Abstract

Primary microcephaly (MCPH) is an autosomal-recessive congenital disorder characterized by smaller-than-normal brain size and mental retardation. MCPH is genetically heterogeneous with six known loci: MCPH1 to MCPH7. The abnormal spindle-like, microcephaly associated (ASPM) gene at MCPH5 locus, which accounts for 37 to 54% of MCPH, appears to be the most common cause of microcephaly. More than 50% of the MCPH families genetically analyzed in Pakistan were mapped to MCPH5 locus including both families in this study. On mutation screening of ASPM gene by PCR amplification and direct DNA sequencing, a common c.3978G>A transition was identified in exon 17 of ASPM gene to be responsible for diseased phenotype in both families. This change results to the substitution of an amino acid residue at position 1326 from tryptophan to a stop codon (p.Trp1326Stop). The same mutation was also identified in several other families of Pakistani origin. Since the disease is both clinically and genetically heterogeneous, the diagnosis of MCPH1–7 is based on clinical findings; brain imaging that shows reduced brain volume with grossly normal architecture, family history consistent with autosomal recessive inheritance and molecular genetic testing when available. The mapping of large number of families to MCPH5 locus and identification of a common mutation, that is, c. 3978A>G of ASPM gene will enable us to formulate future strategies to control and prevent the disease by genetic counseling, prenatal/postnatal diagnosis and carrier testing.

Key words: Primary microcephaly (MCPH), abnormal spindle-like, microcephaly associated (ASPM) mutations, microcephaly, Pakistani families.