Supplementary Table S6—Probands harbouring putative variants with incomplete penetrance;
This variant was found in Patient 074752 in cis with a nonsense (c.6088C>T) and in trans with an intronic variant (c.4253+43G>A); neither of which has been curated yet by the ABCA4 VCEP
W663X
Not sure if this variant is c.1988G>A or c.1989G>A.
Supplementary TableS10
This variant is listed for Stargardt DNAID#067322 in trans with c.5603A>T p.(Asn1868Ile). No phenotype information provided.
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
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.
4.4. Disease Course in Patients Harbouring p.(Gly1961Glu) or p.(Asn1868Ile) Allele
It is known that patients harbouring p.(Gly1961Glu) or p.(Asn1868Ile) allele share some common clinical characteristics and present with a milder disease phenotype than patients carrying other alleles. A typical feature of patients with p.(Gly1961Glu) is BEM, which is otherwise present in around 20% of all STGD1 patients.
4.4. Disease Course in Patients Harbouring p.(Gly1961Glu) or p.(Asn1868Ile) Allele
It is known that patients harbouring p.(Gly1961Glu) or p.(Asn1868Ile) allele share some common clinical characteristics and present with a milder disease phenotype than patients carrying other alleles. A typical feature of patients with p.(Gly1961Glu) is BEM, which is otherwise present in around 20% of all STGD1 patients.
Sequencing of the coding region of ABCA4 and of the entire ABCA4 locus revealed one heterozygous ABCA4 variant c.3113C>T; p.(Ala1038Val). No other (likely) pathogenic coding or noncoding ABCA4 variants including copy number variants were identified.
ABCA4 variant revealed but not target of research and doesn't seem to amount to anything Variantc.3113C>T p.(Ala1038Val)
Sequencing of the coding region of ABCA4 and of the entire ABCA4 locus revealed one heterozygous ABCA4 variant c.3113C>T; p.(Ala1038Val). No other (likely) pathogenic coding or noncoding ABCA4 variants including copy number variants were identified.
ABCA4 variant revealed but not target of research and doesn't seem to amount to anything Variantc.3113C>T p.(Ala1038Val)
Sixty-six individuals representing 54 families were studied (Supplementary Material, Table S1). All individuals were found to harbor two ABCA4 variants likely to cause the retinal disease (18,20–26). In 40 families (74%), independent segregation of the two alleles was demonstrated. The ages at the time of their first visit ranged from 9 to 74 years (mean = 35.9, median = 35.2 years); in the majority of individuals (36/66=55%), data were available from a second visit that occurred on average 8.7 years (range=2–20 years, median = 6.9 years) after the first visit.
Case#: Patient #35, male, 35yo at report, 14yo at onset,
DiseaseAssertion: STGD
FamilyInfo: family 30, segregation was noted as "yes" but no other details provided
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod:
PreviouslyPublished: n/a
Variant: allele 1: A1038V;L541P allele 2: G818E
ClinVar: 99135
CAID: CA227000
SupplementalData: supplemental table 1
STGD87 2588G→C Q1750X Yes
Case#: STGD87, 10-14yo at onset, German
DiseaseAssertion: STGD
FamilyInfo: segregation in family
CasePresentingHPOs:
CaseHPOFreeText: "The diagnosis of STGD was based on the demonstration of bilateral impairment of central vision and the appearance of perimacular and/or peripheral yellow-white flecks, with or without atrophy of the central retinal-pigment epithelium and a normal or only mildly abnormal flash electroretinogram when recorded in early stages of the disease."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: denaturing gradient gel electrophoresis, dHPLC, and SSCP analysis, PCR amplification of individual coding exons and flanking intron sequences, direct DNA sequencing
PreviouslyPublished: n/a
Variant: Q1750X; 2588G→C in trans "Correct segregation of disease alleles was demonstrated in all 39 cases in which family samples were available for study"
ClinVar: 7879
CAID: CA119128
SupplementalData: n/a
STGD47/164 IVS13+1G→A 2588G→C Yes
Case#: STGD47/164, 10-14yo at onset, German
DiseaseAssertion: STGD
FamilyInfo: segregation in family
CasePresentingHPOs:
CaseHPOFreeText: "The diagnosis of STGD was based on the demonstration of bilateral impairment of central vision and the appearance of perimacular and/or peripheral yellow-white flecks, with or without atrophy of the central retinal-pigment epithelium and a normal or only mildly abnormal flash electroretinogram when recorded in early stages of the disease."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: denaturing gradient gel electrophoresis, dHPLC, and SSCP analysis, PCR amplification of individual coding exons and flanking intron sequences, direct DNA sequencing
PreviouslyPublished: n/a
Variant: IVS13+1G→A; 2588G→C in trans "Correct segregation of disease alleles was demonstrated in all 39 cases in which family samples were available for study"
ClinVar: 7879
CAID: CA119128
SupplementalData: n/a
Case 4A 52-year-old male was examined for declining vision OS over the past few months. He was previously clinically diagnosed with STGD 7 years before presentation. Family history was not significant for ocular disease. Best-corrected visual acuity measured 20/100 OD and 20/70 OS. Spherical refractive error measured −3.00 OD and −3.25 OS. Anterior segment examination was unremarkable and applanation tonometry measured 17 mmHg OD and 14 mmHg OS. Posterior segment examination was significant for central atrophy and classic peripheral pisciform flecks sparing the peripapillary regions OU (Figure 4, A and B). Autofluorescence imaging demonstrated inner atrophic flecks and outer hyperautofluorescent flecks. Moderate peripapillary hypoautofluorescence, but not atrophy, was present, likely secondary to the patient’s myopia (Figure 4, C and D). Genotyping revealed two heterozygous ABCA4 mutations, P1380L and S1696N.Open in a separate windowFig. 4Case 4. STGD mutation IVS40 + 5G>A. A, Color Photo OU. B, Red-Free Photo OU reveal central atrophy and classic peripheral pisciform flecks sparing the peripapillary regions OU. C, Autofluorescence OD. D, Autofluorescence OS show that the innermost flecks are hypoautofluorescent, consistent with atrophy, whereas the outermost flecks are hyperautofluorescent, demonstrating excess lipofuscin. There is moderate peripapillary hypoautofluorescence that is not as dark as this patient’s central atrophy or the peripapillary atrophy of Case 1. This finding may thus be due to the patient’s myopia.
Case#: Hwang Case 4, male, 52yo at report, 45yo at onset
DiseaseAssertion: Stargardt
FamilyInfo: Family history was not significant for ocular disease.
CasePresentingHPOs: HP:0000545
CaseHPOFreeText: declining vision OS, BCVA was 20/100 OD and 20/70 OS. Spherical refractive error measured −3.00 OD and −3.25 OS. Posterior segment examination was significant for central atrophy and classic peripheral pisciform flecks sparing the peripapillary regions OU (Figure 4, A and B). Autofluorescence imaging demonstrated inner atrophic flecks and outer hyperautofluorescent flecks. Moderate peripapillary hypoautofluorescence, but not atrophy, was present (Figure 4, C and D).
CaseNotHPOs: HP:0500087
CaseNotHPOFreeText:
GenotypingMethod: Genotyping was performed by the ABCR400 microarray followed by direct sequencing to confirm identified variants.
PreviouslyPublished: n/a
Variant: P1380L and S1696N
ClinVar: 7904
CAID: CA129033
SupplementalData: n/a
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
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
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
Focal choroidal excavation in Stargardt’s dystrophy
PMID: 32843395
Gene: ABCA4
Disease: Stargardt
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
ABCA4 gene sequence variations in patients with autosomal recessive cone-rod dystrophy
PMID: 12796258
Gene: ABCA4
Disease: autosomal recessive cone-rod dystrophy
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
Functional Analysis and Classification of Homozygous and Hypomorphic ABCA4 Variants Associated with Stargardt Macular Degeneration
PMID: 32845050
Gene: ABCA4
Disease: Stargardt Macular Degeneration
Molecular testing for hereditary retinal disease as part of clinical care
PMID: 17296903
Gene: ABCA4
Disease: hereditary retinal disease
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
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).
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
Therefore,a lower homozygous frequency in the BAP dataset than expectedbased on the AF in the general population indicates that a variantis mild
I don't understand what this means, but how I interepret it is if an homozygous STGD1 variant appears at a lower frequency that it is less severe.
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.
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.
ABCA4
Unable to find this variant in the text or supplementary even though Mastermind says it's in supplemental MOESM1
(http://genetics.bwh.harvard.edu/pph2/). In addition, mutation taster predicted both L168F and L168S variant as disease-causing with PROVEAN predictions of L168F (-2.767) and L168S (-4.083) as deleterious (https://www.mutationtaster.org/). As such, it was not surprising that the L168S variant patient had much more severe disease onset and rapid progression compared to other SCA34-causing ELOVL4 variants. For example, a patient carrying the T233M ELOVL4 variant was reported to develop ataxia starting at 15 years of age [10]. However, at the time of examination of this patient at 60 years of age, an MRI of the brain showed only subtle flattening of the ventral pons and mild cerebellar atrophy [10]. Another patient carrying the Q180P ELOVL4 variant developed ataxia in his mid-20 s and showed cerebellar and pontine atrophy [11]. Japanese patients also carrying the W256G variant developed gait ataxia between 13–56 years of age [12]. However, disease progression was reported to be very slow, and patients did not require assistance with walking with a walker or cane until the age of 60 years or older [12]. Taken together, it looks like the nature of the mutation and its effect on normal ELOVL4 function most likely through defects in VLC-FA biosynthesis or conformational changes in protein structure are critical to disease onset and severity of the pathologies.
SupplementalData:
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
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
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
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:
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
ABCA4 mutations and discordant ABCA4 alleles in patients and siblings with bull's‐eye maculopathy
Article Information: ABCA4 mutations and discordant ABCA4 alleles in patients and siblings with bull’s-eye maculopathy British Journal of Ophthalmology, 2007 PMID: 18024811 PMCID: PMC2095527