Biallelic PIGM Coding Variant Causes Intractable Epilepsy and Intellectual Disability Without Thrombotic Events.

Area of Science:

• Genetics
• Neuroscience
• Biochemistry

Background:

• Glycosylphosphatidylinositol (GPI) anchor biosynthesis genes are increasingly linked to early-infantile epileptic encephalopathy.
• A previously identified PIGM promoter mutation caused intractable absence epilepsy, intellectual disability (ID), and thrombotic events.

Purpose of the Study:

• To investigate a novel PIGM gene variant in siblings with intractable epilepsy and ID.
• To characterize the clinical and genetic differences between this novel variant and previously reported PIGM mutations.

Main Methods:

• Genetic sequencing to identify variants in the PIGM gene.
• Segregation analysis within the family.
• Structural modeling of the PIGM protein.
• Functional prediction of the identified variant.

Main Results:

• Three siblings presented with intractable epilepsy and ID, harboring a homozygous c.224G>A p.(Arg75His) missense variant in PIGM.
• The p.(Arg75His) variant is evolutionary conserved, rare, and predicted to be deleterious, located in a sensitive region of the PIGM protein.
• The phenotype associated with this coding variant differs from the PIGM promoter mutation, specifically lacking thrombotic events and alterations in PIGM cDNA levels or CD59 expression.

Conclusions:

• The homozygous p.(Arg75His) missense variant in PIGM is associated with a distinct phenotype of intractable epilepsy and ID.
• This finding expands the spectrum of PIGM-related disorders and highlights the importance of coding variants in GPI anchor biosynthesis defects.
• The absence of thrombotic events differentiates this coding variant from the previously described PIGM promoter mutation.