Developmental and Epileptic Encephalopathy due to Biallelic Pathogenic Variants in PIGM

Area of Science:

• Genetics
• Biochemistry
• Neurology

Background:

• The PIGM gene is crucial for glycosylphosphatidylinositol (GPI)-anchor biosynthesis.
• While promoter mutations cause mild symptoms, coding mutations in PIGM are linked to severe multisystemic disorders.

Purpose of the Study:

• To investigate the role of PIGM coding variants in early-onset developmental and epileptic encephalopathy.
• To expand the understanding of the genotype-phenotype spectrum associated with PIGM deficiency.

Main Methods:

• Whole-exome sequencing reanalysis and patient matchmaking.
• Functional assays to assess variant pathogenicity.
• Review of previously reported PIGM variant cases.

Main Results:

• Identified two patients with a homozygous PIGM missense variant (c.1001A>C, p.Gln334Pro) presenting with severe early-onset developmental and epileptic encephalopathy, neurodevelopmental impairment, multi-organ involvement, and hypomyelination.
• Both patients experienced fatal super-refractory status epilepticus in infancy.
• Functional studies showed partial GPI-anchor deficiency, and a genotype-phenotype correlation suggested increased disease severity with coding region variants.

Conclusions:

• PIGM is confirmed as a causative gene for early-onset developmental and epileptic encephalopathy.
• The clinical spectrum of PIGM deficiency now includes hypomyelination and prenatal onset.
• PIGM deficiency should be considered in the differential diagnosis of developmental and epileptic encephalopathy and leukoencephalopathies, offering insights into GPI-anchor disorder variability.