PDCD6IP, encoding a regulator of the ESCRT complex, is mutated in microcephaly
Amjad Khan1,2,3, Manal Alaamery1, Salam Massadeh1
1Developmental Medicine Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNGHA), Riyadh, Saudi Arabia.
Abstract:
Primary microcephaly (PM) is a highly heterogeneous neurodevelopmental disorder with many contributing risk genes and loci identified to date. We report a consanguineous family with PM, intellectual disability and short stature. Using whole exome sequencing, we identified a homozygous frameshift variant in programmed cell death 6 interacting protein (PDCD6IP, c.154_158dup; p.Val54Profs*18). This gene, PDCD6IP, plays an important role in the endosomal sorting complexes required for transport (ESCRT) pathway in the abscission stage of cytokinesis and apoptosis, and is required for normal brain development in mice. The clinical features observed in our patient were similar to the phenotypes observed in mouse and zebrafish models of PDCD6IP mutations in previous studies. This study provides evidence that clinical manifestations of PDCD6IP mutations as seen in our patients with PM and ID may be a novel cause for neurodevelopmental disorders.
Insights
A novel genetic cause for primary microcephaly (PM) and intellectual disability (ID) was identified. A frameshift variant in the PDCD6IP gene was found in a consanguineous family, linking this gene to neurodevelopmental disorders.
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.
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