Characterization of a New Locus for Autosomal Recessive Intellectual Disability (ARID) in Pakistani Population

Abstract

Intellectual disability is a neurodevelopmental disorder with 1-3 % prevalence in the world population and characterized by limitations in intellectual functioning and adaptive skills with intelligence quotient (IQ) below 70 and inception before 18 years age of an individual. Molecular basis of intellectual disability in Pakistani population is not well studied and present study was designed to fill the gaps in the current knowledge of causative genes/loci responsible for intellectual disability in Pakistani population. This study is part of an institutional project on intellectual disability being executed in “Genetic Diseases lab” of the Centre of Excellence in Molecular Biology (CEMB). Forty five families with two or more affected individuals segregating intellectual disability were ascertained from Punjab province. For confirmation of genetically transmitted intellectual disability and exclusion of environmental causes, complete medical history of affected individuals and their family was documented and written informed consents were obtained. Twenty six consanguineous families, predominantly first cousin marriages, were selected for further study and screened for exclusion of twelve already reported intellectual disability loci. Three families, designated as PKMR173, PKMR 228 and PKMR 116 were found to be linked with MRT11, MRT10/20 and MRT23 respectively. Next generation sequencing/high throughput sequencing was carried out on chromosomal DNA of the affected and one unaffected member in the remaining i.e. unlinked families. Novel mutations in genes already associated with intellectual disability or related disorders were found in four families. A missense mutation in gene WDR73 segregated with phenotype in PKMR242 resulting in amino acid change of (p.(Phe325Ser)) and a missense mutation in protein FRY segregated with phenotype in PKMR264 with amino acid change of (p.(Val761Ile)). A nonsense mutation in GPT2 segregated in PKMR 281 with an amino acid change of (p.(Arg404*)) and a missense mutation in FLNA segregated in PKMR 321 with an amino acid change of (p.Thr1685Met)). Genome wide scan on DNA in family PKMR 177 resulted in mapping of a 34.5 Mb long novel locus along with frameshift mutation in a novel gene SYNRG on chromosome 17p11.2-q22 with maximum two point LOD score (Zmax) of 2.8 at recombination fraction θ=0. This novel region was also found in four other families PKMR15, PKMR 65, PKMR 72 and PKMR 274, however, causative gene was different in additionally linked families. Another 23.95 Mb long novel region was mapped in PKMR 225 on chromosome 6p23-p21.2 with moderate to severe level of intellectual disability. Two potential novel regions of 1.36 Mb and 32.58 Mb length, were mapped in PKMR 165 loop-1 and loop-2 on chromosome 9q31.3-q33.2 and chromosome 3p24.1-p14.2 respectively. In PKMR 199 three potential candidate regions were mapped on chromosome 6q24.1-q24.3, 8q24.13 q24.21 and 20p12.3 of 0.47 Mb, 0.16 Mb and 12.9 Mb respectively. In conclusion, this study is a significant contribution in identification of causes of intellectual disability in Pakistani population and will help to devise strategies to combat with this disorder in a well-organized way. This study is also expected to enlarge the current repository of genes/loci in Pakistani population.