Abstract
Waardenburg syndrome (WS) is a hereditary disorder affecting the auditory system and pigmentation of hair, eyes, and skin. Different variants of the disease exist with the involvement of mutation in six genes. The aim of the study is to identify the genetic defects underlying Waardenburg syndrome in a large family with multiple affected individuals. Here, in this study, we recruited a large family with eleven affected individuals segregating WS type 2. We performed whole genome SNP genotyping, whole exome sequencing and segregation analysis using Sanger approach. Whole genome SNP genotyping, whole exome sequencing followed by Sanger validation of variants of interest identified a novel single nucleotide deletion mutation (c.965delA) in the MITF gene. Moreover, a rare heterozygous, missense damaging variant (c.101T>G; p.Val34Gly) in the C2orf74 has also been identified. The C2orf74 is an uncharacterized gene present in the linked region detected by DominantMapper. Variants in MITF and C2orf74 follows autosomal dominant segregation with the phenotype, however, the variant in C2orf74 is incompletely penetrant. We proposed a digenic inheritance of variants as an underlying cause of WS2 in this family.
Highlights
Waardenburg syndrome (WS) is a group of rare hereditary disorders
We identified pathogenic variants in melanocyte inducing transcription factor (MITF) and C2orf74 genes as an underlying cause of Waardenburg syndrome type 2 (WS2) phenotype
Ocular hypopigmentation was present in all affected individuals except IV:5, IV:7, V:2, V:8, VI:2
Summary
Waardenburg syndrome (WS) is a group of rare hereditary disorders. It is characterized by pigmentary defects of hair (white forelock), eyes (heterochromia iridis) and skin (hypo-pigmented skin), abnormalities in the inner ear (bilateral sensorineural hearing impairment), and dystopia canthorum (lateral displacement of the inner canthi of the eyes). WS syndrome has been categorized into four major types (WS1, WS2, WS3 and WS4). Further subtypes do exist though additional clinical manifestations are required for differential diagnosis of subtypes. WS1 (OMIM: 193500) and WS3 (OMIM: 148820) are characterized by the occurrence of dystopia canthorum.
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