PIGC-related encephalopathy: Lessons learned from 18 new probands

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Biochemistry

Background:

• PIGC gene is crucial for glycophosphatidylinositol-anchored protein (GPI-AP) biosynthesis.
• Previous reports linked biallelic PIGC variants to developmental delay, intellectual disability, and seizures.

Purpose of the Study:

• To characterize the clinical and biomolecular features of PIGC pathogenic variants.
• To expand the understanding of PIGC-related neurodevelopmental disorders.

Main Methods:

• Established a cohort of 18 unreported probands with PIGC variants.
• Collected clinical data and identified variants via genome/exome sequencing.
• Utilized in silico modeling (AlphaFold2) and flow cytometry for GPI-AP analysis.

Main Results:

• Identified severe neurodevelopmental disorder in probands, including cognitive impairment, treatment-resistant seizures, and premature death in 10/18 individuals.
• Observed brain imaging abnormalities, hypotonia, and skeletal anomalies in affected individuals.
• Confirmed reduced cell-surface GPI-AP levels in proband samples and cellular models.

Conclusions:

• Biallelic PIGC variants are associated with refractory seizures, severe developmental impairments, and childhood mortality.
• Dysfunctional PIGC leads to defective GPI-AP biosynthesis.
• This study expands the phenotypic spectrum and molecular understanding of PIGC-related disorders.