Fryns syndrome is an autosomal recessive condition characterized by congenital diaphragmatic hernia (CDH), dysmorphic facial features, distal digital hypoplasia, and other associated malformations, and is the most common syndromic form of CDH. No gene has been associated with this condition. Whole-exome sequence data from two siblings and three unrelated individuals with Fryns syndrome were filtered for rare, good quality, coding mutations fitting a recessive inheritance model. Compound heterozygous mutations inPIGNwere identified in the siblings, with appropriate parental segregation: a novel STOP mutation (c.1966C>T: p.Glu656X) and a rare (minor allele frequency <0.001) donor splice site mutation (c.1674+1G>C) causing skipping of exon 18 and utilization of a cryptic acceptor site in exon 19. A further novel homozygous STOP mutation inPIGN(c.694A>T: p.Lys232X) was detected in one unrelated case. All three variants affected highly conserved bases. The two remaining cases were negative forPIGNmutations. Mutations inPIGNhave been reported in cases with multiple congenital anomalies, including one case with syndromic CDH. Fryns syndrome can be caused by recessive mutations inPIGN. WhetherPIGNaffects other syndromic and non-syndromic forms of CDH warrants investigation.
We identified mutations inPIGNin two siblings and one unrelated individual diagnosed with Fryns syndrome. Mutations inPIGNhave been previously shown to cause multiple congenital anomalies syndrome and a single case of syndromic diaphragmatic hernia was also reported. There is no apparent correlation between the location of the mutations and diagnosis but our review suggests that mutation type may play a role where two protein-truncating alleles are associated with the more severe phenotype of Fryns syndrome/syndromic diaphragmatic hernia.