Mutations in TMC1 contribute significantly to nonsyndromic autosomal recessive sensorineural hearing loss: A report of five novel mutations

Sırmacı, Aslı; Duman, Duygu; Akay, Hatice; Erbek, Seyra; İncesulu, Armağan; Öztürk-Hişmi, Burcu; Arıcı, Zehra Serap; Yüksel-Konuk, E. Berrin; Yılmaz, Seda Taşır; Tokgöz-Yılmaz, Suna; Cengiz, Filiz Başak; Aslan, İdil; Yıldırım, Müzeyyen; Hasanefendioğlu-Bayrak, Aylin; Ayçiçek, Abdullah; Yılmaz, İsmail; Fítöz, Suat; Altın, Fazilet; Özdağ, Hilal; Tekin, Mustafa

doi:10.1016/j.ijporl.2009.01.005

Cited by 49 publications

(48 citation statements)

References 14 publications

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“…Of the 29 reported mutations in this gene, the p.R34X mutation is the most frequent and accounts for over 30% of all TMC1 ARNSHL-causing mutations. This mutation has been reported in hearing-impaired persons originating from Iran, Iraq, Lebanon, Pakistan, Tunisia, and Turkey (Scott et al, 1996;Kurima et al, 2002;Kitajiri et al, 2007;Hilgert et al, 2008;Tlili et al, 2008;Sirmaci et al, 2009), and we have also identified this mutation in Algeria. Its detection in normal control samples of African-American and northern European origin raises the probability that p.R34X is a prevalent contributor to the genetic load of hearing loss in multiple world populations (Kitajiri et al, 2007).…”

Section: Discussionsupporting

confidence: 81%

“…Two Algerian and one Pakistani patients carrying the p.R34X mutation were detected. In addition to these three cases, eight hearing-impaired subjects carrying the p.R34X mutation and originating from Tunisia (n ¼ 4), Iraq (n ¼ 1), Iran (n ¼ 1), Lebanon (n ¼ 1), and Turkey (n ¼ 1) were included into this study (Scott et al, 1996;Hilgert et al, 2008;Tlili et al, 2008;Sirmaci et al, 2009).The p.R34X mutation in all family probands from these populations was confirmed by direct sequencing.…”

Section: Resultsmentioning

confidence: 99%

“…Mutations in TMC1 are a common cause of ARNSHL in India, Pakistan, Tunisia, and Turkey where they account for the hearing-loss phenotype in 3-6% of families (Kurima et al, 2002;Kalay et al, 2005;Santos et al, 2005;Kitajiri et al, 2007;Hilgert et al, 2008;Tlili et al, 2008;Sirmaci et al, 2009). Of the 29 reported mutations in this gene, the p.R34X mutation is the most frequent and accounts for over 30% of all TMC1 ARNSHL-causing mutations.…”

Section: Discussionmentioning

confidence: 99%

“…Twenty-nine different mutations of the transmembrane channel-like gene 1 (TMC1) gene (GenBank accession number: NM_138691.2) have been reported in 48 families with ARNSHL (Kurima et al, 2002;Kalay et al, 2005;Meyer et al, 2005;Santos et al, 2005;Kitajiri et al, 2007;Hilgert et al, 2008;Tlili et al, 2008;Sirmaci et al, 2009). The most common recessive mutation for hearing loss in the TMC1 gene is p.R34X.…”

Section: Introductionmentioning

confidence: 99%

“…T) and is located in exon 7. It accounts for over 30% of mutant alleles of TMC1 and occurs in populations throughout Asia and North Africa (Kurima et al, 2002;Kitajiri et al, 2007;Hilgert et al, 2008;Tlili et al, 2008;Sirmaci et al, 2009). The high frequency of the p.R34X mutation in Tunisian and Pakistani populations has been related to a common ancestral founder (Kitajiri et al, 2007;Tlili et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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High Frequency of the p.R34X Mutation in the TMC1 Gene Associated with Nonsyndromic Hearing Loss Is Due to Founder Effects

Said

Hmani-Aifa

Amar

et al. 2010

Genetic Testing and Molecular Biomarkers

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Section: Discussionsupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

High Frequency of the p.R34X Mutation in the TMC1 Gene Associated with Nonsyndromic Hearing Loss Is Due to Founder Effects

Said

Hmani-Aifa

Amar

et al. 2010

Genetic Testing and Molecular Biomarkers

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Identification of TMC1 as a relatively common cause for nonsyndromic hearing loss in the Saudi population

Ramzan

Al‐Owain

Al‐Numair

et al. 2019

American J of Med Genetics Pt B

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Hearing loss (HL) is the most common sensory disorder worldwide and genetic factors contribute to approximately half of congenital HL cases. HL is subject to extensive genetic heterogeneity, rendering molecular diagnosis difficult. Mutations of the transmembrane channel‐like 1 (TMC1) gene cause hearing defects in humans and mice. The precise function of TMC1 protein in the inner ear is unknown, although it is predicted to be involved in functional maturation of cochlear hair cells. TMC1 mutations result in autosomal recessive (DFNB7/11) and sometimes dominant (DFNA36) nonsyndromic HL. Mutations in TMC1 are responsible for a significant portion of HL, particularly in consanguineous populations. To evaluate the importance of TMC1 mutations in the Saudi population, we used a combination of autozygome‐guided candidate gene mutation analysis and targeted next generation sequencing in 366 families with HL previously shown to lack mutations in GJB2. We identified 12 families that carried five causative TMC1 mutations; including three novel (c.362+3A > G; c.758C > T [p.Ser253Phe]; c.1396_1398delACC [p.Asn466del]) and two reported mutations (c.100C > T [p.Arg34Ter]; c.1714G > A [p.Asp572Asn]). Each of the identified recessive mutation was classified as severe, by both age of onset and severity of HL. Similarly, consistent with the previously reported dominant variant p.Asp572Asn, the HL phenotype was progressive. Eight families in our cohort were found to share the pathogenic p.Arg34Ter mutation and linkage disequilibrium was observed between p.Arg34Ter and SNPs investigated. Our results indicate that TMC1 mutations account for about 3.3% (12/366) of Saudi HL cases and that the recurrent TMC1 mutation p.Arg34Ter is likely to be a founder mutation.

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Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss

Rlp

Faridi

et al. 2018

Human Mutation

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Consanguineous Pakistani pedigrees segregating deafness have contributed decisively to the discovery of 31 of the 68 genes associated with nonsyndromic autosomal recessive hearing loss (HL) worldwide. In this study, we utilized genome-wide genotyping, Sanger and exome sequencing to identify 163 DNA variants in 41 previously reported HL genes segregating in 321 Pakistani families. Of these, 71 (43.6%) variants identified in 29 genes are novel. As expected from genetic studies of disorders segregating in consanguineous families, the majority of affected individuals (94.4%) are homozygous for HL-associated variants, with the other variants being compound heterozygotes. The five most common HL genes in the Pakistani population are SLC26A4, MYO7A, GJB2, CIB2 and HGF, respectively. Our study provides a profile of the genetic etiology of HL in Pakistani families, which will allow for the development of more efficient genetic diagnostic tools, aid in accurate genetic counseling and guide application of future gene-based therapies. These findings are also valuable in interpreting pathogenicity of variants that are potentially associated with HL in individuals of all ancestries. The Pakistani population, and its infrastructure for studying human genetics, will continue to be valuable to gene discovery for HL and other inherited disorders.

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Mutations in TMC1 contribute significantly to nonsyndromic autosomal recessive sensorineural hearing loss: A report of five novel mutations

Cited by 49 publications

References 14 publications

High Frequency of the p.R34X Mutation in the TMC1 Gene Associated with Nonsyndromic Hearing Loss Is Due to Founder Effects

High Frequency of the p.R34X Mutation in the TMC1 Gene Associated with Nonsyndromic Hearing Loss Is Due to Founder Effects

Identification of TMC1 as a relatively common cause for nonsyndromic hearing loss in the Saudi population

Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss

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