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

Authors


  • Communicated by Jürgen Horst

  • Contract grant sponsors: Canadian Foundation for Innovation (New Investigator Award no. 9384; Leaders Opportunity Fund no.13120); Canadian Institute of Health Research (CIHR 207714); Research and Development Corporation (RDC 207711); Genome Canada (Atlantic Medical Genetics and Genomics Initiative to T-L.Y.); CIHR-Regional Partnership Program (RPP) Fellowship (207716/207696 to N.A.).

Correspondence to: Terry-Lynn Young, Discipline of Genetics, Faculty of Medicine, Memorial University, St. John's, Newfoundland and Labrador, Canada AIB 3V6. E-mail: tlyoung@mun.ca

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.

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