Mutation analysis of autosomal recessive neurological disorders in consanguineous families from Saudi Arabia

The focus of this research project is the fundamentally important discovery of genetic mutations present in the Saudi Arabian population, concentrating mainly on offspring with neurological autosomal recessive disorders resulting from consanguineous marriages. The objective is to identify pathogenic gene variantsin known, novel, and potential candidate genes. In this research, microarrays were used for genome-wide homozygosity mapping to locate regions of homozygosity. This technique was followed with whole-exome sequencing to identify the causative gene located within the detected homozygous region, and the Sanger sequencing confirmed the mutations. Consanguineous families who presented at the paediatric or genetic clinics with two or more children having a neurological disorder were recruited, including the healthy parents, siblings, and other family members. Five candidate families have been recruited in this study. One family is a hereditary spastic paraplegia case with four affected children. Another family with two affected children of Perrault syndrome phenotype. Two more families who have children with microcephaly. In addition to three children of intellectual disability in one family. We have identified a DDHD2 truncating mutation in the first family and novel pathogenic variant of CLPP in the second family. In addition to AGMO gene alteration and previously reported stop-gain mutation in ASPM in the microcephaly families. Furthermore, the highlight of 5 candidate genes (ALKBH8, ANKK1, AMOTL1, TRAPPC6A and RSPH6CA) were found to be related to an intellectual disability phenotype. Further investigation by western blotting showed a difference in stability between normal and mutant proteins for both TRAPPC6A and AM0TL1. These are considered to be new findings for this intellectual disability phenotype.