Frameshift variant in MITF gene in a large family with Waardenburg syndrome type II and a co-segregation of a C2orf74 variant.

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.

Whole genome genotyping mapped regions on chromosome 2 and 18 in a family segregating Waardenburg syndrome type II.

OBJECTIVES: Waardenburg syndrome is a rare genetic disorder. It is characterized by sensorineural hearing impairment and pigment defects of the skin, hair and iris. In some cases abnormalities in the tissues derived from neural crest have also been reported. Mutations in several genes have been reported as an underlying cause of Waardenburg syndrome. Objective of this study is to identify the chromosomal region(s) associated with Waardenburg syndrome in an extended Saudi family. METHODS: Genomic DNA was extracted from fifteen individuals of a Saudi family segregating Waardenburg syndrome. Whole genome SNP genotyping was performed to identify common identity by descent chromosomal region(s) shared by affected individuals. RESULTS: Pedigree analysis confirm autosomal dominant inheritance of Waardenburg syndrome type II in a family. Whole genome SNP genotypes were analyzed using AutoSNPa and DominantMapper tools. Shared identity by descent chromosomal regions were identified on chromosome 2 and chromosome 18. Regions were checked for known Waardenburg syndrome genes. No known gene is present in both regions. CONCLUSIONS: In summary, we identified novel chromosomal regions associated with Waardenburg syndrome type II in a Saudi family. Deep sequencing of a complete candidate regions are required to identify the gene underlying Waardenburg syndrome in this family.

Novel homozygous loss-of-function mutations in RP1 and RP1L1 genes in retinitis pigmentosa patients.

Background: Retinitis pigmentosa (RP) is a heterogeneous group of ocular dystrophy. It is challenging to identify the underlying genetic defect in individuals with RP due to huge genetic heterogeneity. This study was designed to delineate the genetic defect(s) underlying RP in extended Saudi families and to describe the possible disease mechanism.Materials and Methods: Fundus photography and a high definition optical coherence tomography (HD-OCT) were performed in order to detect the earlier stages of macular degeneration. Genomic DNA was extracted followed by genome-wide SNP genotyping and whole exome sequencing (WES). Exome data was filtered to identify the genetic variant(s) of interest.Results: Clinical examination showed that affected individuals manifest key features of RP. The fundus exam shows pale optic disc and bone spicules at the periphery. OCT shows macular degeneration as early as at the age of 4 years. Whole genome scan by SNPs identified multiple homozygous regions. WES identified a 10 bps novel insertion mutation (c.3544_3545insAGAAAAGCTG; p.Ala1182fs) in the RP1 gene in both affected individuals of family A. Affected individual from family B showed a large insertion of 48 nucleotides in the coding part of the RP1L1 gene (c.3955_3956insGGACTAAAGTAATAGAAGGGCTGCAAGAAGAGAGGGTGCAGTTAGAGG; p.Ala1319fs). Sanger sequencing validates the autosomal recessive inheritance of the mutations.Conclusion: The results strongly suggest that the insertion mutations in the RP1 and RP1L1 genes are responsible for the retinal phenotype in affected individuals from two families. Heterozygous individuals are asymptomatic carriers. We propose that the protective allele in other homozygous regions in heterozygous carriers contribute to the phenotypic variability in asymptomatic individuals.