LINKAGE ANALYSIS OF FAMILIES WITH INHERITED MENTAL RETARDATIONS

Abstract

Mental Retardation or Intellectual Disability (MRIID) refers significantly sub-averaged intellectual functioning with onset before age 18. The etiologies of MR are extremely heterogeneous and include both genetic and environmental factors. The mode of inheritance of MR can be autosomal or X-linked, dominant or recessive. The current estimates of X-linked genes associated with MR are high but 8 genes (PRSS12, CC2DIA, CRBN, GRIK2, TUSC3, TRAPPC9, TECR and SWIPj and 33 loci have been discovered so far. Mutation in these genes may lead to abnormal function of the brain and nervous system, which may result in mental retardation. Present study involves two consanguineous Pakistani families (A and B), from Khyber Pakhtunkha (KPK) province, demonstrating autosomal recessive non syndromic mental retardation (ARNMR). Affected individuals were initially examined for the presence of malformations and history of metabolic disorders. To identify the causative genes, homozygosity mapping was carried out in both families A and B, by genotyping microsatellite markers linked to currently known ARNSMR loci. Analysis of genotyped results for all known loci showed no disease associated homozygosity. Data for all the genotyped loci in both fami lies was analyzed using easyLINKAGE plus version 5.02, which failed to yield significant LOD score, indicating the exclusion of known loci. Thus linkage to all known loci was conclusively excluded in both families, indicating the involvement of potentially novel loci. The genes responsible for MR in these families can be identified by genome wide scanning using microsatellite markers or by whole genome SNP microarrays. From this study we can conclude that genetic causes of autosomal recessive non syndromic mental retardation are still not fully known and require further investigations.