Global Distribution of Founder Variants Associated with Non-Syndromic Hearing Impairment

Aboagye, Elvis Twumasi; Adadey, Samuel Mawuli; Wonkam‐Tingang, Edmond; Amenga-Etego, Lucas; Awandare, Gordon A.; Wonkam, Ambroise

doi:10.3390/genes14020399

Cited by 10 publications

(9 citation statements)

References 109 publications

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“…The reported differences in the FMD prevalence may be due to differences in the genetic structure of each population. More frequent and founder variants in hearing impairment genes have already been described in European, African, Asian, and American populations (Aboagye et al 2023 ; Adadey et al 2022 ); therefore, finding founder variants in specific genes that cause FMD would not be surprising. Founder variants are those variants found with a high frequency within a particular population caused by the presence of the variant in an ancestor or small group of ancestors (Jain et al 2021 ).…”

Section: Discussionmentioning

confidence: 91%

“…Previous studies have shown that several non-syndromic SNHL genes have a founder effect in the Asian population (48 variants in 14 genes, 85.7%). However, there are few reported genes showing founder variants in the European population [9 variants in GJB2 [OMIM 121,011), TMC1 (OMIM 606,706) , and TMIE (OMIM 607,237) genes] (Aboagye et al 2023 ).…”

Section: Introductionmentioning

confidence: 99%

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An overload of missense variants in the OTOG gene may drive a higher prevalence of familial Meniere disease in the European population

Parra-Perez,

Gallego-Martinez,

Lopez-Escamez

2024

Hum. Genet.

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Meniere disease is a complex inner ear disorder with significant familial aggregation. A differential prevalence of familial MD (FMD) has been reported, being 9–10% in Europeans compared to 6% in East Asians. A broad genetic heterogeneity in FMD has been described, OTOG being the most common mutated gene, with a compound heterozygous recessive inheritance. We hypothesize that an OTOG-related founder effect may explain the higher prevalence of FMD in the European population. Therefore, the present study aimed to compare the allele frequency (AF) and distribution of OTOG rare variants across different populations. For this purpose, the coding regions with high constraint (low density of rare variants) were retrieved in the OTOG coding sequence in Non-Finnish European (NFE).. Missense variants (AF < 0.01) were selected from a 100 FMD patient cohort, and their population AF was annotated using gnomAD v2.1. A linkage analysis was performed, and odds ratios were calculated to compare AF between NFE and other populations. Thirteen rare missense variants were observed in 13 FMD patients, with 2 variants (rs61978648 and rs61736002) shared by 5 individuals and another variant (rs117315845) shared by two individuals. The results confirm the observed enrichment of OTOG rare missense variants in FMD. Furthermore, eight variants were enriched in the NFE population, and six of them were in constrained regions. Structural modeling predicts five missense variants that could alter the otogelin stability. We conclude that several variants reported in FMD are in constraint regions, and they may have a founder effect and explain the burden of FMD in the European population.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

An overload of missense variants in the OTOG gene may drive a higher prevalence of familial Meniere disease in the European population

Parra-Perez,

Gallego-Martinez,

Lopez-Escamez

2024

Hum. Genet.

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“…The reported differences in the FMD prevalence may be due to differences in the genetic structure of each population. More frequent and founder variants in hearing impairment genes have already been described in European, African, Asian, and American populations (14,35), therefore, nding founder variants in speci c genes that cause FMD would not be surprising. Founder variants are those pathogenic variants found with a high frequency within a particular population caused by the presence of the variant in an ancestor or small group of ancestors (36).…”

Section: Discussionmentioning

confidence: 94%

“…Previous studies have shown that several non-syndromic SNHL genes have a founder effect in the Asian population (48 variants in 14 genes, 85.7%). However, there are few genes reported showing founder variants in the European population (9 variants in GJB2 (OMIM: 121011), TMC1 (OMIM: 606706), and TMIE (OMIM: 607237) genes) (14).…”

Section: Introductionmentioning

confidence: 99%

An overload of missense variants in the OTOG gene may drive a higher prevalence of familial Meniere disease in the European descendant population

Lopez-Escamez,

Parra-Perez,

Gallego-Martinez

2023

Preprint

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Meniere's disease is a complex inner ear disorder with significant familial aggregation. A differential prevalence of familial MD (FMD) has been reported, being 9-10% in Europeans compared to 6% in East Asians. A broad genetic heterogeneity in FMD has been described, OTOG being the most common mutated gene, with a compound heterozygous recessive inheritance. We hypothesize that an OTOG-related founder effect may explain the higher prevalence of FMD in the European population. Therefore, the present study aimed to compare the allele frequency (AF) and distribution of OTOG rare variants across different populations. For this purpose, coding regions with high constraint (low density of rare variants) in OTOG coding sequence in Non-Finnish European (NFE) were identified. Missense variants (AF<0.01) were selected from a 100 FMD patients’ cohort, and their population AF was annotated using gnomAD v2.1. A linkage analysis was performed, and odds ratios (OR) were calculated to compare AF between NFE and other populations. Thirteen rare missense variants were observed in 13 FMD patients, with two variants (rs61978648, rs61736002) shared by 5 individuals and one variant (rs117315845) shared by 2 individuals. The results confirm the observed enrichment of OTOGrare missense variants in FMD. Furthermore, 8 variants were enriched in the NFE population, and six of them were in constrained regions. Structural modeling predicts five missense variants could alter the otogelin stability. We conclude that several variants reported in FMD are in constraint regions and may have a founder effect and explain the burden of FMD in the European population.

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“…Hearing loss is one of the most significant hereditary heterogeneous diseases 4,5 present in at least 1 out of every 500 newborns worldwide 6 ; up to 60% of these cases have a genetic aetiology 7,8 . During the past two decades, tremendous progress has been made in the identification of causative genes in hereditary nonsyndromic hearing loss, or NSHL 9,10 . To date, a total of 124 NSHL genes have been identified, estimating 51 autosomal dominant (deafness autosomal dominant; DFNA) genes; 77 autosomal recessives (deafness autosomal recessive; DFNB) genes and 5 X‐linked (deafness X‐linked; DFNX; http://hereditaryhearingloss.org/) genes.…”

Section: Introductionmentioning

confidence: 99%

Novel, pathogenic insertion variant of GSDME associates with autosomal dominant hearing loss in a large Chinese pedigree

Cheng,

Li,

Tan

et al. 2023

J Cellular Molecular Medi

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Nonsyndromic hearing loss (NSHL) is a genetically diverse, highly heterogeneous condition characterised by deafness, and Gasdermin E (GSDME) variants have been identified as directly inducing autosomal dominant NSHL. While many NSHL cases associated with GSDME involve the skipping of exon 8, there is another, less understood pathogenic insertion variant specifically found in Chinese pedigrees that causes deafness, known as autosomal dominant 5 (DFNA5) hearing loss. In this study, we recruited a large Chinese pedigree, conducted whole‐exome and Sanger sequencing to serve as a comprehensive clinical examination, and extracted genomic DNA samples for co‐segregation analysis of the members. Conservation and expression analyses for GSDME were also conducted. Our clinical examinations revealed an autosomal dominant phenotype of hearing loss in the family. Genetic analysis identified a novel insertion variant in GSDME exon 8 (GSDME: NM_004403.3: c.1113_1114insGGGGTGCAGCTTACAGGGTGGGTGT: p. P372fs*36). This variant is segregated with the deafness phenotype of this pedigree. The GSDME gene was highly conserved in the different species we analysed, and its mRNA expression was ubiquitously low in different human tissues. In conclusion, we have successfully identified a novel pathogenic insertion variant of GSDME in a Chinese pedigree that causes deafness, shedding light on the genetic basis of hearing loss within this specific family. Our findings expand the spectrum of known variants associated with GSDME‐related deafness and may further support both the underlying gain‐of‐function mechanism and functional associations of GSDME hearing loss variants.

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Global Distribution of Founder Variants Associated with Non-Syndromic Hearing Impairment

Cited by 10 publications

References 109 publications

An overload of missense variants in the OTOG gene may drive a higher prevalence of familial Meniere disease in the European population

An overload of missense variants in the OTOG gene may drive a higher prevalence of familial Meniere disease in the European population

An overload of missense variants in the OTOG gene may drive a higher prevalence of familial Meniere disease in the European descendant population

Novel, pathogenic insertion variant of GSDME associates with autosomal dominant hearing loss in a large Chinese pedigree

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