Identification of Novel MCPH Genes: A Study of Consanguineous Families of Pakistani Descent

Aims: Autosomal recessive primary microcephaly (MCPH) is a rare, genetically heterogeneous neurodevelopmental disorder. Patients with MCPH have severe microcephaly at birth with a pronounced reduction in brain volume, while the gross brain architecture is normal. Apart from an intellectual deficit, they typically do not have further neurological symptoms or severe malformations. Biallelic mutations in the 12 genes MCPH1, WDR62, CDK5RAP2, CEP152, ASPM, CENPJ, STIL, CEP135, CEP152, ZNF335, PHC1, and CDK6 were identified as genetic causes for MCPH. However, mutations in these genes are not present in approximately 20% of families with MCPH phenotypes, indicating further genetically heterogeneity. The aim of our study is the identification and characterization of novel MCPH genes.

Methods: The study is conducted on 12 consanguineous families from Pakistan with MCPH phenotypes. In a first step, one affected patient per family was tested for mutations in the known MCPH genes through whole-exome sequencing (WES). Mutations were confirmed through Sanger sequencing. In the second step, we are analyzing further family members of those families for which no mutations in known MCPH genes could be detected. WES analyses of these families are performed to identify potentially novel genes that have not been described to cause MCPH so far.

Results: We present the current status of the still ongoing study.

Conclusion: With this study, we want to contribute to the understanding of genetic causes of MCPH.

Keywords: microcephaly, MCPH.