A novel splice-site mutation in the ASPM gene underlies autosomal recessive primary microcephaly

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Autosomal recessive primary microcephaly (MCPH) is a heterogeneous disorder characterized by reduced head circumference and intellectual disability.
• ASPM (abnormal spindle-like, microcephaly associated) is the most frequently mutated gene in MCPH.
• Genetic heterogeneity poses challenges in diagnosing MCPH.

Purpose of the Study:

• To identify the specific genetic cause of MCPH in a consanguineous Saudi family.
• To investigate the molecular basis of the disorder within this family.
• To contribute to the understanding of MCPH genetics.

Main Methods:

• Whole exome sequencing was performed on DNA from 10 family members, including two affected individuals.
• Bioinformatic analysis using VariantStudio was employed to filter and prioritize genetic variants.
• In silico tools like Human Splice Finder were used to predict the functional impact of identified variants.

Main Results:

• A novel homozygous splice-site variant (c.3742-1G > C) was identified in the ASPM gene.
• This variant is predicted to cause skipping of exon 16 in the ASPM transcript.
• The identified mutation segregates with the MCPH phenotype in the studied family.

Conclusions:

• The identified ASPM splice-site variant is likely the causative mutation for MCPH in this Saudi family.
• Exon 16 skipping may alter IQ motif structure in the ASPM protein, leading to the observed phenotype.
• Further studies on larger cohorts are needed to confirm these findings and explore genotype-phenotype correlations.