Mapping of three novel loci for non-syndromic autosomal recessive mental retardation (NS-ARMR) in consanguineous families from Pakistan.

To date, of 13 loci with linkage to non-syndromic autosomal recessive mental retardation (NS-ARMR), only six genes have been established with associated mutations. Here we present our study on NS-ARMR among the Pakistani population, where people are traditionally bound to marry within the family or the wider clan. In an exceptional, far-reaching genetic survey we have collected more than 50 consanguineous families exhibiting clinical symptoms/phenotypes of NS-ARMR. In the first step, nine families (MR2-9 and MR11) with multiple affected individuals were selected for molecular genetic studies. Two families (MR3, MR4) showed linkage to already know NS-ARMR loci. Fifteen affected and 10 unaffected individuals from six (MR2, MR6, MR7, MR8, MR9 and MR11) families were genotyped by using Affymetrix 5.0 or 6.0 single-nucleotide polymorphism (SNP) microarrays. SNP microarray data was visually inspected by dChip and genome-wide homozygosity analysis was performed by HomozygosityMapper. Additional mapping was performed (to exclude false-positive regions of homozygosity called by HomozygosityMapper and dChip) on all available affected and unaffected members in seven NS-ARMR families, using microsatellite markers. In this manner we were able to map three novel loci in seven different families originating from different areas of Pakistan. Two families (MR2, MR5) showed linkage on chromosome 2p25.3-p25.2. Three families (MR7, MR8, and MR9) that have been collected from the same village and belong to the same clan were mapped on chromosome 9q34.3. MR11 maps to a locus on 9p23-p13.3. Analysis of MR6 showed two positive loci, on chromosome 1q23.2-q23.3 and 8q24.21-q24.23. Genotyping in additional family members has so far narrowed, but not excluded the 1q locus. In summary, through this study we have identified three new loci for NS-ARMR, namely MRT14, 15 and 16.