scholarly journals Haplotype Analysis of GJB2 Mutations: Founder Effect or Mutational Hot Spot?

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 250 ◽  
Author(s):  
Jun Shinagawa ◽  
Hideaki Moteki ◽  
Shin-ya Nishio ◽  
Yoshihiro Noguchi ◽  
Shin-ichi Usami
Keyword(s):  
Hearing Loss ◽  
Founder Effect ◽  
Hot Spot ◽  
Distribution Patterns ◽  
Gjb2 Gene ◽  
Founder Effects ◽  
Haplotype Data ◽  
Clock Analysis ◽  
Specific Haplotype ◽  
Gjb2 Mutations

The GJB2 gene is the most frequent cause of congenital or early onset hearing loss worldwide. In this study, we investigated the haplotypes of six GJB2 mutations frequently observed in Japanese hearing loss patients (i.e., c.235delC, p.V37I, p.[G45E; Y136X], p.R143W, c.176_191del, and c.299_300delAT) and analyzed whether the recurring mechanisms for each mutation are due to founder effects or mutational hot spots. Furthermore, regarding the mutations considered to be caused by founder effects, we also calculated the age at which each mutation occurred using the principle of genetic clock analysis. As a result, all six mutations were observed in a specific haplotype and were estimated to derive from founder effects. Our haplotype data together with their distribution patterns indicated that p.R143W and p.V37I may have occurred as multiple events, and suggested that both a founder effect and hot spot may be involved in some mutations. With regard to the founders’ age of frequent GJB2 mutations, each mutation may have occurred at a different time, with the oldest, p.V37I, considered to have occurred around 14,500 years ago, and the most recent, c.176_191del, considered to have occurred around 4000 years ago.

High frequency of heterozygosity in GJB2 mutations among patients with non-syndromic hearing loss

2008 ◽  
Vol 123 (3) ◽  
pp. 273-277 ◽  
Author(s):  
G Khandelwal ◽  
S Bhalla ◽  
M Khullar ◽  
N K Panda
Keyword(s):  
Hearing Loss ◽  
Indian Population ◽  
Gjb2 Gene ◽  
Coding Region ◽  
Syndromic Hearing Loss ◽  
Polymerase Chain ◽  
35Delg Mutation ◽  
Control Study ◽  
Gjb2 Mutations ◽  
Prevalent Mutation

AbstractObjective:To determine the prevalence of GJB2 mutations among subjects with congenital, non-syndromic, sensorineural hearing loss, within a north Indian population.Materials and methods:This was a case–control study in which the frequencies of the three most prevalent GJB2 mutations (35delG, W24X and 167delT) were studied. Polymerase chain reaction restriction fragment length polymorphism assays were performed to detect these mutations. The entire coding region of the GJB2 gene was sequenced in all patients, and also in any of their family members who showed GJB2 mutations.Results:The 35delG mutation was found to be the most prevalent mutation (21 per cent), followed by the W24X mutation (7 per cent). This is the first report of the 35delG mutation in an Indian population. One patient was a compound heterozygote for 35delG/W24X. The 167delT mutation was not observed in any patient.Conclusions:These findings challenge the classical view that the W24X variant of the GJB2 gene represents a single ‘founder’ mutation.

Screening of 10 DFNB Loci Causing Autosomal Recessive Non-Syndromic Hearing Loss in Two Iranian Populations Negative for GJB2 Mutations

2020 ◽  
Author(s):  
Mahbobeh KOOHIYAN ◽  
Somayeh REIISI ◽  
Fatemeh AZADEGAN-DEHKORDI ◽  
Mansoor SALEHI ◽  
Hamidreza ABTAHI ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Autosomal Recessive ◽  
Homozygosity Mapping ◽  
Gjb2 Gene ◽  
Global Public Health ◽  
Relative Contribution ◽  
Syndromic Hearing Loss ◽  
High Degree ◽  
Gjb2 Mutations

Background: Autosomal recessive non-syndromic hearing loss (ARNSHL), one of the global public health concerns, is marked by a high degree of genetic heterogeneity. The role of GJB2, as the most common cause of ARNSHL, is only <20% in the Iranian population. Here, we aimed to determine the relative contribution of several apparently most common loci in a cohort of ARNSHL Iranian families that were negative for the GJB2 mutations. Methods: Totally, 80 Iranian ARNSHL families with 3 or more affected individuals from Isfahan and Hamedan provinces, Iran were enrolled in 2017. After excluding mutations in the GJB2 gene via Sanger sequencing, 60 negative samples (30 families from each province) were analyzed using homozygosity mapping for 10 ARNSHL loci. Results: Fourteen families were found to be linked to five different known loci, including DFNB4 (5 families), DFNB2 (3 families), DFNB7/11 (1 family), DFNB9 (2 families) and DFNB3 (3 families). Conclusion: Despite the high heterogeneity of ARNSHL, the genetic causes were determined in 23.5% of the studied families using homozygosity mapping. This data gives an overview of the ARNSHL etiology in the center and west of Iran, used to establish a diagnostic gene panel including most common loci for hearing loss diagnostics.

scholarly journals Identification of a Potential Founder Effect of a Novel PDZD7 Variant Involved in Moderate-to-Severe Sensorineural Hearing Loss in Koreans

2019 ◽  
Vol 20 (17) ◽  
pp. 4174 ◽  
Author(s):  
Sang-Yeon Lee ◽  
Jin Hee Han ◽  
Bong Jik Kim ◽  
Seung Ha Oh ◽  
Seungmin Lee ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Founder Effect ◽  
Hot Spot ◽  
Usher Syndrome ◽  
Pdz Domain ◽  
Missense Variant ◽  
Normal Hearing ◽  
Causative Gene ◽  
Str Markers ◽  
Korean Families

PDZD7, a PDZ domain-containing scaffold protein, is critical for the organization of Usher syndrome type 2 (USH2) interactome. Recently, biallelic PDZD7 variants have been associated with autosomal-recessive, non-syndromic hearing loss (ARNSHL). Indeed, we identified novel, likely pathogenic PDZD7 variants based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines from Korean families manifesting putative moderate-to-severe prelingual ARNSHL; these were c.490C>T (p.Arg164Trp), c.1669delC (p.Arg557Glyfs*13), and c.1526G>A (p.Gly509Glu), with p.Arg164Trp being a predominantly recurring variant. Given the recurring missense variant (p.Arg164Trp) from our cohort, we compared the genotyping data using six short tandem-repeat (STR) markers within or flanking PDZD7 between four probands carrying p.Arg164Trp and 81 normal-hearing controls. We observed an identical haplotype across three out of six STR genotyping markers exclusively shared by two unrelated hearing impaired probands but not by any of the 81 normal-hearing controls, suggesting a potential founder effect. However, STR genotyping, based on six STR markers, revealed various p.Arg164Trp-linked haplotypes shared by all of the affected subjects. In conclusion, PDZD7 can be an important causative gene for moderate to severe ARNSHL in Koreans. Moreover, at least some, if not all, p.Arg164Trp alleles in Koreans could exert a potential founder effect and arise from diverse haplotypes as a mutational hot spot.

scholarly journals 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 ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 833 ◽  
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.

scholarly journals Carrier frequency of the GJB2 mutations that cause hereditary hearing loss in the Japanese population

2015 ◽  
Vol 60 (10) ◽  
pp. 613-617 ◽  
Author(s):  
Mirei Taniguchi ◽  
Hirotaka Matsuo ◽  
Seiko Shimizu ◽  
Akiyoshi Nakayama ◽  
Koji Suzuki ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Carrier Frequency ◽  
Japanese Population ◽  
Hereditary Hearing Loss ◽  
Gjb2 Mutations

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

2021 ◽  
Author(s):  
Aisen V. Solovyev ◽  
Alena Kushniarevich ◽  
Elena Bliznetz ◽  
Marita Bady-Khoo ◽  
Maria R. Lalayants ◽  
...  
Keyword(s):  
Splice Site ◽  
Founder Effect ◽  
Autosomal Recessive ◽  
Gjb2 Gene ◽  
C 23 ◽  
Common Founder ◽  
Splice Site Variant

scholarly journals Whole-Genome Sequencing Improves the Diagnosis of DFNB1 Monoallelic Patients

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1267
Author(s):  
Anaïs Le Nabec ◽  
Mégane Collobert ◽  
Cédric Le Maréchal ◽  
Rémi Marianowski ◽  
Claude Férec ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Gjb2 Gene ◽  
Whole Genome ◽  
Genetic Origin ◽  
Functional Assays ◽  
Syndromic Hearing Loss ◽  
Sensory Defect

Hearing loss is the most common sensory defect, due in most cases to a genetic origin. Variants in the GJB2 gene are responsible for up to 30% of non-syndromic hearing loss. Today, several deafness genotypes remain incomplete, confronting us with a diagnostic deadlock. In this study, whole-genome sequencing (WGS) was performed on 10 DFNB1 patients with incomplete genotypes. New variations on GJB2 were identified for four patients. Functional assays were realized to explore the function of one of them in the GJB2 promoter and confirm its impact on GJB2 expression. Thus, in this study WGS resolved patient genotypes, thus unlocking diagnosis. WGS afforded progress and bridged some gaps in our research.

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