PIGQ – Developmental and Epileptic Encephalopathy 77

Biallelic variants in PIGQ, encoding a subunit of the glycosylphosphatidylinositol (GPI) N-acetylglucosaminyltransferase (GPI-GnT) complex, underlie developmental and epileptic encephalopathy 77, also known as multiple congenital anomalies-hypotonia-seizures syndrome 4. GPI anchors are essential for anchoring >150 proteins to the eukaryotic cell surface, and disruption of initial GPI biosynthesis manifests as severe neurodevelopmental disease.

Genetic evidence for PIGQ-DEE77 includes 15 unrelated probands from 13 families with autosomal recessive inheritance. All patients harbor biallelic PIGQ variants: loss-of-function alleles (including the novel frameshift c.1092dupC (p.Phe365LeufsTer78)) and missense changes, such as c.1370T>G (p.Leu457Arg), confirmed pathogenic by functional assays (PMID:40718141).

Clinically, affected individuals present with early-onset intractable seizures, profound hypotonia, global developmental delay, and characteristic facial dysmorphism (coarse features, anteverted nares, open mouth) (HP:0000271). Attacks of rhabdomyolysis triggered by febrile illness have been uniquely documented in recent cases.

Functional studies in Chinese hamster ovarian cells demonstrated that the p.Leu457Arg variant impairs GPI-AP expression, validating its pathogenicity. Additionally, ARV1, another GPI biosynthesis protein, associates directly with PIGQ and enhances GPI-GnT activity; ARV1 mutants unable to bind PIGQ show reduced enzymatic efficiency in vitro (PMID:40378954).

Mechanistically, loss of PIGQ function disrupts the initial step of GPI anchor synthesis, leading to deficient cell surface localization of critical proteins and severe neurodevelopmental impairment. The concordance between genetic findings and functional assays supports a causative role for PIGQ in DEE77.

Gene-disease association is classified as Moderate based on 15 probands across 13 families with consistent biallelic variants and corroborating experimental data. Genetic evidence meets ClinGen Moderate criteria, and functional studies provide additional Moderate support.

Key Take-home: PIGQ should be included in diagnostic gene panels for early-onset epileptic encephalopathy, and functional assays may resolve VUS in this GPI biosynthesis disorder.

References

• Frontiers in genetics • 2025 • Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool. PMID:40718141
• The Journal of biological chemistry • 2025 • ARV1 is a component of the enzyme initiating glycosylphosphatidylinositol biosynthesis. PMID:40378954

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