PIGN – Fryns Syndrome

Fryns syndrome is a lethal multiple congenital anomaly disorder characterized by congenital diaphragmatic hernia, pulmonary hypoplasia, craniofacial dysmorphism, distal digital hypoplasia, and central nervous system malformations. The condition follows an autosomal recessive inheritance pattern, and pathogenic variants in PIGN, which encodes a glycosylphosphatidylinositol ethanolamine phosphate transferase, have been implicated as a primary genetic cause of Fryns syndrome (MONDO:0009253).

Initial evidence emerged from a study of two siblings and one unrelated individual with Fryns syndrome, in whom compound heterozygous variants c.1966C>T (p.Gln656Ter), c.1674+1G>C, and a homozygous c.694A>T (p.Lys232Ter) were identified and shown to segregate with disease in parents and affected sibs (PMID:27038415).

A follow-up report described six additional probands harboring biallelic loss-of-function alleles, including an intragenic deletion with a founder effect on La Réunion Island, confirming autosomal recessive inheritance and complete penetrance of severe diaphragmatic hernia and pulmonary hypoplasia phenotypes (PMID:29330547).

A large genotype–phenotype study of 61 biallelic PIGN cases (21 novel and 40 previously published) found that 12 individuals met clinical criteria for Fryns syndrome. Patients with biallelic truncating variants exhibited higher rates of prenatal or early neonatal death and diaphragmatic hernia compared to those with missense or mixed genotypes, underscoring a correlation between complete loss of PIGN function and syndrome severity (PMID:36322149).

A recent prenatal case series reported two recurrent affected siblings carrying novel splice-affecting variants c.2619G>A (p.Leu873=) and c.996_1023+2del. RNA sequencing confirmed exon skipping for both alleles, reinforcing the pathogenic mechanism of splice disruption in Fryns syndrome (PMID:38792648).

Functional assays demonstrate markedly reduced surface expression of GPI-anchored proteins in patient fibroblasts and HEK293 models expressing PIGN mutants. Specifically, CD59 levels were decreased ten-fold in vitro (PMID:21493957), and rescue experiments showed failure of mutant constructs (e.g., p.Ser270Pro, p.Glu308GlyfsTer2) to restore GPI-anchor biosynthesis (PMID:24253414). These findings confirm haploinsufficiency of splice and truncating variants as the disease mechanism.

The collective data from case reports, multi-patient cohorts, and functional studies establish a compelling autosomal recessive association between biallelic PIGN variants and Fryns syndrome. The consistency of variant segregation, concordant functional evidence, and phenotype correlation support a Strong clinical validity classification. Key Take-home: PIGN variant analysis, including splice and truncating mutations, is critical for accurate diagnosis and genetic counseling in Fryns syndrome presentations.

References

• Human mutation • 2016 • Fryns Syndrome Associated with Recessive Mutations in PIGN in two Separate Families. PMID:27038415
• European Journal of Human Genetics • 2018 • Recessive loss of function PIGN alleles, including an intragenic deletion with founder effect in La Réunion Island, in patients with Fryns syndrome PMID:29330547
• 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
• Life (Basel, Switzerland) • 2024 • Prenatal Diagnosis of Fryns Syndrome through Identification of Two Novel Splice Variants in the PIGN Gene-A Case Series. PMID:38792648
• 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

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