Linkage Study of Primary Microcephaly in Pakistani Kindred

Microcephaly is heterogeneous, autosomal recessive trait with reduced head circumference of at least 4 SD below age and sex means due to reduction in neuron production. The brain of microcephalic patient is architecturally normal but severe to mild mental retardation. It is rare disease affecting 2-2.5% of total population specifically in Asia and Arab where the incidence of cousin marriages is relatively high. From seven known currently mapped loci ASPM is found to be the frequent causative agent. In the current investigations exclusion mapping of a microcephalic family was done. DNA from all blood samples was extracted using standard procedure and after gene specific PCR amplifications, 8% non-denaturing PAGE was done. Linkage was observed at MCPH5 locus where ASPM is a candidate gene on chromosome 1q31. The results of DNA sequencing showed G to A transition and Leucine (CTG) to Leucine (CTA) was noted. There are six triplet codons which differ by single nucleotide encoding for Leucine. Hence, no overall change in the effect of protein expression was observed due to the degeneracy of codons. Therefore, the sequencing of the entire ASPM gene with intervening sequences was suggested in order to find the actual cause of microcephaly.