Identification of novel MITF mutations in Chinese families with Waardenburg syndrome type II

Abstract

Background Waardenburg syndrome (WS) is a rare autosomal‐dominant syndrome and is characterized by sensorineural hearing loss and pigment abnormalities. It is subdivided into four types according to the clinical characteristics. MITF is one of the major pathogenic genes for type II. The aim of this study was to investigate MITF mutations and the clinical characteristics of WS type 2 (WS2) in four Chinese families. Method Clinical diagnoses were based on detailed clinical findings. Six WS2 patients from four unrelated Chinese families were enrolled. Massively parallel DNA sequencing was used to find pathogenic genes and Sanger sequencing was used to confirm the variants detected. Results Sensorineural hearing loss was observed in four of six patients, three had heterochromia iridis, and five have freckled faces. We identified three novel MITF heterozygous mutations (c.831dupC, c.650G>A, and c.711‐2A>G) and one recurrent heterozygous mutation (c.328C>T) in the four WS2 families. Intra‐familial phenotypic variability and incomplete penetrance were found in WS2 patients with pathogenic variants of MITF. Conclusion Genetic diagnosis was performed for the involved four families based on the clinical manifestations. Four heterozygous mutations were identified in the MITF gene. Our findings expanded the phenotypic and genotypic spectrum of WS.

Novel mutation leading to splice donor loss in a conserved site ofDMDgene causes Duchenne muscular dystrophy with cryptorchidism

“…The application of various genetic screening techniques, including whole-genome sequencing (WGS) and exome sequencing, has facilitated the precise diagnosis of numerous genetic diseases caused by rare variants. [18][19][20][21][22][23][24][25] For instance, an exome sequencing study on an Indian family identified a rare deleterious homozygous missense variant in the RXFP2 gene, which causes cryptorchidism. 26 Although exome sequencing is more commonly used than WGS due to its lower cost, WGS offers a more uniform distribution of sequencing quality (including single-nucleotide variants, insertions and deletions) and a higher discovery rate of coding-region variants, approximately 3%.…”

Novel mutation leading to splice donor loss in a conserved site ofDMDcauses cryptorchidism

“…The application of various genetic screening techniques, including wholegenome and exome sequencing (WGS/WES), has facilitated the precise diagnosis of numerous genetic diseases caused by rare variants [18][19][20][21][22][23][24][25] . For instance, a WES study on an Indian family identified a rare deleterious homozygous missense variant in the RXFP2 gene, which causes cryptorchidism 26 .…”

Modeling of pigmentation disorders associated with MITF mutation in Waardenburg syndrome revealed an impaired melanogenesis pathway in iPS‐derived melanocytes

“…The high mutation prevalence of MITF in Chinese WS patients has been deeply concerning (Li et al, 2019;Wang et al, 2022). Based on clinical findings, WS patients with MITF mutations usually show complete expression of possible symptoms, such as severe congenital SNHL, extensive skin hypopigmentation, and complete heterochromia iridum (Song et al, 2016;Wang et al, 2018Wang et al, , 2021. Despite the comprehensive investigation in animal models, the pathogenic mechanism of mutated MITF is still poorly described in humans (Chen et al, 2020;Du et al, 2019;Ni et al, 2013;Steingrímsson et al, 1994;Tachibana et al, 2003).…”