oa Discovery of a Probable Gene Mutation Causing Mental Retardation, Microsomia, and Signs of Skeletal Dysplasia in an Arab Family with a Previously Undelineated Autosomal Recessive Disorder

Background: Autosomal recessive diseases are considered as a major group of single-gene disorders among Arab population. We have recruited a family with three siblings with a mental retardation (MR) syndrome who were born to consanguineous Qatari parents. The clinical problems comprised significant mental retardation, microsomia, signs of skeletal dysplasia, and thoracolumbar kyphosis. The oldest patient suffers also from epileptic seizures. Also, the parents and the other three of their six children are healthy. Causative genes and mapping strategy focused on large genomic regions demonstrating homozygosity in all of the affected individuals.

Objectives: Our goal is to identify the genetic causes of undelineated autosomal recessive disorders among Arab families.

Methods: Whole genome genotyping has been performed by (Illumina 300Kb SNPs). Followed by homozygosity mapping and linkage analysis. In addition, targeted resequencing of the candidate genes within the linked homozygous loci was performed.

Results and conclusions: Homozygosity mapping revealed a single large shared region of homozygous SNPs on the long arm of chromosome 4 flanked by rs28419770 (4q13.1) and rs4105671 (4q21.23). This block contains more than 120 genes, none of which has been implicated in MR or any of the above mentioned phenotype so far. Sequencing of candidate genes within the region revealed two novel missense variations in FRAS1 gene; an Arg3099Gln and Thr3149Met. Both variations were found in the three affected siblings in homozygous status, while the parents were heterozygous. Furthermore, these two variations have not been found in 140 individual controls in homozygous pattern, however, a heterozygous pattern of variations were found in three individuals only. Our future plan will be doing the whole exome sequencing for the shared region using next generation sequencing platform.