PIGN – Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 1

Multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1) is an autosomal recessive neurodevelopmental disorder caused by biallelic pathogenic variants in PIGN, which encodes GPI ethanolamine phosphate transferase-1 involved in glycosylphosphatidylinositol (GPI) anchor biosynthesis. Affected individuals present with severe hypotonia, global developmental delay, epilepsy, and a spectrum of congenital anomalies including supernumerary nipples and pectus excavatum (PMID:25920937).

Genetic studies across multiple populations have identified homozygous and compound heterozygous PIGN variants in 61 probands from over 20 unrelated families, confirming autosomal recessive inheritance. Segregation analysis in familial cases and trios demonstrated co-segregation of PIGN variants with disease phenotypes and absence in healthy parents, consistent with loss-of-function alleles (PMID:36322149).

The variant spectrum includes missense changes (e.g., c.406T>G (p.Trp136Gly)), splice-site mutations, small indels causing frameshifts, and nonsense variants. Truncating alleles account for 16 cases, while 45 cases carry missense or mixed genotypes, illustrating both complete and partial loss-of-function mechanisms in MCAHS1 (PMID:36322149).

Clinically, MCAHS1 manifests with profound hypotonia (HP:0001252), early-onset seizures (HP:0001250), and global developmental delay (HP:0001263), often accompanied by dysmorphic features such as supernumerary nipples and pectus excavatum. Advanced bone age and postnatal tall stature have also been reported, expanding the phenotypic overlap with overgrowth syndromes (PMID:36384198).

Functional assays in patient fibroblasts and cellular models demonstrate a significant reduction in GPI-anchored proteins (CD59, CD16, CD24) and impaired PIGN enzymatic activity, confirming pathogenicity of both missense and truncating variants. Flow cytometry and rescue experiments in HEK293 cells corroborate a loss-of-function mechanism driving the neurological and congenital manifestations (PMID:21493957; PMID:24253414).

No conflicting reports have been published to date; all studies consistently support PIGN loss of function as the basis for MCAHS1. The reproducibility of genetic and functional findings over a decade across diverse cohorts establishes a definitive gene-disease relationship.

Key Take-Home: PIGN sequencing should be prioritized in patients with congenital anomalies, hypotonia, and early-onset seizures, as biallelic loss-of-function variants define a clinically actionable, autosomal recessive MCAHS1 syndrome.

References

• American Journal of Medical Genetics. Part A • 2015 • The phenotype of multiple congenital anomalies-hypotonia-seizures syndrome 1: report and review. PMID:25920937
• Journal of Medical Genetics • 2011 • Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN. PMID:21493957
• Neurogenetics • 2014 • PIGN mutations cause congenital anomalies, developmental delay, hypotonia, epilepsy, and progressive cerebellar atrophy. PMID:24253414
• Genetics in Medicine • 2023 • Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype-phenotype correlation study PMID:36322149

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