Genetic heterogeneity in Pakistani microcephaly families

Area of Science:

• Genetics
• Developmental Biology
• Human Disease Genetics

Background:

• Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by reduced brain size.
• Mutations in genes regulating cell division or DNA repair cause MCPH.
• Consanguineous families in South Asia are a significant source for identifying MCPH-related genetic factors.

Purpose of the Study:

• To investigate the genetic heterogeneity and mutational spectrum of MCPH in Pakistani families.
• To identify novel causative genes and mutations for primary microcephaly.

Main Methods:

• Analysis of 57 consanguineous Pakistani MCPH families.
• Linkage analysis to known MCPH loci.
• Mutation detection in coding exons of candidate MCPH genes.
• Whole-exome sequencing for families unlinked to known loci.

Main Results:

• Linkage to five known MCPH loci was detected in 34 families, with mutations identified in 27.
• Twenty-three families remained unlinked to known loci, indicating substantial locus heterogeneity.
• ASPM and WDR62 were the most frequently mutated genes.
• A recurrent ASPM mutation (p.Trp1326*) suggested a Pakistani founder effect.
• Three novel ASPM, four novel WDR62, one novel MCPH1, and two novel CEP152 mutations were identified.
• CEP152 mutations were described for the first time in the Pakistani population.

Conclusions:

• MCPH in Pakistan exhibits significant genetic heterogeneity beyond previously identified loci.
• ASPM and WDR62 are major contributors to MCPH in this cohort.
• The discovery of novel mutations, including CEP152, expands the mutational spectrum of MCPH.
• Identification of a founder mutation in ASPM provides insights into the population genetics of MCPH.