ABSTRACT
Autosomal recessive (AR) gene defects are the leading genetic cause of intellectual disability (ID) in countries with frequent parental consanguinity, which account for about 1/7th of the world population. Yet, compared to autosomal dominant de novo mutations, which are the predominant cause of ID in Western countries, the identification of AR-ID genes has lagged behind. Here, we report on whole exome and whole genome sequencing in 404 consanguineous predominantly Iranian families with two or more affected offspring. In 219 of these, we found likely causative variants, involving 77 known and 77 novel AR-ID (candidate) genes, 21 X-linked genes, as well as 9 genes previously implicated in diseases other than ID. This study, the largest of its kind published to date, illustrates that high-throughput DNA sequencing in consanguineous families is a superior strategy for elucidating the thousands of hitherto unknown gene defects underlying AR-ID, and it sheds light on their prevalence.
Subject(s)
Genes, Recessive/genetics , Intellectual Disability/genetics , Adult , Consanguinity , Exome/genetics , Family , Female , High-Throughput Nucleotide Sequencing/methods , Homozygote , Humans , Iran , Male , Middle Aged , Mutation/genetics , Pedigree , Protein Interaction Maps/genetics , Exome Sequencing/methods , Whole Genome Sequencing/methodsABSTRACT
PTRH2 deficiency is associated with an extremely rare disease, infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). We report the first Iranian patient with IMNEPD. We detected a pathogenic variant in the PTRH2 gene (NM_016077.5: c.68T > C, p.V23A). The proband has myopia, spastic diplegic cerebral palsy, urolithiasis, and a history of seizures.