Congenital diaphragmatic hernia in siblings with PIGA‐related congenital disorder of glycosylation

Abstract There are over 150 proteins involved in glycosylphosphatidylinositol (GPI)‐anchored protein biosynthesis, a class within the larger category of congenital disorders of glycosylation (CDG). Pathogenic variants identified in phosphatidylinositol glycan class A protein (PIGA) are associated with X‐linked PIGA‐CDG, a GPI‐anchor defect. The disease has primarily been characterized by hypotonia, epilepsy, and global developmental delay; however, only 89 known cases are reported, so the phenotypic spectrum has likely not yet been fully delineated. Congenital diaphragmatic hernia (CDH) has been reported in patients with various GPI‐anchor related defects but has only been described in one prior individual with PIGA‐CDG. Here, we describe the second and third reported cases of CDH in two brothers with PIGA‐CDG caused by a pathogenic missense variant in PIGA : c.355C > T, p.R119W. Chromosomal microarray and whole exome sequencing did not reveal another plausible explanation for the CDH. We relate our patients' clinical features to the single previously reported individual with CDH and PIGA‐CDG. We then compare this case series with the subset of individuals with CDH and other GPI‐anchor defects. These findings suggest that CDH should be considered in the phenotypic disease spectrum of PIGA‐CDG.