Fetal megacystis-microcolon: genetic mutational spectrum and identification of PDCL3 as a novel candidate gene.

Megacystis-microcolon-intestinal-hypoperistalsis syndrome (MMIHS) is a severe congenital visceral myopathy characterized by an abdominal distension due to a large non-obstructed urinary bladder, a microcolon and intestinal hypo- or aperistalsis. Most of the patients described to date carry a sporadic heterozygous variant inACTG2. More recently, recessive forms have been reported and mutations inMYH11,LMOD1,MYLKandMYL9have been described at the molecular level. In the present report, we describe five patients carrying a recurrent heterozygous variant inACTG2. Exome sequencing performed in four families allowed us to identify the genetic cause in three. In two families, we identified variants in MMIHS causal genes, respectively a nonsense homozygous variant inMYH11and a previously described homozygous deletion inMYL9. Finally, we identified compound heterozygous variants in a novel candidate gene,PDCL3, c.[143_144del];[380G>A], p.[(Tyr48Ter)];[(Cys127Tyr)]. After cDNA analysis, a complete absence ofPDLC3expression was observed in affected individuals, indicating that both mutated transcripts were unstable and prone to mediated mRNA decay.PDCL3encodes a protein involved in the folding of actin, a key step in thin filament formation. Presumably, loss-of-function of this protein affects the contractility of smooth muscle tissues, makingPDCL3an excellent candidate gene for autosomal recessive forms of MMIHS.