PIGN encodes a glycosylphosphatidylinositol (GPI) anchor protein important in biosynthesis and remodeling pathways. Biallelic variants in PIGN were first reported in connection with autosomal recessive multiple congenital anomalies-hypotonia-seizures syndrome 1 in 2011 (Maydan et. al., PMID: 21493957). This syndrome is characterized by hypotonia, seizures, facial dysmorphisms, developmental delays, brain abnormalities, and cardiac defects. Most reported variants are predicted or confirmed to cause a decrease in PIGN expression. Biallelic variants in PIGN were also reported in connection to Fryns syndrome, a distinct syndrome characterized by diaphragmatic hernia, dysmorphism, distal digital hypoplasia and brain malformations, in 2016 (McInerney-Leo et al., PMID: 27038415). While neonatal lethality is the most common outcome of this disorder, intellectual disability is present for those patients who survive infancy. Variants identified in individuals with the Fryns phenotype are primarily biallelic splice site and premature termination variants, all predicted to result in complete loss of function. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern. Phenotypic variability appears to depend on the degree of PIGN residual activity rather than a distinct molecular mechanism. Therefore, these conditions have been lumped into one disease entity, multiple congenital anomalies-hypotonia-seizures syndrome 1.
Ten variants (three splice site, six missense, and one nonsense), reported in 13 individuals in six publications, are included in this curation (PMIDs: 21493957, 24253414, 24852103, 25920937, 26364997, 29096607). Additional cases are reported in the literature (PMIDs: 26394714, 32220244) but the maximum genetic evidence score (12 points) has been reached. The disease mechanism is believed to be biallelic loss of function. Most included variants are supported by functional evidence demonstrating significant decreases in PIGN expression and/or GPI-anchored proteins CD16, CD18, CD24, and CD59.
In summary, there is definitive evidence to support the relationship between PIGN and multiple congenital anomalies-hypotonia-seizures syndrome 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 28, 2022 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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