Genetics of intellectual disability in consanguineous families.

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.

A novel mutation in MCPH1 gene in an Iranian family with primary microcephaly.

Primary microcephaly (MCPH) is a genetic disorder in which affected individuals present with a head circumference 3 standard deviations (SDs) below the age- and sex-related mean and is accompanied by mental retardation without further associated malformations. Here we report a patient with sporadic MCPH from Northwest of Iran who was investigated for MCPH1 locus. Clinical examination and karyotype analyses were performed and microsatellite based mapping was done by using flanking and intragenic short tandem repeat (STR) markers for MCPH1 locus. For these markers the affected individual was homozygote and the parents were heterozygote. According to this pattern of allele sharing and also the cytogenetic findings, mutation screening of Microcephalin gene was performed and subsequent sequencing revealed a novel mutation in Microcephalin gene.