Recessive TBC1D24 Mutations Are Frequent in Moroccan Non-Syndromic Hearing Loss Pedigrees

Abstract

Mutations in the TBC1D24 gene are responsible for four neurological presentations: infantile epileptic encephalopathy, infantile myoclonic epilepsy, DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation and seizures) and NSHL (non-syndromic hearing loss). For the latter, two recessive (DFNB86) and one dominant (DFNA65) mutations have so far been identified in consanguineous Pakistani and European/Chinese families, respectively. Here we report the results of a genetic study performed on a large Moroccan cohort of deaf patients that identified three families with compound heterozygote mutations in TBC1D24. Four novel mutations were identified, among which, one c.641G>A (p.Arg214His) was present in the three families, and has a frequency of 2% in control Moroccan population with normal hearing, suggesting that it acts as an hypomorphic variant leading to restricted deafness when combined with another recessive severe mutation. Altogether, our results show that mutations in TBC1D24 gene are a frequent cause (>2%) of NSHL in Morocco, and that due to its possible compound heterozygote recessive transmission, this gene should be further considered and screened in other deaf cohorts.

Unresolved questions regarding human hereditary deafness

“…Mutation nomenclature is based on the full‐length isoform of TBC 1D24 ( NM _001199107.1). The c.1333dupG(p.Val445Glyfs*33) was reported as c.1316insG(p.Val439Glyfs*32) in Bakhchane et al , , based on a shorter isoform of TBC 1D24 ( NM _020705, personal communication with the last author). (b) TBC 1D24 gene structure and location of a splice site mutation c.1206+5G>A that, in compound heterozygosity with p.His336Glnfs*12, causes DOORS syndrome.…”

“…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 , ).…”

“…The association of TBC1D24 with non‐syndromic deafness was further solidified by identification of three missense and one frameshift mutation segregating in three Moroccan families (Bakhchane et al , ). Affected individuals from three families displayed severe to profound congenital sensorineural deafness and were compound heterozygous for two mutant alleles of TBC1D24 .…”

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...…”

“…Using these criteria, two heterozygous variants confirmed by Sanger sequencing were identified in TBC1D24 (Supplementary Figure 1): 1) a previously reported missense change c.457G>A (p.Glu153Lys; rs376712059)6,13,15 and 2) a previously unreported frameshift mutation, c.545del (p.Thr182Serfs*6) predicted to cause nonsense-mediated RNA decay or result in a truncated protein. Both mutations showed appropriate familial segregation.…”