Multiple congenital anomalies-hypotonia-seizures syndrome type 1 (MCAHS1) is a rare autosomal recessive genetic disease belonging to glycosylphosphatidylinositols biosynthesis defects (GPIBD), a group of recessive disorders characterized by intellectual disability, hypotonia, and seizures. Glycosylphosphatidylinositols (GPIs) are glycolipids that anchor and remodel cell proteins. These processes are highly conserved and fundamental in the metabolism of all eukaryotes, including humans. Here, we have reported a male patient presenting with hypotonia, intellectual disability, and epilepsy, who underwent whole exome sequencing (WES). The analysis revealed the presence of two deleterious variants in PIGN that encodes GPI ethanolamine phosphate transferase-1 - one novel (c.1247_1251delAAGTG; p.Glu416Glyfs*22), and one that has been previously reported in the medical literature (c.1434+5G>A) resulting in MCAHS1. The detailed clinical assessment followed by the medical literature review also pointed out transient macrosomia and unreported in MCAHS1 advanced bone age and postnatal tall stature. These symptoms suggest that MCAHS1 shares a phenotypic overlap with disorders associated with overgrowth. To conclude, our case report and summary of the medical literature may be helpful for clinicians and geneticists who diagnose patients presenting with hypotonia accompanied by tall stature, advanced bone age, and transient macrosomia.

Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported.
Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp).
Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period.
We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered.

BACKGROUND: Multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1) associated with mutations in PIGN gene.
METHODS: The authors report 1 case of a 16 years old girl who was presented with epilepsy, developmental delay and cerebellar atrophy. She harbors a compound heterozygous variant in the PIGN gene, include a nonsense splice site mutation (c.2557A>C) which was inherited from her mother, and a novel site mutation (c.980del) which was inherited from her father.
CONCLUSIONS: This case report expands the mutation spectrum found in PIGN gene, and strengthens the association between PIGN mutation and MCAHS1. Mutations in PIGN gene may be an underestimated cause of epilepsy. The authors recommend that, for patients with epilepsy or prenatal diagnosis of highly suspicious fetus, gene sequencing should be the preferred detection method.

Mutations in the PIGN gene involved in the glycosylphoshatidylinositol (GPI) anchor biosynthesis pathway cause Multiple Congenital Anomalies-Hypotonia-Seizures syndrome 1 (MCAHS1). The syndrome manifests developmental delay, hypotonia, and epilepsy, combined with multiple congenital anomalies. We report on the identification of a homozygous novel c.755A>T (p.D252V) deleterious mutation in a patient with Israeli-Arab origin with MCAHS1. The mutated PIGN caused a significant decrease of the overall GPI-anchored proteins and CD24 expression. Our results, strongly support previously published data, that partial depletion of GPI-anchored proteins is sufficient to cause severe phenotypic expression.