Refining the phenotype associated with CASC5 mutation.

Area of Science:

• Genetics and Molecular Biology
• Neurodevelopmental Disorders
• Human Population Genetics

Background:

• Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder defined by a significantly reduced head circumference at birth.
• MCPH is associated with intellectual disability and minimal neurological deficits, with no brain structural abnormalities.
• Twelve genetic loci (MCPH1-12) have been identified, with most genes encoding centrosomal proteins crucial for cell division and development.

Observation:

• A homozygous missense mutation in the CASC5 gene (c.6125G>A; p.Met2041Ile) was identified in an Algerian family using whole exome sequencing.
• This specific mutation was previously reported in three unrelated Moroccan families with MCPH.
• Patients presented with consistent clinical features: congenital microcephaly, cognitive impairment, short stature, and specific dysmorphic traits.

Findings:

• The Algerian family's patients exhibited similar phenotypes to the Moroccan cohort, including severe microcephaly (-3 to -4 SD), moderate to severe cognitive impairment, and short stature.
• Dysmorphic features included a sloping forehead, thick eyebrows, synophris, and a low columella. One patient showed vermis hypoplasia and a posterior fossa cyst.
• Microsatellite marker analysis revealed identical alleles between the Algerian and Moroccan patients, strongly supporting a shared founder effect for the CASC5 mutation.

Implications:

• This study confirms CASC5 as a key gene involved in autosomal recessive primary microcephaly.
• The findings support a founder effect for the c.6125G>A CASC5 mutation, indicating its prevalence in specific populations.
• The report refines the clinical phenotype associated with CASC5 mutations, aiding in the diagnosis and understanding of this microcephaly subtype.