Recessive <i>PIGN</i> Mutations in Fryns Syndrome: Evidence for Genetic Heterogeneity

Fryns syndrome (MIM# 229850) is an autosomal recessive multiple congenital anomaly syndrome that is usually lethal in the neonatal period. It is characterized by diaphragmatic defects, a characteristic facial appearance, distal digital hypoplasia, multiple congenital abnormalities, severe intellectual disability and developmental delay. In this issue, the advances in molecular diagnosis described by McInerney et al. (Hum Mutat 37: 695–702, 2016) represent real progress in the delineation of the molecular etiologies underlying this devastating disorder. The authors present three cases from two unrelated families affected by Fryns syndrome. The patients were found to have pathogenic variants in the phosphatidyl inositol glycan biosynthesis, type N (PIGN) gene. The enzyme catalyzes addition of ethanolamine to the first mannose residue of the glycan moiety, the seventh step in the glycosylphosphatidylinositol (GPI) plasma membrane anchor biosynthesis pathway. Although PIGN mutations have been associated previously with multiple congenital anomalies-hypotonia syndrome (MCAHS1; MIM# 614080), the authors present strong evidence that the mutations they identified in Fryns syndrome are more severe. Like the work of Krawitz et al. (Nat Genet. 42:827-829, 2010) that identified the first mutations in Mabry syndrome (MIM# 239300; hyperphosphatasia with neurologic deficit and seizures), the present work is based on advances made possible by exome sequencing. Through exome data analysis, the authors ruled out pathogenic coding variants in other known GPI-pathway genes. Since two patients in this cohort did not show coding mutations in PIGN, the authors consider this evidence that Fryns syndrome is genetically heterogeneous. Studies of similar disorders (e.g., Mabry syndrome; Knaus et al., Hum Mutat 37; 2016; DOI: 10.1002/humu.23006), indicate that GPI-anchor deficiencies can be linked to non-coding mutations in the genes of the GPI-biosynthetic pathway. McInerney's study of Fryns syndrome is significant not only because it adds to the catalogue of GPI biosynthesis pathway genes that are disrupted in a wide variety of human disorders (Cole et al., Subcell Biochem. 76:343-361, 2015), but because it opens the way for further study of coding and non-coding variants that disrupt this pathway. The steady rise in the number of phenotypes associated with mutations in the GPI pathway suggests that expansion of genotype-phenotype correlations related to GPI pathobiology has not yet plateaued.

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