Background: X-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.
Methods: The 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).
Results: The 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).
Conclusion: 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: SMPX; DFNX4; X-linked hearing loss; novel variant; splicing; whole-exome sequencing.
© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
Conflict of interest statement
The authors declare no conflicts of interest.
A novel frameshift mutation of SMPX causes a rare form of X-linked nonsyndromic hearing loss in a Chinese family.PLoS One. 2017 May 25;12(5):e0178384. doi: 10.1371/journal.pone.0178384. eCollection 2017. PLoS One. 2017. PMID: 28542515 Free PMC article.
A novel splicing mutation in SMPX is linked to nonsyndromic progressive hearing loss.Int J Pediatr Otorhinolaryngol. 2018 Jan;104:47-50. doi: 10.1016/j.ijporl.2017.10.040. Epub 2017 Nov 2. Int J Pediatr Otorhinolaryngol. 2018. PMID: 29287879
A likely pathogenic variant putatively affecting splicing of PIGA identified in a multiple congenital anomalies hypotonia-seizures syndrome 2 (MCAHS2) family pedigree via whole-exome sequencing.Mol Genet Genomic Med. 2018 Sep;6(5):739-748. doi: 10.1002/mgg3.428. Epub 2018 Jul 4. Mol Genet Genomic Med. 2018. PMID: 29974678 Free PMC article.
Nonsyndromic Hearing Loss and Deafness, Mitochondrial.2004 Oct 22 [updated 2018 Jun 14]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020. GeneReviews®. 1993–2020. PMID: 20301595 Free Books & Documents. Review.
A novel ABHD12 nonsense variant in Usher syndrome type 3 family with genotype-phenotype spectrum review.Gene. 2019 Jul 1;704:113-120. doi: 10.1016/j.gene.2019.04.008. Epub 2019 Apr 8. Gene. 2019. PMID: 30974196 Review.
- Abdelfatah N., Merner N., Houston J., Benteau T., Griffin A., Doucette L., … Young T. L. (2013). A novel deletion in SMPX causes a rare form of X‐linked progressive hearing loss in two families due to a founder effect. Human Mutation, 34(1), 66–69. - PubMed
- Cediel R., Riquelme R., Contreras J., Diaz A., & Varela‐Nieto I. (2006). Sensorineural hearing loss in insulin‐like growth factor I‐null mice: A new model of human deafness. European Journal of Neuroscience, 23(2), 587–590. - PubMed