Genetic analysis of autosomal recessive intellectual disability in consanguineous families

Abstract

Intellectual disability (ID) is a common and highly heterogeneous neurodevelopmental disorder. It affects 1–3% of the world’s population and its prevalence is almost twice as high in underdeveloped than in affluent world. ID has an enormous socio-economic burden and devastating impact on the lives of affected individuals and their families. More than 700 genes have been discovered so far across different studies pertaining to X-linked, autosomal dominant and recessive ID. Autosomal recessive intellectual disability (ARID), being the most common form of ID. Till date, more than 577 genes involved in ARID have been discovered mostly in consanguineous communities. ARID is further grouped into syndromic ARID (nARID) and non-syndromic ARID (nsARID) types primarily based upon the phenotypic appearance. In Pakistan, the rate of consanguinity is approaching 70% and this high rate results in higher rates of recessive disorders including ARID. Inbred families provide a unique opportunity to find pathogenic variants in known as well as candidate genes responsible for recessive disorders due to the extensive regions of homozygosity in the genomes of these individuals. We enrolled 25 suspected consanguineous ARID families based on pedigree analysis and clinical evaluation from Kohat district, KPK province of Pakistan. The identified consanguineous families were subjected to genetic analysis through Whole exome sequencing (WES) and genome-wide SNP array. Bioinformatics analysis was carried out using Genome Analysis Tool Kit (GATK) based bioinformatics pipeline and Consanguinity Analysis Through Common Homozygosity (CATCH) software. Subsequent prioritization was carried out by application of various quality filters. Finally, the selected putative causative variants were validated by Sanger sequencing. Out of 25 families, known causative mutations in five known genes (ASPM, ATRX, GPR56, NAGLU and DOLK) were identified in eight different families for ARID. Furthermore, novel mutations in seven known ID genes (ABAT, SLC12A6, SHANK3, BCKDK, DDHD2, ERCC2 and GPT2) were found in seven families. Three potential likely pathogenic mutations were identified in three different families in three novel genes (DYNC1I2, FBXL3 and LINGO1). However, seven families remained unsolved; probably we missed the causative variants. Our study showed that

v exome sequencing in combination with microarray genotyping is a powerful technique to find out the causative variants in rare ARID families and can be used to establish correlation between candidate genes and phenotypes. The diagnostic yield of the strategy used in our whole ID project was found to be approximately 32% (32/100). Furthermore, the present work also revealed that the genetic variations are associated with a significant number of consanguineous ARID families from Pakistan.