Abstract
BackgroundX‐linked deafness‐4 (DFNX4) caused by functional loss of SMPX is a nonsyndromic form of progressive hearing loss with post‐lingual onset. Herein, we describe a male neonate from an ethnic Han Chinese family who presented with congenital deafness.MethodsThe proband and the family members were subjected to comprehensively hearing screen. Genetic testing was carried out using whole‐exome sequencing (WES). The result was verified by Sanger sequencing. Functional characterization of the identified variant was completed by reverse transcription PCR (RT‐PCR), Sanger sequencing, and fluorogenic quantitative PCR (qPCR).ResultsThe proband was diagnosed with progressive sensorineural hearing loss. The proband's mother showed normal hearing at present. The proband's maternal grandmother exhibited mild HL since the age of 50. Using whole‐exome sequencing (WES), we identified a donor splice‐site variant (NM_014332.2: c.132 + 1G>A) in the SMPX gene in the proband. The mother and maternal grandmother were both carriers, which suggested a X‐linked inheritance of the condition in the family. RT‐PCR and Sanger sequencing revealed that four alternative splice pairs within intron 3 have led to four aberrant RNAs transcripts, including two non‐canonical splice‐pairs (GC‐AG and CT‐AG). The variant generated a novel frameshift variant, creating a premature termination codon (PTC) upstream of a newly formed splice site (p.Met45Glyfs*16). SMPX mRNA expression assay showed that the PTC has caused degradation of mRNA via nonsense‐mediated mRNA decay (NMD).ConclusionThis is the first study to report a SMPX (DFNX4) splicing variant in a Chinese family. These findings, especially congenital deafness, contributed to existing knowledge regarding the genotypic and phenotypic spectrum of SMPX‐associated hearing loss.
Highlights
Hearing loss (HL) is one of the most common sensory disorders, affecting over 5% of the population worldwide (466 million in total; including 432 million adults and 34 million children)
First cloned from skeletal muscle, the SMPX gene consists of five exons and maps to Xp.22.1 (Kemp et al, 2001; Patzak, Zhuchenko, Lee, & Wehnert, 1999)
We hereby report on identification of a novel splicing variant (NM_014332.2:c.132 + 1G>A, p.Met45Glyfs*16) in the SMPX gene in a three‐generation ethnic Han Chinese family by whole‐exome sequencing (WES)
Summary
This is the first study to report a SMPX (DFNX4) splicing variant in a Chinese family. These findings, especially congenital deafness, contributed to existing knowledge regarding the genotypic and phenotypic spectrum of SMPX‐associated hearing loss. KEYWORDS DFNX4, novel variant, SMPX, splicing, whole‐exome sequencing, X‐linked hearing loss
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