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

Gali Heimer1,2,3, Ben Pode-Shakked2,3,4, Dina Marek-Yagel2,5

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A novel PIGM gene variant causes intractable epilepsy and intellectual disability in siblings. This genetic mutation differs from previously identified PIGM promoter mutations, notably lacking thrombotic events.

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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.