Skewed X-chromosome inactivation and next-generation sequencing to identify a novel SMPX variants associated with X-linked hearing loss in a Chinese family

Abstract Objective Hereditary nonsyndromic hearing loss is extremely heterogeneous and an X-linked form accounts for 1–5% of all cases. The aim of this study was to identify the pathogenic variants in a nonsyndromic X-linked dominant hearing loss family, and explain the reason of different hearing phenotype in hearing between the two sisters with the same variant. Methods Targeted gene capture and next-generation sequencing were used to study the genetic cause. What's more, methylation differences among the androgen receptor genes were used to investigate whether the different hearing levels of the two sisters is related to X-chromosome inactivation (Xi). Results We identified SMPX c.29insA (p.Asn10Lysfs*3) as the novel variant causing deafness. The skewed X-chromosome inactivation was relevant to the hearing difference between the two sisters. Conclusion Targeted gene capture and NGS is an efficient way to identify pathogenic variants in genes. Analysis of X-chromosome inactivation is beneficial to the diagnosis and genetic counseling of X-linked dominant hearing loss families.