Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8

Fujinami, Kaoru; Strauss, Rupert W.; Chiang, John; Audo, Isabelle; Bernstein, Paul S.; Birch, David G.; Bomotti, Samantha; Cideciyan, Artur V.; Ervin, Ann‐Margret; Marino, Meghan J; Sahel, José‐Alain; Mohand‐Saïd, Saddek; Sunness, Janet S.; Traboulsi, Elias I.; West, Sheila K.; Wojciechowski, Robert; Zrenner, Eberhart; Michaelides, Michel; Scholl, Hendrik P. N.

doi:10.1136/bjophthalmol-2018-312064

Cited by 51 publications

(56 citation statements)

References 25 publications

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“…Sequencing of ABCA4 introns enabled us to explain some of the missing heritability, thanks to the identification of several deep intronic variants that affect the correct splicing of primary ABCA4 transcripts, as previously reported. [13][14][15][16][17] In our cohort, 2.6% of all alleles were found to be deep intronic variants, a rate that closely matches the 2% to 2.4% reported by Schulz and associates 30 and Fujinami and associates 31 in large cohorts of >300 STGD1 cases. However, in Khan and associates, 17 these variants represented 15% of the missing alleles, most likely because these patients had been previously screened for coding variants and because all studied probands were analyzed for deep intronic variants.…”

Section: We Report the Largest Cohort Of Patients Withsupporting

confidence: 90%

“…Novel variants accounted for 22% of all variants and 7.2% of ABCA4 patient alleles, and other studies based on large cohorts of patients with STGD1 have found similar rates of novel variants. 17,30,31 Using comprehensive targeted NGS-based screening, we were able to observe the highly diverse allelic and mutational spectrum of the ABCA4 gene.…”

Section: We Report the Largest Cohort Of Patients Withmentioning

confidence: 99%

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Genotype–Phenotype Correlations in a Spanish Cohort of 506 Families With Biallelic ABCA4 Pathogenic Variants

Pozo‐Valero

Riveiro-Álvarez

Blanco‐Kelly

et al. 2020

American Journal of Ophthalmology

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To define genotype-phenotype correlations in the largest cohort study worldwide of patients with biallelic ABCA4 variants, including 434 patients with Stargardt disease (STGD1) and 72 with cone-rod dystrophy (CRD). DESIGN: Cohort study. METHODS: We characterized 506 patients with ABCA4 variants using conventional genetic tools and next-generation sequencing technologies. Medical history and ophthalmologic data were obtained from 372 patients. Genotype-phenotype correlation studies were carried out for the following variables: variant type, age at symptom onset (AO), and clinical phenotype. RESULTS: A total of 228 different pathogenic variants were identified in 506 ABCA4 patients, 50 of which were novel. Genotype-phenotype correlations showed that most of the patients with biallelic truncating variants presented with CRD and that these cases had a significantly earlier AO than patients with STGD1. Three missense variants are associated with CRD for the first time (c.1804C>T; p.[Arg602Trp], c.3056C>T; p.[Thr1019Met], and c.6320G>C; p.[Arg2107Pro]).

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Section: We Report the Largest Cohort Of Patients Withsupporting

confidence: 90%

Section: We Report the Largest Cohort Of Patients Withmentioning

confidence: 99%

Genotype–Phenotype Correlations in a Spanish Cohort of 506 Families With Biallelic ABCA4 Pathogenic Variants

Pozo‐Valero

Riveiro-Álvarez

Blanco‐Kelly

et al. 2020

American Journal of Ophthalmology

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“…The median age of onset for CRX-RD was in the fifth decade in our cohort, although it varied from teenage years to the 8 th decade, which is considerably later than that of other CORD/MD/STGD patients (e.g., 19.0 years for ABCA4-associated retinal disorder) 37 . In addition, over half of patients with late-onset disease (>45 years) have preserved favourable VA, and two maintained VA even after 10 years of disease history (Patients 13 and 15).…”

Section: Discussionmentioning

confidence: 59%

Clinical and Genetic Characteristics of 18 Patients from 13 Japanese Families with CRX-associated retinal disorder: Identification of Genotype-phenotype Association

Fujinami‐Yokokawa

Fujinami

Kuniyoshi

et al. 2020

Sci Rep

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Inherited retinal disorder (IRD) is a leading cause of blindness, and CRX is one of a number of genes reported to harbour autosomal dominant (AD) and recessive (AR) causative variants. Eighteen patients from 13 families with CRX-associated retinal disorder (CRX-RD) were identified from 730 Japanese families with IRD. Ophthalmological examinations and phenotype subgroup classification were performed. The median age of onset/latest examination was 45.0/62.5 years (range, 15-77/25-94). The median visual acuity in the right/left eye was 0.52/0.40 (range, −0.08-2.00/−0.18-1.70) logarithm of the minimum angle of resolution (LogMAR) units. There was one family with macular dystrophy, nine with cone-rod dystrophy (CORD), and three with retinitis pigmentosa. In silico analysis of CRX variants was conducted for genotype subgroup classification based on inheritance and the presence of truncating variants. Eight pathogenic CRX variants were identified, including three novel heterozygous variants (p.R43H, p.P145Lfs*42, and p.P197Afs*22). A trend of a genotype-phenotype association was revealed between the phenotype and genotype subgroups. A considerably high proportion of CRX-RD

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“…The mean onset age in 12 families was 12.25 years (range 2–34 years), which was younger than that of the previously reported patients with STGD1. The average age of onset in these reported cohorts is mostly around 20 years [ 18 , 24 , 25 ]. However, some studies have also shown that the onset age of STGD1 patients is earlier, with the average age of onset between 10 and 14 years [ 23 , 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…Our analyses have revealed that the allele frequencies of these three prevalent variants are about 20% [ 18 ], which are lower than those of some high frequency variants in STGD1 patients from Europe. For instance, the frequencies of p.Gly1961Glu and p.[Leu541Pro;Ala1038Val] may exceed 30% in European populations [ 25 , 28 ]. Meanwhile, in another study of ABCA4 gene screening for STGD1 patients in Chinese population, the frequencies of the prevalent variants (namely, c.101_106delCTTTAT, c.2424C > G, c.2894A > G, and c.6563 T > C) are actually only 14% [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Novel variants of ABCA4 in Han Chinese families with Stargardt disease

Hu¹,

Gao²,

et al. 2020

BMC Med Genet

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Background Stargardt disease (STGD1) is a common recessive hereditary macular dystrophy in early adulthood or childhood, with an estimated prevalence of 1:8000 to 1:10,000. ABCA4 is the causative gene for STGD1. The current study aims at identifying the novel disease-related ABCA4 variants in Han Chinese families with STGD1 using next-generation sequencing (NGS). Methods In the present study, 12 unrelated Han Chinese families (19 males and 17 females) with STGD1 were tested by panel-based NGS. In order to capture the coding exons and the untranslated regions (UTRs) plus 30 bp of intronic flanking sequences of 792 genes, which were closely associated with usual ophthalmic genetic disease, we designed a customized panel, namely, Target_Eye_792_V2 chip. STGD1 patients were clinically diagnosed by experienced ophthalmologists. All the detected variants were filtered and analyzed through the public databases and in silico programs to assess potential pathogenicity. Results Twenty-one ABCA4 mutant variants were detected in 12 unrelated Han Chinese families with STGD1, containing 14 missense, three splicing, two frameshift, one small deletion, and one nonsense variants. Base on the American College of Medical Genetics (ACMG) guidelines, 8 likely pathogenic and 13 pathogenic variants were determined. The functional consequences of these mutant variants were predicted through in silico programs. Of the 21 mutant variants in ABCA4, two novel coding variants c.3017G > A and c.5167 T > C and one novel null variant c.3051-1G > A were detected in three unrelated probands. Conclusions By panel-based NGS, 21 ABCA4 variants were confirmed in 12 unrelated Han Chinese families. Among them, 3 novel mutant variants were found, which further expanded the ABCA4 mutation spectrum in STGD1 patients.

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Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8

Cited by 51 publications

References 25 publications

Genotype–Phenotype Correlations in a Spanish Cohort of 506 Families With Biallelic ABCA4 Pathogenic Variants

Genotype–Phenotype Correlations in a Spanish Cohort of 506 Families With Biallelic ABCA4 Pathogenic Variants

Clinical and Genetic Characteristics of 18 Patients from 13 Japanese Families with CRX-associated retinal disorder: Identification of Genotype-phenotype Association

Novel variants of ABCA4 in Han Chinese families with Stargardt disease

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