title: Genetic causes of moderate to severe hearing loss point to modifiers.
abstract: The genetic underpinnings of recessively inherited moderate to severe sensorineural hearing loss are not well understood, despite its higher prevalence in comparison to profound deafness. We recruited 92 consanguineous families segregating stable or progressive, recessively inherited moderate or severe hearing loss. We utilized homozygosity mapping, Sanger sequencing, targeted capture of known deafness genes with massively parallel sequencing and whole exome sequencing to identify the molecular basis of hearing loss in these families. Variants of the known deafness genes were found in 69% of the participating families with the SLC26A4, GJB2, MYO15A, TMC1, TMPRSS3, OTOF, MYO7A and CLDN14 genes together accounting for hearing loss in 54% of the families. We identified 20 reported and 21 novel variants in 21 known deafness genes; 16 of the 20 reported variants, previously associated with stable, profound deafness were associated with moderate to severe or progressive hearing loss in our families. These data point to a prominent role for genetic background, environmental factors or both as modifiers of human hearing loss severity.
authors: School of Biological Sciences, University of the Punjab, Lahore, Pakistan.
authors: Sadaf
authors: S
authors: Naz
authors: School of Biological Sciences, University of the Punjab, Lahore, Pakistan.|Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, USA 20892.
authors: Ayesha
authors: A
authors: Imtiaz
authors: School of Biological Sciences, University of the Punjab, Lahore, Pakistan.
authors: Ghulam
authors: G
authors: Mujtaba
authors: School of Biological Sciences, University of the Punjab, Lahore, Pakistan.
authors: Azra
authors: A
authors: Maqsood
authors: School of Biological Sciences, University of the Punjab, Lahore, Pakistan.
authors: Rasheeda
authors: R
authors: Bashir
authors: School of Biological Sciences, University of the Punjab, Lahore, Pakistan.
authors: Ihtisham
authors: I
authors: Bukhari
authors: School of Biological Sciences, University of the Punjab, Lahore, Pakistan.
authors: Muhammad R
authors: MR
authors: Khan
authors: School of Biological Sciences, University of the Punjab, Lahore, Pakistan.
authors: Memoona
authors: M
authors: Ramzan
authors: School of Biological Sciences, University of the Punjab, Lahore, Pakistan.
authors: Amara
authors: A
authors: Fatima
authors: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, USA 20892.
authors: Atteeq U
authors: AU
authors: Rehman
authors: School of Biological Sciences, University of the Punjab, Lahore, Pakistan.
authors: Muddassar
authors: M
authors: Iqbal
authors: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, USA 20892.
authors: Taimur
authors: T
authors: Chaudhry
authors: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, USA 20892.
authors: Merete
authors: M
authors: Lund
authors: Audiology Unit, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, USA 20892.
authors: Carmen C
authors: CC
authors: Brewer
authors: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, USA 20892.|Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, USA 20892.
authors: Robert J
authors: RJ
authors: Morell
authors: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, USA 20892.
authors: Thomas B
authors: TB
authors: Friedman
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D059472:Exome; D005260:Female; D005808:Genes, Recessive; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000503:physiopathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D055815:Young Adult
keywords: DFNB; Pakistan; deafness; etiology; hearing loss; modifiers; mutation