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Clinical and genetic analyses reveal novel pathogenic ABCA4 mutations in Stargardt disease families.

ABSTRACT: Stargardt disease (STGD1) is a juvenile macular degeneration predominantly inherited in an autosomal recessive pattern, characterized by decreased central vision in the first 2 decades of life. The condition has a genetic basis due to mutation in the ABCA4 gene, and arises from the deposition of lipofuscin-like substance in the retinal pigmented epithelium (RPE) with secondary photoreceptor cell death. In this study, we describe the clinical and genetic features of Stargardt patients from four unrelated Chinese cohorts. The targeted exome sequencing (TES) was carried out in four clinically confirmed patients and their family members using a gene panel comprising 164 known causative inherited retinal dystrophy (IRD) genes. Genetic analysis revealed eight ABCA4 mutations in all of the four pedigrees, including six mutations in coding exons and two mutations in adjacent intronic areas. All the affected individuals showed typical manifestations consistent with the disease phenotype. We disclose two novel ABCA4 mutations in Chinese patients with STGD disease, which will expand the existing spectrum of disease-causing variants and will further aid in the future mutation screening and genetic counseling, as well as in the understanding of phenotypic and genotypic correlations.

SUBMITTER: Lin B

PROVIDER: S-EPMC5064356 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Clinical and genetic analyses reveal novel pathogenic ABCA4 mutations in Stargardt disease families.

Lin Bing B Cai Xue-Bi XB Zheng Zhi-Li ZL Huang Xiu-Feng XF Liu Xiao-Ling XL Qu Jia J Jin Zi-Bing ZB

Scientific reports 20161014

Stargardt disease (STGD1) is a juvenile macular degeneration predominantly inherited in an autosomal recessive pattern, characterized by decreased central vision in the first 2 decades of life. The condition has a genetic basis due to mutation in the ABCA4 gene, and arises from the deposition of lipofuscin-like substance in the retinal pigmented epithelium (RPE) with secondary photoreceptor cell death. In this study, we describe the clinical and genetic features of Stargardt patients from four u ...[more]

PMID: 27739528

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Project description:To resolve the spectrum of causative retina-specific ATP-binding cassette transporter gene (ABCA4) gene mutations in Portuguese Stargardt (STGD) patients and compare allele frequencies obtained in this cohort with those of previous population surveys.Using a microarray technique (ABCR400 gene chip), we screened all previously reported ABCA4 gene mutations in the genomic DNA of 27 patients from 21 unrelated Stargardt families whose phenotypes had been clinically evaluated using psychophysics and electrophysiological measurements. Furthermore, we performed denaturing high performance liquid chromatography whenever one or both mutant alleles failed to be detected using the ABCR gene chip.A total of 36 mutant alleles (out of the 54 tested) were identified in STGD patients, resulting in a detection rate of 67%. Two mutant alleles were present in 12 out of 21 STGD families (57%), whereas in four out of 21 (19%) of the families, only one mutant allele was found. We report the presence of 22 putative pathogenic alterations, including two sequence 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). The great majority of the mutations were missense (72.7%). Seven frameshift variants (19.4%), three nonsense mutations (8.3%), and one splicing sequence change (2.7%) were also found in STGD chromosomes. The most prevalent pathologic variant was the missense mutation p.Leu11Pro. Present in 19% of the families, this mutation represents a quite high prevalence in comparison to other European populations. In addition, 23 polymorphisms were also identified, including four novel intronic sequence variants.To our knowledge, this study represents the first report of ABCA4 mutations in Portuguese STGD patients and provides further evidence of different mutation frequency across populations. Phenotypic characterization of novel putative mutations was addressed.

Project description:PurposeBased on the previous indications of founder ATP-binding cassette sub-family A member 4 gene (ABCA4) mutations in a South African subpopulation, the purpose was to devise a mechanism for identifying common disease-causing mutations in subjects with ABCA4-associated retinopathies (AARs). Facilitating patient access to this data and determining the frequencies of the mutations in the South African population would enhance the current molecular diagnostic service offered.MethodsThe majority of subjects in this study were of Caucasian ancestry and affected with Stargardt macular dystrophy. The initial cohort consisted of DNA samples from 181 patients, and was screened using the ABCR400 chip. An assay was then designed to screen a secondary cohort of 72 patients for seven of the most commonly occurring ABCA4 mutations in this population. A total of 269 control individuals were also screened for the seven ABCA4 mutations.ResultsMicroarray screening results from a cohort of 181 patients affected with AARs revealed that seven ABCA4 mutations (p.Arg152*, c.768G>T, p.Arg602Trp, p.Gly863Ala, p.Cys1490Tyr, c.5461-10T>C, and p.Leu2027Phe) occurred at a relatively high frequency. The newly designed genetic assay identified two of the seven disease-associated mutations in 28/72 patients in a secondary patient cohort. In the control cohort, 12/269 individuals were found to be heterozygotes, resulting in an estimated background frequency of these mutations in this particular population of 4.46 per 100 individuals.ConclusionsThe relatively high detection rate of seven ABCA4 mutations in the primary patient cohort led to the design and subsequent utility of a multiplex assay. This assay can be used as a viable screening tool and to reduce costs and laboratory time. The estimated background frequency of the seven ABCA4 mutations, together with the improved diagnostic service, could be used by counselors to facilitate clinical and genetic management of South African families with AARs.

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Clinical and genetic analyses reveal novel pathogenic ABCA4 mutations in Stargardt disease families.

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Clinical and genetic analyses reveal novel pathogenic ABCA4 mutations in Stargardt disease families.

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