Functional analysis of a novel intronic variant of MCPH1 with autosomal recessive primary microcephaly

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Reproductive Biology

Background:

• Primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by reduced brain size and intellectual disability.
• MCPH is often linked to mutations in the MCPH1 gene, which plays a crucial role in brain development.
• Genetic variations in MCPH1 contribute to the spectrum of MCPH phenotypes.

Purpose of the Study:

• To identify the genetic cause of autosomal recessive primary microcephaly in a patient with azoospermia.
• To characterize a novel mutation in the MCPH1 gene and its functional impact.
• To contribute to the understanding of MCPH genetics and potential therapeutic targets.

Main Methods:

• Whole-exome sequencing (WES) and Sanger sequencing were used to identify and confirm the genetic mutation.
• Magnetic Resonance Imaging (MRI) assessed head circumference, and the Wechsler Intelligence Scale evaluated cognitive function.
• B-ultrasound and semen analysis were performed to assess reproductive status. Minigene assays verified the splicing defect.

Main Results:

• A novel splice-site homozygous mutation (c.233+2T>G) in the MCPH1 gene was identified in the proband and inherited from parents.
• The mutation was confirmed to affect MCPH1 gene splicing.
• The proband presented with primary microcephaly and azoospermia.

Conclusions:

• The novel MCPH1 mutation is associated with autosomal recessive primary microcephaly and male infertility.
• This finding expands the known mutation spectrum of the MCPH1 gene.
• The identified mutation provides insights for the diagnosis and potential gene therapy of MCPH.