A novel single base pair duplication in WDR62 causes primary microcephaly.

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Human Molecular Genetics

Background:

• Primary microcephaly (MCPH) is a congenital brain disorder characterized by significantly reduced head circumference.
• MCPH is often associated with intellectual disability but typically lacks other major neurological abnormalities.
• The genetic basis of MCPH is complex, with mutations in various genes implicated in brain size determination.

Observation:

• This study investigated three Pakistani males from a consanguineous family diagnosed with autosomal recessive primary microcephaly.
• Genotyping, Sanger sequencing, and bioinformatic analyses were employed to identify the causative mutation.
• An 11Mb autozygous region was detected within the MCPH2 locus on chromosome 19q13.12 using a 250K SNP array.

Findings:

• Sequencing of the WDR62 gene within the identified autozygous region revealed a single base pair duplication, c.2527dupG.
• This mutation results in a frameshift, predicted to alter the structural conformation and function of the WDR62 protein.
• The affected amino acid at position 843 (Aspartic acid) is evolutionarily conserved, suggesting functional importance.

Implications:

• The identification of the c.2527dupG mutation in WDR62 provides a specific genetic marker for primary microcephaly.
• These findings contribute to understanding the molecular mechanisms underlying WDR62-associated microcephaly.
• This discovery will aid in the genetic diagnosis of patients with primary microcephaly and inform future research on WDR62 function.