A consanguineous Qatari family having an autosomal recessive disorder characterized by severe mental retardation, cerebellar vermis hypoplasia, retinal degeneration, optic nerve atrophy, ataxic gait, and seizures was studied for identification of the offending gene and mutation. Homozygosity mapping identified an 11.4 Mb critical interval at 4q12 to q13.2 that would contain the gene responsible for the disorder. Ten positional candidate genes were screened for pathogenic mutations, but none were identified. Next-generation exome sequencing in one affected individual identified a novel SRD5A3 missense mutation c.T744G/p.F248L, which was subsequently confirmed by Sanger sequencing, suggesting a congenital disorder of glycosylation type IQ defect. Isoelectric focusing of serum transferrin showed a type I pattern indicative of an N-glycan assembly defect. This is a novel pathogenic mutation and the first SRD5A3 missense mutation as all others are protein-truncating mutations.
Autism spectrum disorder (ASD) is an increasingly prevalent disorder. Although around 15% of cases are caused by specific genetic causes, most cases involve a complex and variable combination of genetic risk and environmental factors that are not yet identified. There is a paucity of studies on ASD in Qatar, mostly in the form of case reports and genetic causes. The current study was designed to describe the clinical characteristics of ASD and its correlates in Qatar. Individuals with ASD were recruited from the Shafallah Center for Children with Special Needs which is the largest special needs center in Qatar. Within the sample of 171 individuals with ASD, 47% were ethnic Qataris, while 53% were nonethnic Qataris (Arabs and other nationalities). The analysis included the following factors: nationality, age, gender, socioeconomic status, consanguinity, prenatal/postnatal complications, and comorbidities. Eighty percent of the identified cases were males, with a 4:1 male to female ratio. Additionally, 83% of the families had one proband, 9.9% with 2 probands, and 7.1% with more than two. Comorbid conditions included: intellectual disabilities (ID) in 83% and epilepsy in 18.8%. 76.6% of subjects were nonverbal. There were 3 (1.8%) children with Rett’s syndrome, 3 (1.8%) with Fragile X, and 1 (0.6%) with tuberous sclerosis. There are currently no publications that clarify the mean age of diagnosis in Qatar, however, the present study showed that more than half of the diagnosed cases were among the ages of 7–14 years (56%). The effect of consanguinity as a risk factor was not found to be significant.
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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