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.

Unresolved questions regarding human hereditary deafness

“…As illustrated in Figure , seven of 26 mutations of TBC1D24 are associated with non‐syndromic deafness (i.e. no additional clinical anomalies) (Ali et al , ; Azaiez et al , ; Rehman et al , ; Zhang et al , ; Bakhchane et al , ). There are also ten mutant alleles of TBC1D24 reported in patients with epileptic syndromes (Corbett et al , ; Falace et al , ; Afawi et al , ; Guven and Tolun, ; Milh et al , ; Doummar et al , ; Muona et al , ; Poulat et al , ; Strazisar et al , ).…”

Slc26a4-insufficiency causes fluctuating hearing loss and stria vascularis dysfunction

“…Mouse Slc26a4 is expressed in the inner ear, thyroid, kidney, lung, and several other organs (Alesutan et al, 2011; Everett et al, 1997; Rehman et al, 2014). Pendrin mediates Cl − /HCO 3 − exchange in the developing inner ear and is required for proper endolymphatic pH and volume (Choi et al, 2011; Wangemann et al, 2007).…”

TBC1D24 Mutations in a Sibship with Multifocal Polymyoclonus

“…Ictal EEG not availableFocal migrating EEG discharges during seizuresInterictal EEG: disorganizedSlow background in EEGMultifocal or bilateral generalized multiple spikes and spike waves in EEG associated with myoclonias.Generalized spike-wave discharges with frontocentral predominance during seizuresNo clear EEG correlate for myoclonic jerksImaging findingsNormal 1 individual with nodular periventricular heterotopia 1 individual had MRI abnormalities in lentiform nuclei, ventricular dilatation and white matter changes post-cardiac arrest. An earlier MRI was normalSelective atrophy and signal abnormality in cerebellumCerebral cortical thickening most marked in cingulate regions and occipital polesGlobal cerebral atrophy sparing the posterior fossaThin corpus callosumDelayed myelinationDiffuse cerebral atrophy (asymmetrical for one patient)Cerebellar atrophyProminent frontotemporal atrophyClinical PhenotypeSpectrum of Epilepsy Phenotypes Including DOORS SyndromeDOORS Syndrome (OMIM 220500)Non-syndromic Deafness (DFNB86) (OMIM 614617)Non-syndromic Hearing Loss (DFNA65) (OMIM 616044)Migrating Paroxysmal Myoclonus and Cerebellar SignsReferencesBalastrini et al13Campeau et al18Rehman et al14, Bakhchane et al15Azaiez et al16, Zhang et al17Doummar et al22Reported mutations/genotypec.32A>G (p.Asp11Gly)c.58C>T (p.Gln20*)c.115G>C (p.Ala39Pro)c.118C>T (p.Arg40Cys)c.119G>T (p.Arg40Leu)c.277C>T (p.Pro93Ser)c.313T>C (p.Cys105Arg)c.328G>A (p.Gly110Ser)c.439G>C (p.Asp147His)c.457G>A (p.Glu153Lys)c.468C>A (p.Cys156*)c.533C>G (p.Ser178Trp)c.619C>T (p.Gln207*)c.679C>T (p.Arg227Trp)c.680G>A (p.Arg227Gln)c.686T>C (p.Phe229Ser)c.724C>T (p.Arg242Cys)c.731C>T (p.Ala244Val)c.751T>C (p.Phe251Leu)c.809G>A (p.Arg270His)c.845C>G (p.Pro282Arg)c.919A>G (p.Asn307Asp)c.957G>C (p.Lys319Asn)c.969_970delGT(p.Ser324Thrfs*3)c.999G>T (p.Leu333Phe)c.1008delT (p.His336Glnfs*12)c.1126G>C (p.Gly376Arg)c.1384del (p.Glu462Serfs*61)c.1460dup (p.His487Glnfs*71)c.1079G>T (p.Arg360Leu)c.1499C>T (p.Ala500Val)c.1544C>T (p.Ala515Val)c.1661_1667del (p.Gln554Leufs*12)c.724C>T (p.Arg24...…”