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Phosphatidylinositol-glycan biosynthesis class T (PIGT) encodes a subunit of the GPI transamidase complex required for anchoring proteins to the cell membrane. Biallelic pathogenic variants in PIGT cause multiple congenital anomalies-hypotonia-seizures syndrome 3 (MCAHS3), an autosomal recessive disorder characterized by severe global developmental delay, hypotonia, seizures, and multi-system malformations. The autosomal recessive inheritance pattern is confirmed by compound heterozygous or homozygous variants segregating in sibships and consanguineous families across multiple studies, and functional assays consistently demonstrate loss of GPI-anchored proteins on patient cells.
Initial case reports described two non-consanguineous siblings presenting with early-onset hypotonia, intractable seizures, and developmental delay; exome sequencing revealed compound heterozygous PIGT variants c.918dup (p.Val307ArgfsTer13) and c.1342C>T (p.Arg448Trp) in both children (PMID:25943031). Flow cytometry confirmed decreased surface expression of GPI-anchored proteins on granulocytes, corroborating pathogenicity. Segregation analysis within this family and others supports autosomal recessive transmission with multiple affected sibs.
A multi-center series of 13 patients from eight unrelated families further defined the phenotypic and allelic spectrum of PIGT-CDG. All individuals harbored homozygous or compound heterozygous PIGT variants, including six loss-of-function and missense alleles, and uniformly exhibited hypotonia, developmental delay, and epilepsy (PMID:30976099). A broader review has now documented approximately 50 affected individuals from >9 families worldwide, establishing robust genetic evidence for this gene-disease relationship.
Genotype-phenotype analysis reveals recurrent and founder missense variants associated with a milder epilepsy phenotype. The c.1582G>A (p.Val528Met) and c.1580A>G (p.Asn527Ser) alleles, particularly prevalent in Polish cohorts, correlate with later-onset seizures and better therapeutic response, whereas other variants result in severe neonatal encephalopathy (PMID:32725661; PMID:36970549).
Functional studies across multiple models reinforce the loss-of-function mechanism. Flow cytometry of patient granulocytes consistently shows reduced GPI-anchored protein levels, and zebrafish morpholino knockdown of pigt fails to rescue gastrulation defects with mutant PIGT mRNA (p.Thr183Pro) (PMID:23636107). Cellular rescue assays in PIGT-deficient lines demonstrate partial restoration of GPI-anchored proteins by wild-type but not mutant constructs, confirming pathogenicity of key alleles (e.g., p.Arg448Trp) (PMID:24906948).
No conflicting evidence has been reported. The cumulative genetic and experimental data, encompassing over 45 unique variants and multiple functional assays, support a strong gene-disease association. Comprehensive phenotyping and flow cytometric screening should be integrated into diagnostic workflows for early-onset hypotonia and seizure syndromes.
Key Take-home: Biallelic PIGT variants cause MCAHS3 via a loss-of-function mechanism, and targeted genetic and functional testing enables accurate diagnosis and informs prognosis based on genotype.
Gene–Disease AssociationStrong~50 probands from >9 unrelated families with autosomal recessive segregation and consistent functional data Genetic EvidenceStrongOver 45 unique PIGT variants identified in ~50 AR cases including loss-of-function and missense alleles Functional EvidenceModerateFlow cytometry, zebrafish knockdown, and cellular rescue models confirm loss-of-function mechanism |