A consanguineous Qatari family affected by a novel autosomal recessive disorder characterized by severe mental retardation, retinal degeneration, optic nerve atrophy, ataxic gait and edematous puffiness of hands was studied by genome-wide SNP genotyping with Illumina 200K SNP-chips, candidate gene mutation screening and whole exome sequencing for one affected member. Homozygosity mapping indicated a 19.6 MB segment in the long arm of chromosome 4 from 55.8-56.0 Mb. LOD score is calculated for the region of homozygosity to establish linkage. This interval contains more than 100 genes, none of which has been implicated in any of the relevant phenotype. Candidate genes within the region of homozygosity were prioritized by examination of their physiologic roles and possibility of producing the disease phenotype. Screening 30 positional candidate genes showed no pathogenic mutations. Whole exome target enrichment sequencing was performed on ABI SOLiD4 for a single-affected individual. Three non-synonymous variants were positioned within the homozygosity intervals. At the same time a report appeared in the literature describing an Iranian family with very similar clinical characteristics with a defect in the Steroid 5 alpha-Reductase 3 [SRD5A3] gene. This gene localizes within the homozygosity interval and it showed one novel missense variation c.T744G/p.F248L on whole exome sequencing in our Qatari family. The mutation was validated by Sanger sequencing, it co-segregates with the disease phenotype and is not present in the 1000 genome database. The mutation is predicted to be damaging by Polyphen and SIFT protein-modeling software and it is absent in 162 ethnically matched control chromosomes. The protein encoded by this gene is a 318 amino acid enzyme that belongs to the steroid 5-alpha reductase family, and polyprenol reductase subfamily. This protein is necessary for the conversion of polyprenol into dolichol, which is required for the synthesis of dolichol-linked monosaccharides and the oligosaccharide precursor used for N-linked glycosylation of proteins. Mutations in this gene are associated with congenital disorder of glycosylation type I. Biochemical testing reconfirmed a glycosylation defect in the affected individuals. This family presents a unique phenotype in the spectrum of glycosylation defect related disorders.


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