ABCA4 mutational spectrum in Mexican patients with Stargardt disease: Identification of 12 novel mutations and evidence of a founder effect for the common p.A1773V mutation

Aim. To evaluate the frequency and pattern of disease-associated mutations of ABCA4 gene among Greek patients with presumed Stargardt disease (STGD1). Materials and Methods. A total of 59 patients were analyzed for ABCA4 mutations using the ABCR400 microarray and PCR-based sequencing of all coding exons and flanking intronic regions. MLPA analysis as well as sequencing of two regions in introns 30 and 36 reported earlier to harbor deep intronic disease-associated variants was used in 4 selected cases. Results. An overall detection rate of at least one mutant allele was achieved in 52 of the 59 patients (88.1%). Direct sequencing improved significantly the complete characterization rate, that is, identification of two mutations compared to the microarray analysis (93.1% versus 50%). In total, 40 distinct potentially disease-causing variants of the ABCA4 gene were detected, including six previously unreported potentially pathogenic variants. Among the disease-causing variants, in this cohort, the most frequent was c.5714+5G>A representing 16.1%, while p.Gly1961Glu and p.Leu541Pro represented 15.2% and 8.5%, respectively. Conclusions. By using a combination of methods, we completely molecularly diagnosed 48 of the 59 patients studied. In addition, we identified six previously unreported, potentially pathogenic ABCA4 mutations.

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Further Evidence of Mutational Heterogeneity of theXPCGene in Tunisian Families: A Spectrum of Private and Ethnic Specific Mutations

BioMed Research International ◽

10.1155/2013/316286 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 7

Author(s):

Mariem Ben Rekaya ◽

Manel Jerbi ◽

Olfa Messaoud ◽

Ahlem Sabrine Ben Brick ◽

Mohamed Zghal ◽

...

Keyword(s):

Molecular Diagnosis ◽

Founder Effect ◽

Xeroderma Pigmentosum ◽

Direct Sequencing ◽

Mutation Screening ◽

Novel Mutations ◽

Mutational Spectrum ◽

Early Appearance ◽

Southern Tunisia ◽

Pathogenic Effect

Xeroderma Pigmentosum(XP) is a rare recessive autosomal cancer prone disease, characterized by UV hypersensitivity and early appearance of cutaneous and ocular malignancies. We investigated four unrelated patients suspected to be XP-C. To confirm linkage toXPCgene, genotyping and direct sequencing ofXPCgene were performed. Pathogenic effect of novel mutations was confirmed by reverse Transciptase PCR. Mutation screening revealed the presence of two novel mutations g.18246G>A and g.18810G>T in theXPCgene (NG_011763.1). The first is present in one patient XP50NEF, but the second is present in three unrelated patients (XP16KEB, XP28SFA, and XP45GB). These 3 patients are from three different cities of Southern Tunisia and bear the same haplotype, suggesting a founder effect. Reverse Transciptase PCR revealed the absence of theXPCmRNA. In Tunisia, as observed in an other severe genodermatosis, the mutational spectrum of XP-C group seems to be homogeneous with some clusters of heterogeneity that should be taken into account to improve molecular diagnosis of this disease.

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Prevalent Pathogenic Variants of ATP7B in Chinese Patients with Wilson’s Disease: Geographical Distribution and Founder Effect

Genes ◽

10.3390/genes12030336 ◽

2021 ◽

Vol 12 (3) ◽

pp. 336

Author(s):

Guo-Min Yang ◽

Rou-Min Wang ◽

Nan Xia ◽

Zi-Wei Zheng ◽

Yi Dong ◽

...

Keyword(s):

Geographical Distribution ◽

Founder Effect ◽

Wilson’S Disease ◽

Autosomal Recessive Disorder ◽

Wilson's Disease ◽

Chinese Patients ◽

Mainland Chinese ◽

Pathogenic Variants ◽

Specific Distribution ◽

The Common

Wilson’s disease (WD) is an autosomal recessive disorder caused by ATP7B pathogenic variants. This study aimed to show the geographical distribution and haplotype spectrum of three prevalent pathogenic variants (p.R778L, p.P992L, p.T935M) in mainland Chinese population and clarify whether the founder effect may account for their origins. We firstly summarized the frequency and geographical distribution of p.R778L, p.P992L and p.T935M in 715 WD patients. Then, to construct haplotypes associated with the three variants, Sanger sequencing and microsatellite typing at three dinucleotide-repeat markers (D13S314, D13S301, D13S316) flanking the ATP7B gene were performed in 102 WD families. An obvious regional-specific distribution feature was found in p.T935M. Linkage disequilibrium at the three markers was shown in all the three variants and we found the common haplotypes specific for p.R778L, p.P992L and p.T935M respectively, represented successively by 10-7-7, 10-9-5 and 12-4-8, which all exhibited great significance vs. the control chromosomes (p < 0.01). Meanwhile, haplotypes for the three variants differed from the studies in other regions to some extent. The common haplotypes we found indicate that three prevalent pathogenic variants emerge due to the founder effect. Furthermore, the study contributes to expand our knowledge of the genetic diversity of WD from a cross-regional perspective.

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Clinical and Genetic Spectrum of Stargardt Disease in Argentinean Patients

Frontiers in Genetics ◽

10.3389/fgene.2021.646058 ◽

2021 ◽

Vol 12 ◽

Author(s):

Marcela D. Mena ◽

Angélica A. Moresco ◽

Sofía H. Vidal ◽

Diana Aguilar-Cortes ◽

María G. Obregon ◽

...

Keyword(s):

Retrospective Study ◽

Next Generation Sequencing ◽

Final Analysis ◽

The Other ◽

South American ◽

Stargardt Disease ◽

Targeted Next Generation Sequencing ◽

Mutational Spectrum ◽

Genetic Features ◽

Generation Sequencing

PurposeTo describe the clinical and molecular spectrum of Stargardt disease (STGD) in a cohort of Argentinean patients.MethodsThis retrospective study included 132 subjects comprising 95 probands clinically diagnosed with STGD and relatives from 16 of them. Targeted next-generation sequencing of the coding and splicing regions of ABCA4 and other phenocopying genes (ELOVL4, PROM1, and CNGB3) was performed in 97 STGD patients.ResultsWe found two or more disease-causing variants in the ABCA4 gene in 69/95 (73%) probands, a single ABCA4 variant in 9/95 (9.5%) probands, and no ABCA4 variants in 17/95 (18%) probands. The final analysis identified 173 variants in ABCA4. Seventy-nine ABCA4 variants were unique, of which nine were novel. No significant findings were seen in the other evaluated genes.ConclusionThis study describes the phenotypic and genetic features of STGD1 in an Argentinean cohort. The mutations p.(Gly1961Glu) and p.(Arg1129Leu) were the most frequent, representing almost 20% of the mutated alleles. We also expanded the ABCA4 mutational spectrum with nine novel disease-causing variants, of which eight might be associated with South American natives.

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