outer segment loss on macular OCT, Yellow/white lesions of the macula
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
Genotyping Method: n/a
PreviouslyPublished: n/a
Variant: Allele 1: NM_000350.3:c.5714+5G>A Allele 2: NM_000350.3:c.4469G>A
ClinVar: Allele 1: NM_000350.3(ABCA4):c.5714+5G>A Allele 2: NM_000350.3(ABCA4):c.4469G>A (p.Cys1490Tyr)
CAID: Allele 1: CA227338 Allele 2: CA227198
SupplementalData: composite mask analysis shown in figure 3 for patient 19, show large areas of matched degeneration and isolated IS/OS loss
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Table S9. List of unique causative variants detected in 858 STGD probands mmc8.xlsx (19.3KB, xlsx) Table S11. STGD1 cases with at least two (likely) causal ABCA4 variants mmc9.xlsx (39.6KB, xlsx)
Case#: DNAID 072962/Pat272, male
DiseaseAssertion: STGD1
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: "In classic STGD1, loss of central vision starts around the second decade of life, but both early- and late-onset subtypes have been extensively described." No patient-specific details provided
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: smMIPs sequencing of the complete ABCA4 locus
PreviouslyPublished: n/a
Variant: c.6416G>A (p.Arg2139Gln); c.6445C>T (p.Arg2149Ter)
CAID: CA956878
SupplementalData: tables s9 and s11
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Table S9. List of unique causative variants detected in 858 STGD probands mmc8.xlsx (19.3KB, xlsx) Table S11. STGD1 cases with at least two (likely) causal ABCA4 variants mmc9.xlsx (39.6KB, xlsx)
Case#: DNAID 072284/Pat191, female
DiseaseAssertion: STGD1
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: "In classic STGD1, loss of central vision starts around the second decade of life, but both early- and late-onset subtypes have been extensively described." No patient-specific details provided
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: smMIPs sequencing of the complete ABCA4 locus
PreviouslyPublished: n/a
Variant: c.1519G>T (p.Asp507Tyr); c.4139C>T (p.Pro1380Leu) phase not confirmed
CAID: CA958508
SupplementalData: tables s9 and s11
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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14-year-old patient
Case#: 14-year-old, female, asian (Chinese) patient
DiseaseAssertion: ABCA-4 associated retinal dystrophy
FamilyInfo: The effect of the deep intronic variant on splicing was validated by a minigene assay in our previous study (Tian et al., 2022). Co-segregation analysis result exhibited that the variant c.1222C>T p.(Arg408Ter) came from the female parent, and the deep intronic variant c.2919-884G>T p.[Phe973LeufsTer3,=] from the male parent
ParentalTesting: Co-segregation analysis result exhibited that the variant c.1222C>T p.(Arg408Ter) came from the female parent, and the deep intronic variant c.2919-884G>T p.[Phe973LeufsTer3,=] from the male parent
CasePresentingHPOs: HP:0000556
CasePhenotypeFreeText: ABCA4-associated retinal dystrophy
CaseNotHPOs: NR
CaseNotPhenotypeFreeText: NR
CasePreviousTesting:NR
GenotypingMethod:
In the present study, we recruited a 14-year-old female patient diagnosed with ABCA4-RD. Biallelic variants were found in this patient, including the nonsense variant c.1222C>T p.(Arg408Ter) detected by Sanger sequencing and the deep intronic variant c.2919-884G>T p.[Phe973LeufsTer3,=] identified by next-generation sequencing.
We isolated peripheral blood mononuclear cells (PBMCs) from the patient’s peripheral venous blood and introduced three episomal plasmids containing transcription factors OCT4, SOX2, NANOG, LIN28, c-MYC, KLF4, and SV40LT into PBMCs. The reprogramming iPSC line, named BIOi003-A, showed stabilized morphology (Fig. 1A) and a normal karyotype in culture (Fig. 1B). Then, the endogenous expression of two pluripotent biomarkers, POU5F1 and NANOG, was detected (Table 2). The expression levels were compared with human embryonic stem cell line H1(hESC-H1) and mesenchymal stem cell line P3 (MSC-P3) by qRT-PCR (Fig. 1C). Surface markers SSEA4 and TRA-1–81 were analyzed by flow cytometry (Fig. 1D). the ABCA4 compound heterozygous variants c.(1222C>T;2919-884G>T) p.[Arg408Ter;Phe973LeufsTer3,=] were verified by Sanger sequencing (Fig. 1E). Furthermore, the teratoma assay exhibited the differentiation capacity of this iPSC line in vivo (Fig. 1F). Short tandem repeats (STR) analysis exhibited that the PBMCs and the iPSC line came from the same patient. PCR proved negative for mycoplasma contamination
Variant: NM_000350.3(ABCA4):c.1222C>T (p.Arg408Ter) and NM_000350.3(ABCA4):c.2919G>T (p.Leu973Phe)
LegacyVariant: c.1222C>T (p.Arg408Ter) and c.2919G>T (p.Leu973Phe)
ClinVar: 99035 and NR
CAID: CA179692 and CA341275270
gnomeAD: 1:94544895 G / A and NR
MultipleGeneVariants: No
PreviouslyPublished:No
AdditionalInfo: One patient was homozygous at the ABCA-4 gene, so there is information about both variants in one annotation because there is only one patient.
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Induced pluripotent stem cell line BIOi003-A from a patient with ABCA4-associated retinal dystrophy carrying compound heterozygous c.(1222C>T;2919-884G>T) variants in ABCA4
PMID: 35973334
Gene: ABCA4
HGNC ID: 34
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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23-year-old female with a history of STGD oculus uterque (OU) and severe myopia OU who presented for refractive surgery evaluation. The patient’s STGD was double allele ABCA4 genotype proven with two different mutations, p.Arg2107Cys:c.6319C>T and p.Gly607Arg:c.1819G>A
Case#: Patient 23, Female
DiseaseAssertion: STGD
FamilyInfo: Not evaluated
CasePresentingHPOs: HP:0000609, HP:0012632, HP:0007906
CaseHPOFreeText: The patient also had a history of bilateral optic nerve hypoplasia, labile intraocular pressure (IOP), and ocular hypertension without glaucoma.
CaseNotHPOs: n/a
CaseNotHPOFreeText:n/a
Genotyping Method: Not listed
PreviouslyPublished: n/a
Variant: p.Arg2107Cys:c.6319C>T and p.Gly607Arg:c.1819G>A
ClinVar: 635988, 99087
CAID: CA956906, CA226936
SupplementalData: Phenotype shown in case report with continued treatment below
Tags
- ClinVarID:635988
- BilateralOpticNerveHypoplasia
- CAID:CA956906
- CAID:CA226936
- Zygosity:Homozygous
- DiseaseEntity:STGD1
- Gene:ABCA4
- OcularHypertension
- HGNC:34
- LabileIntraocularPressure
- ClinGen ABCA4 Annotations
- InheritancePatter:AutosomalRecessive
- automated_hgnc_source:hgnc_tag
- automated_hgnc:34
Annotators
URL
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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PROM1 gene variations in Brazilian patients with macular dystrophy
PMID: 28095140
Gene: ABCA4
Disease: macular dystrophy
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Deducing the pathogenic contribution of recessive ABCA4 alleles in an outbred population
PMID: 20647261
Gene: ABCA4
Disease: retinal phenotypes ranging from Stargardt disease to retinitis pigmentosa
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www.jbc.org www.jbc.org
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Biochemical Defects in Retina-specific Human ATP Binding Cassette Transporter Nucleotide Binding Domain 1 Mutants Associated with Macular Degeneration*
PMID: 11919200
Gene: ABCA4
Disease: MD
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Analysis of the rates of hydrolysis of ATP and CTP in the mutant protein demonstrated that they were significantly reduced (Fig. 3). The results presented in Fig. 3A indicated that the ATPase function of G863A mutant protein was reduced ∼3-fold as compared with NBD1wt, indicating ∼70% of inhibition of the ATPase activity. TheVmax (ATPase) for G863A mutant was 128 pmol/min/mg and that of the wild-type NBD1 was 584 pmol/min/mg (Table II). A time-course analysis of ATP hydrolysis using 2.5 μg of protein (Fig. 3C) suggested the actual rates of ATP hydrolysis were attenuated 3-fold as a consequence of the mutation. We have earlier reported that the NBD1wt has significantly higher CTPase than ATPase activity (1717.Biswas, E.E.Biochemistry. 2001; 40:8181-8187CrossrefScopus (25)PubMedGoogle Scholar). However, in the mutant G863A protein the CTPase activity was reduced (Fig.3B). In this case, the CTP hydrolysis of G863A was reduced to ∼30% of the activity of NDB1wt. The Vmaxfor G863A mutant was 104 pmol/min/mg and that of the wild-type NBD1 was 376 pmol/min/mg (Table II).
ATPase function of G863A mutant protein was reduced ∼3-fold as compared with NBD1wt, indicating ∼70% of inhibition of the ATPase activity (Fig. 3). TheVmax (ATPase) for G863A mutant was 128 pmol/min/mg and that of the wild-type NBD1 was 584 pmol/min/mg (Table II).
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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proband at age 5, targeted testing of ABCA4
Case#: 1
DiseaseAssertion: stargardt disease originally but didn;t have fishtail flecks
FamilyInfo: both unaffected parents carrying heterozygous MFSD8 variants
CasePresentingHPOs:HP:0001272
CaseHPOFreeText:at 5 years old BCVA was measured at a Snellen equivalent at 0.13 in both eyes, at age 8, BCVA had decreased to 0.07 in both eyes, complete absence of all retinal responses on full‐field flash ERG, No fishtail flecks typical of Stargardt disease were observed
CaseNotHPOs: n/a
CaseNotHPOFreeText:n/a
Genotyping Method: HaloPlex target enrichment kit amplified and sequenced using illumina, then WES
PreviouslyPublished: n/a
Variant: c.3113C>T p.(Ala1038Val)
ClinVar: https://www.ncbi.nlm.nih.gov/clinvar/variation/7894/
SupplementalData: MFSD8 variants identified
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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In 20 patients (19 STGD and 1 CRD), 18 different genotypes were identified (Table 1). Except p.Arg187His and p.Tyr954Ser variants, the rest of changes were previously reported as disease-associated allele. 14 The p.Arg187His and p.Tyr954Ser variants were not found in 100 ethnically matched control chromosomes. All the mutations identified in the 20 patients except one were detected by HRM for sensitivity of 95%; however, only 16 variants were identified by dHPLC for sensitivity of 80%. Table 1. View Table Mutations AnalyzedTable 1. Mutations Analyzed Family Exon Genotype Mutation Detected by dHPLC Mutation Detected by HRM Nucleotide Change Amino Acid Change ARDM-167 5 c.560G>A p.Arg187His No Yes ARDM-257 5 c.560G>A p.Arg187His No Yes ARDM-164 6 c.700C>T p.Gln234X Yes Yes ARDM-135 8 c.1029_1030insT p.Asn344fsX Yes No ARDM-240 15 c.2285C>A p.Ala762Glu Yes Yes ARDM-248 19 c.2861A>C p.Tyr954Ser Yes Yes ARDM-90 — IVS21-2A>T — Yes Yes ARDM-40 27 c.3943C>T p.Gln1315X Yes Yes ARDM-158 30 c.4537delC p.Gln1513fsX1525 Yes Yes ARDM-38 33 c.4739delT p.Leu1580fs Yes Yes ARDM-163 36 c.5172G>T p.Trp1724Cys Not Yes ARDM-197 36 c.5172G>T p.Trp1724Cys Yes Yes ARDM-181 — IVS38+5G>A — Yes Yes ARDM-125 40 — p.KNLFA1876dup Yes Yes ARDM-183 43 c.5929G>A(False −) p.Gly1977Ser(False −) Yes Yes ARDM-146 44 c.6140T>A p.lle2047Asn Yes Yes ARDM-174 — IVS44+2T>A — Yes Yes ARDM-247 47 c.6410G>A p.Cys2137Tyr* Yes Yes ARDM-84 47 c.6410G>A p.Cys2137Tyr† No Yes ARDM-225 48 c.6559C>T p.Gln2187X Yes Yes Previously unreported mutations are shown in bold. * Mutation in heterozygous. † Mutation in homozygous. Homozygous sequence alteration (p.Cys2137Tyr) could be identified from wild-type by HRM analyses (Fig. 1). In contrast, dHPLC did not distinguish any homozygous mutation, except when we mixed it, in a 1:1 proportion, with a previously sequenced wild-type sample at the end of each PCR session and before heteroduplex formation.
Case#: Family MD-0247/ARDM-247 Proband, 12yo at onset
DiseaseAssertion: AR cone rod dystrophy
FamilyInfo:
CasePresentingHPOs:
CaseHPOFreeText: STGD diagnosed based on "bilateral central vision loss; fundus presenting with a beaten-bronze appearance and/or the presence of orange-yellow flecks in the retina from the posterior pole to the mid-periphery; fluorescein angiography showing typical dark choroid; and normal to subnormal electroretinogram (ERGs)." VA loss, VF loss, BCVA=0.05/0.1, cone-pattern on ERG
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: PMID: 19028736
Variant: c.6410G>A (p.Cys2137Tyr); c.3386G>T (p.Arg1129Leu) found by ABCR400 + dHPLC + HRM
ClinVar: 2202779
CAID: CA341277358
SupplementalData: n/a
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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1654G→A V552I 0 0 2 This study
This variant was found in 2 control alleles. No additional details
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A Comprehensive Survey of Sequence Variation in the ABCA4 (ABCR) Gene in Stargardt Disease and Age-Related Macular Degeneration
PMID: 10958763
Gene: ABCA4
Disease: Stargardt
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Case 2
Case#:2, 29-year-old woman
DiseaseAssertion:NR
FamilyInfo:NR
CasePresentingHPOs:
CaseHPOFreeText:decreased ability to focus, increasing difficulty to adapt in the dark, normal visual acuity in both eyes (logMar BCVA OD/OS: 0.02), PERG responses were diminished in both eyes.
CaseNotHPOs:
CaseNotHPOFreeText:
Genotyping Method: ”Analysis of the ABCA4 gene”
PreviouslyPublished:No
Variant:NM_000350.3:c.1805G>A, NM_000350.3:c.6079C>T
ClinVar: 99085, 7882
CAID:CA226933, CA119129
SupplementalData:
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Phenotype/genotype correlation in a case series of Stargardt's patients identifies novel mutations in the ABCA4 gene
PMID: 23949494 HGNC: 34 Gene: ABCA4 DiseaseAssertion: Stargardt Disease
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Microarray-based mutation analysis of the ABCA4 gene in Spanish patients with Stargardt disease: evidence of a prevalent mutated allele
PMID: 16917483
Gene: ABCA4
Disease: Stargardt
This paper was referenced by PMID: 23755871 as containing variant c.6410G>A (p.Cys2137Tyr), but this variant foes not appear to be in the text or tables
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Unusual clinical phenotype of Stargardt disease
PMID: 34008801
Gene: ABCA4
HGNC ID: 34
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease
PMID: 28559085
Gene: ABCA4
Disease: IRD
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Predicting Progression of ABCA4-Associated Retinal Degenerations Based on Longitudinal Measurements of the Leading Disease Front
PMID: 26377081
Gene: ABCA4
Disease: ABCA4-Associated Retinal Degenerations
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www.sciencedirect.com www.sciencedirect.com
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Quantifying fixation in patients with Stargardt disease
PMID: 17562343 GeneName: ABCA4
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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13/8 35 0.017 163 0 – 3 – 3 4 L541P R1098C
Case#: Patient 13, 35yo
DiseaseAssertion: STGD
FamilyInfo: Family 8
CasePresentingHPOs:
CaseHPOFreeText: Visual acuity=0.017. OCT ft (μm)=163. MP (dB)=0. Fundus=3(extensive atrophic-appearing RPE changes). ERG=3(abnormal responses involving both rods and cones). mfERG=4(subnormal mfERG in the entire test field (0°–30°) plus pathologic Ganzfeld ERG).
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: PCR of coding regions, intron/exon boundaries, and 5′ and 3′ regions of ABCA4; Standard cycle-sequencing reactions with BigDye Terminator
PreviouslyPublished:
Variant: L541P; R1098C
CAID: CA226911;
SupplementalData: n/a
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link.springer.com link.springer.com
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STGD-02
Case#: Case2, Sex:Female, Age:15
DiseaseAssertion: STGD
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: Clinical Notes: Few yellowish Flecks without autofluorescence. General notes: participant presented with atypical macular degeneration.
CaseNotHPOs:n/a
CaseNotHPOFreeText: n/a
Genotyping Method: Exome sequencing data generation. Additional sequencing targeted amplification fo PRPH2 and ELOVL4 using PCR.
PreviouslyPublished: n/a
Variant: Variant 1 given as p.G1961E; NM_000350.3:c.5882G>A p.(Gly1961Glu) . Variant 2 given as p.Q636X; NM_000350.3(ABCA4):c.1906C>T (p.Gln636Ter).
ClinVar: Variation ID: 7888 ; Variation ID: 265012
CAID: ; CA10588302
SupplementalData: Proband variant information given in Table 1.
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Molecular diagnosis of putative Stargardt disease probands by exome sequencing
PMID: 22863181
Gene: ABCA4
HGNC ID: 34
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease.
PMID: 9973280
Gene: ABCA4
Disease: Stargardt
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Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease.
Analysis of ABCA4 variants in 150 families with Stargardt disease. Most of which were of northern or central European ancestry. For comparison, 220 racially matched individuals with no personal history or known family history of STGD served as controls (Anderson et al. 1995; Allikmets et al. 1997b).
PMID: 9973280
Gene: ABCA4
HGNCID: HGNC:34
GenotypingMethod: combined SSCP and heteroduplex analyses of all 50 exons of ABCA4, Sanger sequencing
Pedigree AR417: onset at 8 years 2 segregations, 2 out of 3 offspring affected by STGD, parents and grandmother unaffected Variant: G1961E, A1038V CAID: CA119132, CA119135)
Pedigree AR427: onset at 12 years 1 segregation, 1 out of 2 offspring affected by STGD, parents unaffected Variant: G1961E, C75G CAID: CA119132, CA226985
Pedigree AR370: onset at 13 years 1 segregation, 1 out of 3 offspring affected by STGD, parents and grandparents unaffected Variant: G1961E, C1490Y CAID: CA119132, CA227198
Pedigree AR 218: onset at 14 years family history of AMD, was first reported by Anderson et al. [1995] Variant: G1961E, 2160+1G>C CAID: CA119132, CA226984
Pedigree AR 373: onset at 19 years 2 segregations, 2 out of 3 offspring affected by STGD, parents and grandparents unaffected Variant: G1961E, 4253+5G>T CAID: CA119132, CA227174
Pedigree AR 274: onset at 20 years 1 segregation, 1 out of 4 siblings affected by STGD, parents and grandparents unaffected Variant: G1961E, A1038V CAID: CA119132, CA119135
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Mutation scanning and direct DNA sequencing of all 50 exons of ABCR were completed for 150 families segregating recessive Stargardt disease (STGD1). ABCR variations were identified in 173 (57%) disease chromosomes, the majority of which represent missense amino acid substitutions. These ABCR variants were not found in 220 unaffected control individuals (440 chromosomes) but do cosegregate with the disease in these families with STGD1, and many occur in conserved functional domains. Missense amino acid substitutions located in the amino terminal one-third of the protein appear to be associated with earlier onset of the disease and may represent misfolding alleles. The two most common mutant alleles, G1961E and A1038V, each identified in 16 of 173 disease chromosomes, composed 18.5% of mutations identified. G1961E has been associated previously, at a statistically significant level in the heterozygous state, with age-related macular degeneration (AMD). Clinical evaluation of these 150 families with STGD1 revealed a high frequency of AMD in first- and second-degree relatives. These findings support the hypothesis that compound heterozygous ABCR mutations are responsible for STGD1 and that some heterozygous ABCR mutations may enhance susceptibility to AMD.
Annotating here since the full text is a PDF.
Case#: Family AR321 proband, US, 6yo at onset
DiseaseAssertion: Stargardt
FamilyInfo: proband and two other siblings are affected
CasePresentingHPOs: The essential and defining features of STGD were (1) pedigrees with at least one living affected individual compatible with autosomal recessive inheritance; (2) an ophthalmoscopically characteristic retinal disorder in families with both parents living; (3) bilateral central visual loss with both “beaten metal” elliptical foveal dystrophy and temporal pallor of the optic discs, documented by retinal color photography, with or without yellow-pigment epithelial flecks in the macular and/or retinal “near periphery”; and (4) the characteristic fluorescein angiographic feature of a dark choroid (Blacharski 1988).
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText: (1) evidence of autosomal dominant inheritance; (2) any history of night blindness, loss of peripheral vision, or "retinitis pigmentosa"; (3) cataracta complicata or cells in the vitreous; (4) substantially abnormal electroretinographic or electrooculographic responses; (5) no fluorescein angiography performed or no dark choroid documented; (6) neurological disease (including loss of cognition or seizures); 7) drug exposures (especially to antimalarial and agents known to cause crystalline retinopathies); or (8) any "atypical" maculopathies in which a unique diagnosis of STGD could not be established.
PreviouslyPublished: PMID: 8533764
Variant: c.3113C>T p.A1038V; c.1715G>C p.R572P . Heteroduplex and SSCP analyses were used to screen the 50 exons of ABCA4. Linkage analysis and haplotype analysis were previously performed
ClinVar: 99073
CAID: CA226919
SupplementalData: n/a
Tags
- CAID:CA119132
- General
- automated_hgnc_source:Gene_Name
- Gene:ABCA4
- CAID:CA119135
- Individual
- automated_hgnc_source:hgnc_tag
- CaseInfo
- ABCA4
- PMID:9973280
- CAID:CA226919
- automated_hgnc_source:CAID
- HGNC:34
- ClinGen
- PreviouslyPublished
- ClinVarID:99073
- FamilyInfo
- ClinGen ABCA4 Annotations
- automated_hgnc:34
Annotators
URL
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Protein interactions and disease phenotypes in the ABC transporter superfamily
PMID: 17990484
Gene: ABCA4
Disease: Stargardt disease (STGD), Fundus flavimaculatus (FFM), Age-related macular degeneration 2 (ARMD2)
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Early-Onset Stargardt Disease Caused by Homozygosity of a Complex ABCA4 Allele from Eastern Africa: Two Case Reports
PMID: 41063816
Gene: ABCA4
HGNC ID: 34
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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3 39 6/6 1 RCD Val552Ile 6/6
Case#: Case 3, 39yo
DiseaseAssertion: BEM, RCD
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: a ring of increased AF surrounding decreased foveal AF, visual acuity= 6/6, 6/6
CaseNotHPOs:
CaseNotHPOFreeText: acquired toxic aetiology
GenotypingMethod: The entire coding sequence (50 exons), including exon–intron boundaries, of the ABCA4 gene of each patient was screened using single‐stranded conformational polymorphism (SSCP) analysis and direct sequencing.
PreviouslyPublished: n/a
Variant: Val552Ile heterozygous
CAID: CA239745
SupplementalData: n/a
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Application of targeted exome and whole-exome sequencing for Chinese families with Stargardt disease
PMID: 31674661
Gene: ABCA4
Disease: Stargardt
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iovs.arvojournals.org iovs.arvojournals.org
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Mutations in ABCR (ABCA4) in Patients with Stargardt Macular Degeneration or Cone-Rod Degeneration
PMID: 11527935
Gene: ABCA4
Disease: Stargardt Macular Degeneration or Cone-Rod Degeneration
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Family 1ABCA4c.[1957C>T];[4604dup]M7.06.0PV, PP0.200.15MA, TPOD, ARAMA, TPOD, ARANormalReduced
Case#: Family 1 proband, male, 6yo at onset, Chinese
DiseaseAssertion: CORD
FamilyInfo: heterozygous unaffected parents
CasePresentingHPOs: HP:0000613, HP:0000505, HP:0007401, HP:0012511, HP:0008043, HP:0000512
CaseHPOFreeText: ERG responses from cones reduced, BVA=0.20/0.15
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: c.[1957C>T];[4604dup] phase confirmed
ClinVar: n/a
CAID: CA645372205
SupplementalData:
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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024 m Caucasian STGD ABCA4 NM_000350.2 c.[6601_6602delAG];[=], c.[4253+43G>A];[=] p.Arg2201fs* p.Ile1377Hisfs*3 Not found 0.004694 AR Pathogenic Pathogenic 2 [36] [19]
Case#: Patient 24, male, Caucasian, onset at 50yo, Germany
DiseaseAssertion: STGD
FamilyInfo: co-segregation of variant in 2 family members (siblings) but they do not appear to be affected based on pedigree
CasePresentingHPOs: HP:0030528, HP:0000505, HP:0012508, HP:0001105, HP:0025148
CaseHPOFreeText: progressive paracentral scotoma OU, progressive visual impairment OU (blurry vision). BCVA: OD-0.1, OS-0.22. Tension: 13mmHg/14mmHg. FAF: bilateral hyperautofluorescent macular and peripapillary spots, few spots of paracentral retinal atrophy (foveal sparing). Autofluorescence and deposits (severity): deposits medium, atrophy low. OCT: hyperreflective spots, partially invading into the outer retina, partly confluent lesions of cRORA, foveal sparing, degenerative intraretinal fluid. Central macular thickness: 328µm/322µm. Macular volume: 9.31mm³/9.00mm³. mfERG: bilateral amplitudes in normal range, slight relative reduction in the paracentral areas. Fluorescein angiography: bilateral dark choroid, mild paracentral dye pooling in the late phase. Color vision: Inconspicuous. Clinical examination: pattern-like distribution of the lesions.
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
GenotypingMethod: WES, in-house RD-associated gene panel including 619 candidates and disease-associated genes
PreviouslyPublished: n/a
Variant: ABCA4 NM_000350.2 c.[6601_6602delAG] (p.Arg2201fs);[=], c.[4253+43G>A] p.Ile1377Hisfs3;[=]
CAID: CA227421; CA227172
SupplementalData: phenotype and segregation info in supplemental data (table s1, figure s1)
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iovs.arvojournals.org iovs.arvojournals.org
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In Mexican patients, p.A1773V and p.G818E were identified in 17% and 15%, respectively, of the total mutant alleles.
This variant was mentioned in reference to a previous publication. PMID: 23419329
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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CLINICAL CHARACTERIZATION OF STARGARDT DISEASE PATIENTS WITH THE p.N1868I ABCA4 MUTATION
PMID: 30204727
Gene: ABCA4
HGNC ID: 34
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The proband (Patient #20
Case#: Female, family #5, Patient #20
DiseaseAssertion: STGD
FamilyInfo: Proband's sister presented with same clinical prognosis. Sister diagnosed with pattern dystrophy and photoaversion at age 57, with difficulty seeing at night. Sister has nuclear sclerotic and cortical cataracts in both eyes.
CasePresentingHPOs: HP:0000662, HP:0000603, HP:0000603, HP:0000493
CaseHPOFreeText: Proband presented with localized blur at age 62, (late onset) in her left eye. BVCA 20/20-3 and 20/20-2 at age 70. Also has macular lesions with stage 2 fundus flecks.
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
Genotyping Method: Genotyping performed at Columbia University, sequencing technology used is not disclosed.
PreviouslyPublished: n/a
Variant: p.N18681, IVS36:c.5196+1G>A
ClinVar: M2) 99067, M6) 99351
CAID: N/A
SupplementalData: Fig 1: Pedigree illustrating ABCA4 variants and the associated Stargardt phenotype for 5 families. Proband Labeled w/ white arrow for each family. Fig 2: retinal scan measuring melanin in 4 patients of family 2. Panel shows bull's-eye ring of RPE atropy. Fig 3: Macular SD-OCT line profile from b-scans. Reflectivity plotted against function of retinal depth. Table 1: table shows patients with p.N18681 variant, type of mutation, and pathogenicity class. Table 2: Patients, age on-set and first symptom
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Increasing the Yield in Targeted Next-Generation Sequencing by Implicating CNV Analysis, Non-Coding Exons and the Overall Variant Load: The Example of Retinal Dystrophies
PMID: 24265693
Gene: ABCA4
Disease: Retinal Dystrophies
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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A Splicing Variant in RDH8 Is Associated with Autosomal Recessive Stargardt Macular Dystrophy
PMID: 37628710
Gene: ABCA4
HGNC ID: 34
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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ABCA4 gene mutation
Case#: 1 female, 12 years old.
DiseaseAssertion: bilateral stage 2B Coats disease. ABCA4 gene mutations were found upon genetic analysis but Stargardt disease was not diagnosed.
FamilyInfo: Single affected individual. Past medical history and family history was reported as normal. No additional information about family is provided in text.
CasePresentingHPOs: HP:0007663 - Reduced visual acuity, HP:0001147 - Retinal exudate, HP:0007763 - Retinal telangiectasia, HP:0025355 - Retinal arteriolar macroaneurysms, HP:0011505- Cystoid macular edema, HP:0020032 - Hyperreflective retinal dots on OCT, HP:0001045 - Vitiligo
CaseHPOFreeText: bilateral significant capillary nonperfusion noted mostly in the temporal retinal periphery together with light-bulb-like capillary dilations and staining of telangiectatic vessels. Mild intravitreal hemorrhage
CaseNotHPOs: HP:0012045 - Retinal flecks, HP:0025010 - Foveal atrophy, HP:0000603 - Central scotoma, HP:0000556 - Retinal dystrophy, HP:0000512 - Abnormal electroretinogram
CaseNotHPOFreeText: Relatively normal foveal architecture.
Genotyping Method: Genetic analysis was performed using Sanger sequencing for the NDP gene, which revealed no pathogenic variants. Exome sequencing was then used with the Illumina HiSeq 2500 platform, which identified two compound heterozygous variants in the ABCA4 gene. Lastly, no mutations were found in the TINF2 gene.
PreviouslyPublished: N/A
Variant: NM_000350.3(ABCA4):c.1373C>T (p.Arg458Cys), NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu)
ClinVar: Variation ID: 7888 ( for p.Arg458Cys variant however I believe this is mislabeled for this variant NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu), no variantion ID found for NM_000350.3(ABCA4):c.1373C>T (p.Arg458Cys)
CAID: N/A
SupplementalData: N/A
Tags
- ClinVarID:7888
- UnregisteredVariant
- Zygosity:CompoundHeterozygous
- InheritancePattern:AutosomalRecessive
- Gene:ABCA4
- HGNC:34
- MultipleGeneVariants
- PreviousTesting
- DecreasedCentralVA
- ClinGen ABCA4 Annotations
- AlleleOrigin:Germline
- automated_hgnc_source:hgnc_tag
- DiseaseEntity:NoDiseaseAssertion
- automated_hgnc:34
Annotators
URL
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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The variant was c.52C>T (p.Arg18Trp).
PMID:39398711
Gene: ABCA4
HGNC ID: 34
Case Annotation Template
Case#: 19-year-old male
DiseaseAssertion: Stargardt disease 1 (STGD1)
FamilyInfo: No family history of eye disease reported. Autosomal recessive inheritance consistent with STGD1. Homozygous ABCA4 variant identified.
CasePresentingHPOs: DecreasedCentralVA, MacularAtrophy, MacularFlecks, PeripapillarySparing, OpticNervePallor
CaseHPOFreeText: Five-year history of progressive bilateral central vision loss, worse at near. Alternating exotropia measuring 16 prism diopters in all gazes OU. Best corrected visual acuity 20/200 OU. Fundus examination revealed pigment deposition and macular mottling. Fundus autofluorescence showed central decreased autofluorescence surrounded by increased autofluorescence. Fluorescein angiography demonstrated dark choroid. OCT showed loss of the central ellipsoid zone with hyperreflective deposits. Multifocal ERG demonstrated significant functional loss.
CaseNotHPOs: NightBlindness
CaseNotHPOFreeText: Patient denied nyctalopia, photophobia, or flashes. Color vision normal on Ishihara testing.
Genotyping Method: Genotyping Method: Next-generation sequencing (NGS) with deletion/duplication analysis (Invitae Corporation).
PreviouslyPublished: N/A
Variant: ABCA4 c.52C>T (p.Arg18Trp)
ClinVar: ClinVarID:7899
CAID: N/A
SupplementalData: N/A
Tags
- Gene:ABCA4
- PeripapillarySparing
- DecreasedCentralVA
- automated_hgnc_source:hgnc_tag
- ClinVarID:7899
- MultipleGeneVariants
- OpticNervePallor
- stargardt disease
- Zygosity:Homozygous
- DiseaseEntity:STGD1
- InheritancePattern:AutosomalRecessive
- MacularAtrophy
- HGNC:34
- automated_hgnc:34
- MacularFlecks
- ClinGen ABCA4 Annotations
- AlleleOrigin:Germline
- ocular disease
- exotropia
Annotators
URL
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Functional Relevance and Structural Correlates of Near Infrared and Short Wavelength Fundus Autofluorescence Imaging in ABCA4-Related Retinopathy
PMID: 31879568
Gene: ABCA4
Disease: ABCA4-Related Retinopathy
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Monoallelic ABCA4 Mutations Appear Insufficient to Cause Retinopathy: A Quantitative Autofluorescence Study
PMID: 26720470
Gene: ABCA4
Disease: retinopathy
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Screening of reported pathogenic variants in ABCA4 for Stargardt (STGD) The disease prevalence of STGD is estimated as 1 in 10000 individuals4. It has been estimated that about 70% of STGD patients carry variants in ABCA45. Therefore, this represents the scenario of a recessive disease with a relatively homogeneous genetic cause. We screened 945 reported pathogenic variants in ABCA4 genes collected in HGMD. Among them, 11 variants are likely benign, as their population AF in is higher than 0.7% (1/20000‾‾‾‾‾‾‾‾√)<math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="M11"><mrow><mrow><mo>(</mo><mrow><msqrt><mrow><mn>1</mn><mo>/</mo><mn>20000</mn></mrow></msqrt></mrow><mo>)</mo></mrow></mrow></math>, the cutoff based on STGD disease prevalence, therefore were excluded from further analysis. The remaining 934 variants were subjected to our test model. As a result, 26 variants with the AF in the range of 0.46% to 0.03% were identified as likely benign (Binomial test1, Bonferroni correction p-value ≤ 0.05/934 and test2 Bonferroni correction p-value > 0.05/934) (Figure 3A).
This variant is reported in Table S6, but only location, predictions, frequencies, etc are reported for it, not cases.
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Screening of reported pathogenic variants in ABCA4 for Stargardt (STGD) The disease prevalence of STGD is estimated as 1 in 10000 individuals4. It has been estimated that about 70% of STGD patients carry variants in ABCA45. Therefore, this represents the scenario of a recessive disease with a relatively homogeneous genetic cause. We screened 945 reported pathogenic variants in ABCA4 genes collected in HGMD. Among them, 11 variants are likely benign, as their population AF in is higher than 0.7% (1/20000‾‾‾‾‾‾‾‾√)<math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="M11"><mrow><mrow><mo>(</mo><mrow><msqrt><mrow><mn>1</mn><mo>/</mo><mn>20000</mn></mrow></msqrt></mrow><mo>)</mo></mrow></mrow></math>, the cutoff based on STGD disease prevalence, therefore were excluded from further analysis. The remaining 934 variants were subjected to our test model. As a result, 26 variants with the AF in the range of 0.46% to 0.03% were identified as likely benign (Binomial test1, Bonferroni correction p-value ≤ 0.05/934 and test2 Bonferroni correction p-value > 0.05/934) (Figure 3A).
This variant is reported in Table S6, but only location, predictions, frequencies, etc are reported for it, not cases.
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www.dovepress.com www.dovepress.com
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Stargardt Disease Due to an Intronic Mutation in the ABCA4: A Case Report
PMID: 36471740
Gene: ABCA4
HGNC ID: 34
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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ABCA4
Unable to find this variant in the text or supplementary even though Mastermind says it's in supplemental MOESM1
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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F17-003
Case#: Patient 225, Female, age of onset 7 y.o, Poland
DiseaseAssertion: STGD-1
FamilyInfo: no given family information.
CasePresentingHPOs: HP:0007722, HP:0000608, HP:0025158
CaseHPOFreeText: RPE atrophy, macular degeneration, central hyper-autofluorescence in fundus autofluorescence
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a, non-proband identified HPO's mentioned, but not assignable to individual proband.
Genotyping Method: DNA isolated from peripheral blood from patients and relatives via MagNA Pure 24, samples screened with MIPs targeting 108 genes involved in pathogensis of IRD's. PCR completed on library, analysed with NGS fragment analysis kit.
PreviouslyPublished: yes
Variant: c.[1622T>C;3113C>T]
ClinVar: 99067, 7894
CAID: n/a
gnomeAD 0.0001266 allele frequency
SupplementalData: Fig1: List of families displaying pseudo-dominant inheritance. Fig2: Number of alleles for most common variants.
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www.tandfonline.com www.tandfonline.com
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WDR19-associated retinopathy presenting with adult-onset Stargardt-likephenotype
PMID:39967245
Gene: ABCA4
HGNC ID: 34
Case#:39 man
DiseaseAssertion:NA
FamilyInfo:NA
CasePresentingHPOs:Snellen in both eye, visual impairment with night blindnessisual acuity was 20/20Snellen in both eyes, with a minor correction for astig-matism. The anterior segment and intraocular pressurewere within normal limits. On fundus examination, dif-fuse fleck-like lesions were scattered both inside and out-side the arcades, while sharply demarcated areas ofmacular atrophy with foveal sparing, more pronouncedin the left eye, were visible.
CaseHPOFreeText:NA
CaseNotHPOs:NA
CaseNotHPOFreeText:
Genotyping Method:Next-Generation Sequencing (NGS), using theTruSight One Clinical Exome sequencing panel on anIllumina NexSeq500 platform, enriching for 4800 genesincluding ABCA4, CNGB3, ELOVL4, PROM1, and PRPH2
PreviouslyPublished:Under refernces?
Variant:WDR19 variants:the novel deletion at c.1777 + 1 within the donor splicingsite (class 4) and the rare c.1430 G>T variant causing theamino-acid substitution p.(Arg477Leu) (class 3) in the putative protein. Additionally, a heterozygous c.1793A>G(class 3) variant in the CDH23 gene was found, though it was deemed as not contributive to the patient’s clinical phenotype. All reported variants were confirmed throughSanger sequencing
ClinVar:NA
CAID:NA
SupplementalData:NA
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Focal choroidal excavation in Stargardt’s dystrophy
PMID: 32843395
Gene: ABCA4
Disease: Stargardt
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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The STGD patient from Family 12 is a compound heterozygous with p.Val931Met and a novel nonsense mutation at exon 33 (p.Glu1574X; Figure 1B). Disease onset for this patient was at age 43. Ophthalmic examination revealed moderate central retinal changes, decreased mfERG responses exclusively in the central 15 degrees, and decreased visual acuity.
Case#: Family 12 Proband, male, 43yo at onset, Portuguese
DiseaseAssertion: Stargardt
FamilyInfo: no affected family members in pedigree (Fig. 1)
CasePresentingHPOs: HP:0007663
CaseHPOFreeText: "The criteria for STGD phenotype included bilateral central vision loss and pigmentary macular lesions, normal caliber of retinal vessels, absence of pigmented bone spicules, and compatibility with recessive mode of inheritance." Moderate central retinal changes, decreased mfERG responses exclusively in the central 15 degrees
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: p.Glu1574X; p.Val931Met. Several other polymorphisms also reported. ABCR400 gene chip microarray, DHPLC
ClinVar: 1460063
CAID: CA341283936
SupplementalData: n/a
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jamanetwork.com jamanetwork.com
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ABCA4 gene sequence variations in patients with autosomal recessive cone-rod dystrophy
PMID: 12796258
Gene: ABCA4
Disease: autosomal recessive cone-rod dystrophy
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Functional Analysis and Classification of Homozygous and Hypomorphic ABCA4 Variants Associated with Stargardt Macular Degeneration
PMID: 32845050
Gene: ABCA4
Disease: Stargardt Macular Degeneration
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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JB260 Stargardt ABCA4 c.6119G>A p.Arg2040Gln rs148460146 Zernant et al (2014)50 c.2879del p.Ala960Aspfs*17 N/A
Case#: Bryant Subject JB260, US
DiseaseAssertion: Stargardt
FamilyInfo:
CasePresentingHPOs: "Stargardt disease is a childhood-onset macular degeneration and is most commonly caused by mutations in ABCA4. Characteristic yellow flecks are typically seen under the macula during a fundus exam."
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: WES; previously screened using arrayed primer extension (APEX) multigene panels for the relevant disease and no disease-causing variants had been identified; PCR and Sanger for verification
PreviouslyPublished: n/a
Variant: c.6119G>A p.Arg2040Gln; c.2879del p.Ala960Aspfs*17
CAID: CA232815
SupplementalData:
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jamanetwork.com jamanetwork.com
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Molecular testing for hereditary retinal disease as part of clinical care
PMID: 17296903
Gene: ABCA4
Disease: hereditary retinal disease
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www.e-mjm.org www.e-mjm.org
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An uncommon case of retinitis pigmentosa patients basedon clinical and genetic studyAyudha Bahana Bahana Ilham Perdamaian, MSc2, Dewi Kartikawati Paramita, PhD3, Riris Istighfari Jenie,PhD4, Supanji Supanji, PhD11Universitas Gadjah Mada Fakultas Kedokteran Kesehatan Masyarakat dan Keperawatan, 2Doctorate Program of Health andMedicine Science, Faculty of Medicine, Public Health, and Nurse, Universitas Gadjah Mada, Yogyakarta, Indonesia. Departmentof Ophthalmology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, 3Department of Histology andMolecular Biology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia,Integrated Research Laboratory, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakar,4Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gadjah Mada University, Yogyakarta, IndonesiaCASE REPORTThis article was accepted: 25 August 2024Corresponding Author: Supanji SupanjiEmail: supanji@ugm.ac.id19-An uncommon00304.qxp_3-PRIMARY.qxd 29/08/2024 3:47 PM Page 98
PMID:39215425
Gene: ABCA4
HGNC ID: 34
case27-year-old male, the brother of case 1
DiseaseAssertion: Table 1 The summary of the clinical assessment of IRD patients’ family in this research fro there down they did a whole pannel on the family
Pedigree one can be fore form the beggginnings of case presention section?
CasePresentingHPOs: Case 2, a 27-year-old male, the brother of case 1 had blurry vision which was not corrected with an eyeglass and inconveniences under bright light starting from 14 years ago. Case 2 also underwent a fundus examination after finding that case 1 was RP. In further examination of those patients and their family members found that case 1 was confirmed as RP and case 2
CaseHPOFreeText:NA
CaseNotHPOs:NA
CaseNotHPOFreeText:NA
Genotyping Method:NA
PreviouslyPublished:NA
Variant:NA
ClinVar:
CAID:NA
SupplementalData:NA
Inheritance pattern Autosomal Recessive
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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See Supplementary Table S2 for a complete genotypic glossary of the cohort.
Case#: Patients were identified from the inherited retinal disease (IRD) database at UC San Diego (UCSD).
DiseaseAssertion: RP with macular edema
FamilyInfo:
CasePresentingHPOs:
CaseHPOFreeText: Dx of RP based on "a history of progressive peripheral vision loss or nyctalopia, and ocular examination findings of RP including bone spicule pigmentation, disc pallor and attenuated vessels and genetic confirmation."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: Next-generation sequencing (NGS), exome sequencing, and/or targeted Sanger sequencing were the primary genetic testing approaches.
PreviouslyPublished: PMID:10206579 is referenced but it seems a reference to the variant and not the proband
Variant: c.6383A>G (p.His2128Arg); c.3G>T (p.Met1?). phase unknown
ClinVar: 99455
CAID: CA227399
SupplementalData: Variant is found in table S2
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