Genetic analysis of primary microcephaly in Indian families: novel ASPM mutations.

Patients with primary microcephaly, an autosomal recessive trait, have mild to severe mental retardation without any other neurological deficits. It is a genetically heterogeneous disorder with six known loci: MCPH1 to MCPH6. Only the genes for MCPH1 and MCPH5 have been identified so far. We have ascertained nine consanguineous families with primary microcephaly from India. To establish linkage of these nine families to known MCPH loci, microsatellite markers were selected from the candidate regions of each of the six known MCPH loci and used to genotype the families. The results were suggestive of linkage of three families to the MCPH5 locus and one family to the MCPH2 locus. The remaining five families were not linked to any of the known loci. DNA-sequence analysis identified one known (Arg117X) and two novel (Trp1326X and Gln3060X) mutations in the three MCPH5-linked families in a homozygous state. Three novel normal population variants (i.e., c.7605G > A, c.4449G > A, and c.5961 A > G) were also detected in the ASPM gene.