A common founder effect of the splice site variant c.-23 + 1G > A in GJB2 gene causing autosomal recessive deafness 1A (DFNB1A) in Eurasia

Abstract The mutations in the GJB2 gene are known to be a major cause of autosomal recessive deafness 1A (OMIM 220290). The most common pathogenic variants of the GJB2 gene have high ethno-geographic specificity in their distribution that being attributed to a founder effect related with Neolithic migration routes of Homo sapiens. Curiously, the c.-23+1G>A splice site variant is frequently found among deaf patients of both Caucasian and Asian origin. It is currently unknown whether this mutation did spread across Eurasia as a result of the founder effect or it could have multiple local centers of origin. To determine the origin of the c.-23+1G>A we reconstructed 𝑓2-haplotypes by genotyping SNPs on the Illumina OmniExpress 730K platform in 23 deaf individuals homozygous for this variant from different populations of Eurasia (Yakuts, Tuvinians, Evenk, Kumyk, Armenian, Russians and Slovak). The analysis revealed that the homozygosity regions in different individuals overlapped in one short region with the length of ~5.2 kb. These data support the hypothesis of the common founder effect in distribution of the c.-23+1G>A variant of GJB2 gene. Based on the published data on the c.-23+1G>A prevalence among 16,177 deaf people and calculation of TMRCA of the 𝑓2-haplotypes carrying this variant we reconstructed the potential migration routes of the c.-23+1G>A carriers around the world. This analysis indicates that the c.-23+1G>A variant may have originated approximately 6,000 years ago in the territory of the Caucasus or Middle East, followed by spread throughout Europe, South and Central Asia and other regions of the world.

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Autosomal recessive deafness 1A (DFNB1A) in Yakut population isolate in Eastern Siberia: extensive accumulation of the splice site mutation IVS1+1G>A in GJB2 gene as a result of founder effect

Journal of Human Genetics ◽

10.1038/jhg.2011.72 ◽

2011 ◽

Vol 56 (9) ◽

pp. 631-639 ◽

Cited By ~ 20

Author(s):

Nikolay A Barashkov ◽

Lilya U Dzhemileva ◽

Sardana A Fedorova ◽

Fedor M Teryutin ◽

Olga L Posukh ◽

...

Keyword(s):

Splice Site ◽

Founder Effect ◽

Autosomal Recessive ◽

Splice Site Mutation ◽

Gjb2 Gene ◽

Eastern Siberia ◽

Site Mutation ◽

Yakut Population

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Novel splice-site variant of UCHL1 in an Indian family with autosomal recessive spastic paraplegia-79

Journal of Human Genetics ◽

10.1038/s10038-018-0463-6 ◽

2018 ◽

Vol 63 (8) ◽

pp. 927-933 ◽

Cited By ~ 7

Author(s):

Aneek Das Bhowmik ◽

Siddaramappa J. Patil ◽

Dipti Vijayrao Deshpande ◽

Venkatraman Bhat ◽

Ashwin Dalal

Keyword(s):

Splice Site ◽

Autosomal Recessive ◽

Spastic Paraplegia ◽

Indian Family ◽

Splice Site Variant

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Genetic testing of two Pakistani patients affected with rare autosomal recessive Fanconi-Bickel syndrome and identification of a novel SLC2A2 splice site variant

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2019-0235 ◽

2019 ◽

Vol 32 (11) ◽

pp. 1229-1233 ◽

Cited By ~ 1

Author(s):

Hajira Batool ◽

Bibi Zubaida ◽

Muhammad Almas Hashmi ◽

Muhammad Naeem

Keyword(s):

Splice Site ◽

Autosomal Recessive ◽

Complete Blood Count ◽

Mutation Screening ◽

Clinical Manifestations ◽

Tubular Dysfunction ◽

Renal Tubular Dysfunction ◽

Glucose Transporter 2 ◽

The Family ◽

Splice Site Variant

Abstract Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive carbohydrate metabolism disorder caused by mutations in SLC2A2 encoding the glucose transporter 2 (GLUT2) protein. The clinical manifestations include hepatomegaly, conditional hypo/hyperglycemia, rickets, short stature and proximal renal tubular dysfunction. GLUT2 regulates monosaccharide homeostasis through sugar sensing and transmembrane transportation during high/low glucose levels. In the current study, we present two siblings suffering from FBS. The patients presented with doll-like facies, failure to gain weight and height, abdominal distension and firm hepatomegaly. The family had a history of deaths of twin male siblings in the neonatal period and twin female siblings at ages 10 months and 2.5 years, respectively. Clinical presentation and biochemical investigations including a complete blood count, electrolytes, liver and renal function tests suggested FBS. Mutation screening of SLC2A2 confirmed the diagnosis with identification of a novel homozygous splice site variant predicting an in-frame deletion [p.(Gly166-S169del)] in the GLUT2 protein. The in-silico analysis predicted the variant to affect the three-dimensional conformation of the fourth transmembrane helix of the encoded protein, rendering the non-functionality of GLUT2 in both patients of the family under study.

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Genetic analysis of autosomal recessive osteopetrosis in Chuvashiya: the unique splice site mutation in TCIRG1 gene spread by the founder effect

European Journal of Human Genetics ◽

10.1038/ejhg.2008.234 ◽

2009 ◽

Vol 17 (5) ◽

pp. 664-672 ◽

Cited By ~ 20

Author(s):

Elena A Bliznetz ◽

Svetlana M Tverskaya ◽

Rena A Zinchenko ◽

Anna V Abrukova ◽

Ekaterina N Savaskina ◽

...

Keyword(s):

Genetic Analysis ◽

Splice Site ◽

Founder Effect ◽

Autosomal Recessive ◽

Splice Site Mutation ◽

Site Mutation ◽

Autosomal Recessive Osteopetrosis

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High Rates of Three Common GJB2 Mutations c.516G>C, c.-23+1G>A, c.235delC in Deaf Patients from Southern Siberia Are Due to the Founder Effect

Genes ◽

10.3390/genes11070833 ◽

2020 ◽

Vol 11 (7) ◽

pp. 833 ◽

Cited By ~ 2

Author(s):

Marina V. Zytsar ◽

Marita S. Bady-Khoo ◽

Valeriia Yu. Danilchenko ◽

Ekaterina A. Maslova ◽

Nikolay A. Barashkov ◽

...

Keyword(s):

Founder Effect ◽

Transmembrane Protein ◽

Indigenous Populations ◽

Gjb2 Gene ◽

Southern Siberia ◽

C 23 ◽

High Prevalence ◽

Ethnic History ◽

Single Marker ◽

Gjb2 Mutations

The mutations in the GJB2 gene (13q12.11, MIM 121011) encoding transmembrane protein connexin 26 (Cx26) account for a significant portion of hereditary hearing loss worldwide. Earlier we found a high prevalence of recessive GJB2 mutations c.516G>C, c.-23+1G>A, c.235delC in indigenous Turkic-speaking Siberian peoples (Tuvinians and Altaians) from the Tyva Republic and Altai Republic (Southern Siberia, Russia) and proposed the founder effect as a cause for their high rates in these populations. To reconstruct the haplotypes associated with each of these mutations, the genotyping of polymorphic genetic markers both within and flanking the GJB2 gene was performed in 28 unrelated individuals homozygous for c.516G>C (n = 18), c.-23+1G>A (n = 6), or c.235delC (n = 4) as well as in the ethnically matched controls (62 Tuvinians and 55 Altaians) without these mutations. The common haplotypes specific for mutations c.516G>C, c.-23+1G>A, or c.235delC were revealed implying a single origin of each of these mutations. The age of mutations estimated by the DMLE+ v2.3 software and the single marker method is discussed in relation to ethnic history of Tuvinians and Altaians. The data obtained in this study support a crucial role of the founder effect in the high prevalence of GJB2 mutations c.516G>C, c.-23+1G>A, c.235delC in indigenous populations of Southern Siberia.

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Founder Effect of a c.828+3A>T Splice Site Mutation in Peripherin 2 (PRPH2) Causing Autosomal Dominant Retinal Dystrophies

JAMA Ophthalmology ◽

10.1001/jamaophthalmol.2014.6115 ◽

2015 ◽

Vol 133 (5) ◽

pp. 511 ◽

Cited By ~ 6

Author(s):

Suma P. Shankar ◽

David G. Birch ◽

Richard S. Ruiz ◽

Dianna K. Hughbanks-Wheaton ◽

Lori S. Sullivan ◽

...

Keyword(s):

Splice Site ◽

Founder Effect ◽

Autosomal Dominant ◽

Splice Site Mutation ◽

Site Mutation ◽

Retinal Dystrophies

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A rare large duplication of MLH1 identified in Lynch syndrome

Hereditary Cancer in Clinical Practice ◽

10.1186/s13053-021-00167-0 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Abhishek Kumar ◽

Nagarajan Paramasivam ◽

Obul Reddy Bandapalli ◽

Matthias Schlesner ◽

Tianhui Chen ◽

...

Keyword(s):

Amino Acid ◽

Lynch Syndrome ◽

Splice Site ◽

Stop Codon ◽

Premature Stop Codon ◽

Splice Donor Site ◽

Laboratory Diagnostics ◽

Mmr Genes ◽

Base Pair Deletion ◽

Splice Site Variant

Abstract Background The most frequently identified strong cancer predisposition mutations for colorectal cancer (CRC) are those in the mismatch repair (MMR) genes in Lynch syndrome. Laboratory diagnostics include testing tumors for immunohistochemical staining (IHC) of the Lynch syndrome-associated DNA MMR proteins and/or for microsatellite instability (MSI) followed by sequencing or other techniques, such as denaturing high performance liquid chromatography (DHPLC), to identify the mutation. Methods In an ongoing project focusing on finding Mendelian cancer syndromes we applied whole-exome/whole-genome sequencing (WES/WGS) to 19 CRC families. Results Three families were identified with a pathogenic/likely pathogenic germline variant in a MMR gene that had previously tested negative in DHPLC gene variant screening. All families had a history of CRC in several family members across multiple generations. Tumor analysis showed loss of the MMR protein IHC staining corresponding to the mutated genes, as well as MSI. In family A, a structural variant, a duplication of exons 4 to 13, was identified in MLH1. The duplication was predicted to lead to a frameshift at amino acid 520 and a premature stop codon at amino acid 539. In family B, a 1 base pair deletion was found in MLH1, resulting in a frameshift and a stop codon at amino acid 491. In family C, we identified a splice site variant in MSH2, which was predicted to lead loss of a splice donor site. Conclusions We identified altogether three pathogenic/likely pathogenic variants in the MMR genes in three of the 19 sequenced families. The MLH1 variants, a duplication of exons 4 to 13 and a frameshift variant, were novel, based on the InSiGHT and ClinVar databases; the MSH2 splice site variant was reported by a single submitter in ClinVar. As a variant class, duplications have rarely been reported in the MMR gene literature, particularly those covering several exons.

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