title: Mutations in TBC1D24, a gene associated with epilepsy, also cause nonsyndromic deafness DFNB86.
abstract: Inherited deafness is clinically and genetically heterogeneous. We recently mapped DFNB86, a locus associated with nonsyndromic deafness, to chromosome 16p. In this study, whole-exome sequencing was performed with genomic DNA from affected individuals from three large consanguineous families in which markers linked to DFNB86 segregate with profound deafness. Analyses of these data revealed homozygous mutation c.208G>T (p.Asp70Tyr) or c.878G>C (p.Arg293Pro) in TBC1D24 as the underlying cause of deafness in the three families. Sanger sequence analysis of TBC1D24 in an additional large family in which deafness segregates with DFNB86 identified the c.208G>T (p.Asp70Tyr) substitution. These mutations affect TBC1D24 amino acid residues that are conserved in orthologs ranging from fruit fly to human. Neither variant was observed in databases of single-nucleotide variants or in 634 chromosomes from ethnically matched control subjects. TBC1D24 in the mouse inner ear was immunolocalized predominantly to spiral ganglion neurons, indicating that DFNB86 deafness might be an auditory neuropathy spectrum disorder. Previously, six recessive mutations in TBC1D24 were reported to cause seizures (hearing loss was not reported) ranging in severity from epilepsy with otherwise normal development to epileptic encephalopathy resulting in childhood death. Two of our four families in which deafness segregates with mutant alleles of TBC1D24 were available for neurological examination. Cosegregation of epilepsy and deafness was not observed in these two families. Although the causal relationship between genotype and phenotype is not presently understood, our findings, combined with published data, indicate that recessive alleles of TBC1D24 can cause either epilepsy or nonsyndromic deafness.
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, MD 20850, USA.
authors.forename: Atteeq U
authors.initials: AU
authors.lastname: Rehman
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Regie Lyn P
authors.initials: RL
authors.lastname: Santos-Cortez
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, MD 20850, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Morell
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, MD 20850, USA.
authors.forename: Meghan C
authors.initials: MC
authors.lastname: Drummond
authors.affiliation: Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, MD 20850, USA.
authors.forename: Taku
authors.initials: T
authors.lastname: Ito
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Kwanghyuk
authors.initials: K
authors.lastname: Lee
authors.affiliation: Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 54500, Pakistan.
authors.forename: Asma A
authors.initials: AA
authors.lastname: Khan
authors.affiliation: Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 54500, Pakistan.
authors.forename: Muhammad Asim R
authors.initials: MA
authors.lastname: Basra
authors.affiliation: Center for Research in Molecular Medicine, Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore 54000, Pakistan.
authors.forename: Naveed
authors.initials: N
authors.lastname: Wasif
authors.affiliation: Institute of Biochemistry, University of Baluchistan, Quetta 87300, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ayub
authors.affiliation: Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 54500, Pakistan.
authors.forename: Rana A
authors.initials: RA
authors.lastname: Ali
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad 45320, Pakistan.
authors.forename: Syed I
authors.initials: SI
authors.lastname: Raza
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bamshad
authors.affiliation: Division of Pediatric Otolaryngology - Head and Neck Surgery, Cincinnati Children's Research Foundation, Cincinnati, OH 45229 USA; Department of Otolaryngology - Head and Neck Surgery, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Saima
authors.initials: S
authors.lastname: Riazuddin
authors.affiliation: Laboratory of Molecular Physiology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Billington
authors.affiliation: Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 54500, Pakistan.
authors.forename: Shaheen N
authors.initials: SN
authors.lastname: Khan
authors.affiliation: Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Penelope L
authors.initials: PL
authors.lastname: Friedman
authors.affiliation: Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, MD 20850, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Griffith
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-I-Azam University, Islamabad 45320, Pakistan.
authors.forename: Wasim
authors.initials: W
authors.lastname: Ahmad
authors.affiliation: Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 54500, Pakistan; Allama Iqbal Medical College and Jinnah Hospital Complex, University of Health Sciences, Lahore 54550, Pakistan.
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: sleal@bcm.edu.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, MD 20850, USA. Electronic address: friedman@nidcd.nih.gov.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Friedman
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D003241:Consanguinity; D003638:Deafness / Q000235:genetics; D004827:Epilepsy / Q000235:genetics*; D059472:Exome; D005091:Exons; D005260:Female; D020690:GTPase-Activating Proteins; D005808:Genes, Recessive; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins; D010154:Pakistan; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D002352:Carrier Proteins; D020690:GTPase-Activating Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C552551:TBC1D24 protein, human