Expanding the mutational spectrum of congenital microcephaly in Pakistani families

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Human Molecular Genetics

Background:

• Autosomal recessive primary microcephaly (MCPH) is a severe neurodevelopmental disorder characterized by significantly reduced head circumference at birth.
• MCPH is genetically heterogeneous, with over 32 genes implicated, and is more common in consanguineous populations.
• ASPM and WDR62 are the most frequent genes associated with MCPH, accounting for a substantial proportion of cases.

Purpose of the Study:

• To investigate the genetic basis of congenital microcephaly in four consanguineous Pakistani families.
• To identify novel pathogenic variants in genes associated with MCPH.
• To expand the understanding of the mutational spectrum of MCPH genes.

Main Methods:

• Genetic analysis of four consanguineous families presenting with congenital microcephaly.
• Identification and characterization of variants in CPAP, WDR62, and ASPM genes.
• In silico analyses, including computational predictions and structural modeling, to assess variant pathogenicity.

Main Results:

• Three novel variants were identified: a missense variant in CPAP (c.3947C>A; p. (Thr1316Lys)), a splice-site variant in WDR62 (c.2867 + 5G>T), and a novel nonsense variant in ASPM (c.3188T>G; p. (Leu1063*)).
• A previously reported pathogenic variant in ASPM (c.9730C>T; p. (Arg3244*)) was also identified.
• Computational analyses suggested that all identified variants are likely deleterious, impacting protein function.

Conclusions:

• The study expands the known mutational spectrum for CPAP and WDR62.
• ASPM is confirmed as a major causative gene for MCPH in the Pakistani population.
• These findings contribute to the genetic diagnosis and understanding of MCPH.