Molecular genetics of primary microcephaly in Indian families

¹Arun Kumar, ¹MR Duvvari, ²SH Blanton, ³SC Girimaji
¹Indian Institute of Science, Dept. of Molecular Reproduction, Development and Genetics, Bangalore, India, ²Miami Institute of Human Genomics, University of Miami, Miami, United States of America, ³National Institute of Mental Health and Neurosciences, Department of Psychiatry, Bangalore, India

Microcephaly (small head) is defined as a condition in which the head circumference of an affected individual is >3 SD below the population age and sex related mean. The small cranial capacity results from underlying hypoplasia of the cerebral cortex rather than abnormal development of the overlying skull. Primary microcephaly (MCPH; OMIM 251200) is a distinct subtype that is defined by the absence of associated malformations and of secondary or environmental causes. It is inherited as an autosomal recessive trait. Patients with MCPH have mild to severe mental retardation but without any other neurological deficits. It has an incidence of 1/30,000 to 1/250,000 live births in western populations. The actual incidence of MCPH is not known in India, but it could be higher in south Indian states of Karnataka, Andhra Pradesh, Kerala and Tamil Nadu where ~33% of marriages are consanguineous. It is a genetically heterogeneous disorder with six known loci: MCPH1-MCPH6. So far, genes for MCPH1 (MCPH1), MCPH3 (CDK5RAP2), MCPH5 (ASPM) and MCPH 6 (CENPJ) loci have been identified. We have ascertained a total of 42 families with MCPH from the states of Karnataka, Andhra Pradesh and Tamil Nadu. We have carried out linkage analysis of a majority of these families using PCR-based microsatellite markers from the candidate regions of six known MCPH loci. Our analysis showed that the ASPM gene is a major cause of MCPH in Indian families. The presence of unlinked families to any of the known MCPH loci in our dataset suggested the involvement of a seventh locus for this disorder. We are performing a genome-wide screening of unlinked families to identify a novel MCPH locus. DNA sequence analysis in MCPH5-linked families has identified one known and four novel mutations in the ASPM gene in a homozygous state.