RP-0298 CRD 8 c.950del p.(Gly317Alafs*57) 33 c.4720G>T p.(Glu1574*) yes 10 10 8 36y - HM/HM This stud
This variant is found in compound heterozygosity with c.950del p.(Gly317Alafs*57) in family RP-0298 in this study. Proband is 10yo at onset of VA loss and VF loss, 8yo at night blindness, and 36yo at opthalmological exam. BCVA=HM/HM.
Through a meta-analysis of published literature38,39, we also found that individuals with inherited retinal disease caused by recessive ABCA4 deficiency (Stargardt disease or cone rod dystrophy) are likely to have ASO-amenable variants in similar proportions (Supplementary Note 7 and Supplementary Tables 15 and 16), leading us to suggest that around 15% is a reasonable first estimate for other recessive genetic conditions.
This variant is found in supplemental table 16, but is referencing the cases from PMID 32619608
6Mc.4720G>Tp.Glu1574*not detected 20/15020/2006/38/32
Case#: Patient #16, male, 6yo at onset, Brazilian
DiseaseAssertion: stargardt
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: type II (an area of foveal hypofluorescence surrounded by an area with a heterogeneous appearance and hyperautofluorescent and hypoautofluorescent points that extend to the temporal arcades, giving the retina a reticulate appearance). visual acuity: OD=20/150, OS=20/200
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: c.4720G>T p.(Glu1574*), no second variant. NGS and conclusive molecular testing regarding other Stargardt genes were excluded
ClinVar: 1460063
CAID: CA341283936
SupplementalData: n/a
Case 3 showed a p.Ala643Gly variant in the PROM1 gene and a single variation in the ABCA4 gene, but molecular testing results were inconclusive.
Annotating here since unable on the PDF.
Case 3 is a 6yo male. VA: OD: 20/150, OS: 20/200. Proband had macular atrophy and flecks at the posterior pole. In the autofluorescence exam, there was peripapillary sparing of the hyper-autofluorescent flecks. On OCT images the atrophic areas at the macula correlated to disruption of the elipsoid layer and decrease in the foveal thickness. OCT showed loss of the photoreceptor layer and EPR layer. Proband has only 1 ABCA4 variant, so not eligible for PP4. Also has a variant in PROM1 (p.Ala643Gly). ABCA4, PROM1, and ELOVL4 genes sequenced by next-generation sequencing (NGS) test.
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.
RP-029895-0103 ABCA4 c.4720G>Tp.E1574*known [44]
Case#: Proband 95-0103, Spanish, onset at 8yo
DiseaseAssertion: cone-rod dystrophy
FamilyInfo: Family RP-0298. Affected sister, 95-0101, with same genotype
CasePresentingHPOs: HP:0001133, HP:0000529, HP:0000662, HP:0000512, HP:0000543, HP:0007737, HP:0007641, HP:0007787
CaseHPOFreeText: BCVA=0.1/0.1; ERG: scotopic-Low amplitude, normal latency, photopic-abolished, mixed-diminished a and b waves; dense pigment accumulation at macular region;, bilateral posterior subcapsular cataract.
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: 19365591
Variant: c.4720G>T p.E1574; c.950delG p.G317Afs57. WES, All patients were previously tested and all resulted to be negative for known autosomal recessive retinitis pigmentosa (ARRP) or Leber Congenital Amaurosis (LCA) mutations by microarray screening
ClinVar: 1460063
CAID: 341283936
SupplementalData: Table S2 has phenotype details
Supplementary TableS10
This variant is listed for Stargardt DNAID#071103 in trans with c.1927G>A p.(Val643Met). No phenotype information provided.
This work reported presence of 22 alterations, including two changes not found in other populations, c.2T>C (p.Met1Thr) and c.4036_4037delAC (p.Thr1346fs), and two novel disease associated variants, c.400C>T (p.Gln134X) and c.4720G>T (p.Glu1574X).
This variant was mentioned only as a previously published report.
A cohort of 12 unrelated STGD families diagnosed on the basis of clinical manifestations underwent analysis by targeted exome or whole-exome sequencing. Bioinformatics analysis, Sanger sequencing, and cosegregation analysis of available family members were used to validate sequencing data and confirm the presence of disease-causing genes. Results: Using targeted exome and whole-exome sequencing, we found that eight families had disease-causing variants in the ABCA4 gene, one family had only one heterozygous variant in the ABCA4 gene, and the remaining three families have not been identified with any disease-causing variants for STGD. We identified 15 variants in the ABCA4 gene; of these, five variants have not been previously described for STGD.
Unable to annotate on PDF, so annotating here.
Case#: Proband #4, male, Chinese, onset at 12yo
DiseaseAssertion: stargardt
FamilyInfo: parents are deceased, so phase is unknown. daughter is an unaffected carrier of this variant
CasePresentingHPOs: HP:0025147, HP:0011507, HP:0000608
CaseHPOFreeText: BCVA=0.3/CF, mean retinal nerve fiber layer(µm)=167/154, Visual field(mean deviation)= 7.52/NA, fundus fluorescein angiography=type C (a pattern of speckled hypofluorescence and hyperfluorescence without central hypofluorescence)
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: c.6289C > T p.(Pro2097Ser); c.4720G > T p.(Glu1574*) on targeted exome sequencing or WES
ClinVar: 2202780; 1460063
CAID: CA341277622; CA341283936
SupplementalData: n/a
To determine the overall CF for all AR-IRD–causing mutations in different subpopulations, we initially calculated CF for each of the 10,044 likely pathogenic variants in each subpopulation (SI Appendix, Tables S2 and S3).
This variant is found in Supplemental Table S3, but this table lists frequencies and does not give case information
Table S2. ABCA4 variant categorization:
This variant is found in table S2A to have an OR of infinity with a CI (10.92-infinity).
Supplementary Materials
Supplemental Table 1. Patient WHP103 has this variant in compound heterozygosity with c.4720G>T(p.E1574*). Cannot confirm this is not the same proband as in PMID 31674661 since both have the same genotype and are of Chinese ancestry
ABCA4
Supplementary table 2 lists this variant as previously reported in 3 individuals from PMID: 19365591
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
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
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