PDCD6IP, encoding a regulator of the ESCRT complex, is mutated in microcephaly.

Area of Science:

• Genetics
• Neurodevelopmental Biology
• Molecular Biology

Background:

• Primary microcephaly (PM) is a complex neurodevelopmental disorder with diverse genetic etiologies.
• Identifying novel risk genes is crucial for understanding PM pathogenesis and improving diagnosis.

Purpose of the Study:

• To investigate the genetic basis of PM in a consanguineous family presenting with PM, intellectual disability, and short stature.
• To identify the specific gene mutation responsible for the observed neurodevelopmental phenotype.

Main Methods:

• Whole exome sequencing (WES) was performed on affected individuals from a consanguineous family.
• Segregation analysis of the identified variant was conducted within the family.
• Literature review and comparison with existing animal models.

Main Results:

• A homozygous frameshift variant (c.154_158dup; p.Val54Profs*18) in the programmed cell death 6 interacting protein (PDCD6IP) gene was identified.
• The identified PDCD6IP variant segregated with the phenotype in the family.
• The patient's clinical features, including PM and intellectual disability, align with phenotypes observed in PDCD6IP-deficient mouse and zebrafish models.

Conclusions:

• Mutations in PDCD6IP represent a novel genetic cause of primary microcephaly and intellectual disability in humans.
• PDCD6IP's role in the ESCRT pathway and cytokinesis is critical for normal human brain development.
• This finding expands the spectrum of neurodevelopmental disorders associated with PDCD6IP dysfunction.