Genetic Analysis of Hereditary Primary Microcephaly in Selected Families of Pakistani Origin

Abstract

Microcephaly is defined as the neurological distortion in which affected individuals have an unusually smaller head as compared to other children of the same age and sex. There are several environmental and genetic factors leading to microcephaly. Autosomal recessive primary microcephaly is a genetically heterogeneous neurodevelopmental imperfection described by a significantly reduced head circumference existing at birth, intellectual disability and mental retardation. Up till date, 18 MCPH loci (MCPH1–MCPH18) have been discovered in various populations around the world. MCPH genes play a significant role in centriole biosynthesis, DNA replication and genome stability. Blood samples from three families (A, B, C) segregating with MCPH were obtained from different remote regions of Pakistan. Family A and C genotyping examination displayed that normal and affected individuals were heterozygous within these known genes, thus excluding the linkage. Linkage analysis of family B indicated MCPH5 locus on chromosome 19 harboring ASPM gene. Sequence analysis of specific exon in these MCPH5 linked families resulted in the identification of an already known non-sense mutation in the exon 17 of ASPM gene. In such mutation, G to A conversion occurs at 3978 position of nucleotide, creating premature stop codon. Exact nomenclature for this mutation is 3978G>A W1326*. The emphasis of current genetic study was investigation of causative gene and DNA variant at nucleotide level which will help in future genetic testing and genetic counseling to reduce the risk of genetic disorders in Pakistani population.