A Novel Deletion inSMPXCauses a Rare form of X-Linked Progressive Hearing Loss in Two Families Due to a Founder Effect

Abstract

X-linked hearing loss is the rarest form of genetic hearing loss contributing to <1% of cases. We identified a multiplex family from Newfoundland (Family 2024) segregating X-linked hearing loss. Haplotyping of the X chromosome and sequencing of positional candidate genes revealed a novel point deletion (c.99delC) in SMPX which encodes a small muscle protein responsible for reducing mechanical stress during muscle contraction. This novel deletion causes a frameshift and a premature stop codon (p.Arg34GlufsX47). We successfully sequenced both SMPX wild-type and mutant alleles from cDNA of a lymphoblastoid cell line, suggesting that the mutant allele may not be degraded via nonsense-mediated mRNA decay. To investigate the role of SMPX in other subpopulations, we fully sequenced SMPX in 229 Canadian probands with hearing loss and identified a second Newfoundland Family (2196) with the same mutation, and a shared haplotype on the X chromosome, suggesting a common ancestor.

X-Linked Hearing Loss: Two Gene Mutation Examples Provide Generalizable Implications for Clinical Care

“…The molecular genetics associated with the 99delC SMPX mutation carried by the DFNX4 families described in this article have been reported in detail in a previous publication (Abdelfatah et al, 2013). In our DFNX4 families, the auditory phenotype for male carriers of this mutation is a bilateral, symmetrical, sensorineural hearing loss with progression from a mild impairment to a severe or profound high frequency loss by middle age.…”

“…These clinical data were combined with prospective family interview data provided by relatives participating in the study; some phenotype data used for chromosome-wide mapping was reported previously (Abdelfatah et al, 2013). Pedigrees were drawn with a pedigree software program (Progeny Inc.), and auditory phenotypes associated with specific SMPX and POU3F4 genotypes were determined.…”

“…All research protocols were approved by the research ethics boards of the University of Western Ontario, Memorial University, and the Hospital for Sick Children. Genetic analyses were obtained for the DFNX4 families as part of an earlier chromosome-wide mapping study that led to the discovery of a premature stop mutation (c.99delC; p.Arg34GlufsX47) in exon 3 of the SMPX gene in two families (Abdelfatah et al, 2013). For the DFNX2 proband, routine testing for GJB2 point mutations by DNA sequencing and GJB6 deletions by Multiple Ligation Probe Amplification (MLPA) was performed according to manufacturer's instructions (kit P153-B1 GJB-WFS, MRC Holland, Amsterdam, the Netherlands).…”

A common variant in CLDN14 causes precipitous, prelingual sensorineural hearing loss in multiple families due to founder effect

“…All probands recruited to the study were screened for population-specific deafness alleles (Supplementary Table 1; Abdelfatah et al 2013a, b; Ahmed et al 2004; Doucette et al 2009; Young et al 2001). To identify other candidate genes to screen, audiograms were submitted to Audiogene (Hildebrand et al 2009) for computerized comparison with known average audiograms of 16 autosomal dominant loci (under the assumption that hearing loss was segregating as an autosomal dominant trait in these NL families).…”

“…Religious and geographic isolation within small coastal fishing (outport) communities (Manion 1977) has resulted in a higher inbreeding coefficient in the NL population (Bear et al 1987, 1988; Zhai et al 2015). We have previously identified several founder deafness mutations in the NL populations (Abdelfatah et al 2013a, b; Ahmed et al 2004; Doucette et al 2009; Young et al 2001). …”