LAUSR

This investigation aimed at characterizing penetrance and interrelation of the loss-of-function phenotypes, Hirschsprung’s disease and kidney malformations, in carriers of exon 10 REarranged during Transfection (RET) mutations. Comparative analysis of penetrance of and interdependencies between Hirschsprung’s disease and kidney malformations among carriers of mutations in RET codons 609, 611, 618, and 620. Hirschsprung’s disease and kidney malformations (kidney agenesis, ureteropelvicalyceal dilatation, or polycystic kidney disease) each affected 3.6% (4 patients) of 112 carriers of RET mutations in exon 10. This percentage increased to 13% (4 patients) and 9% (3 patients) of 32 p.Cys620 carriers and 22% (4 patients) and 17% (3 patients) of 18 p.Cys620Arg carriers, respectively. Overall, Hirschsprung’s disease (17%, 4 of 24 carriers; P = 0.002) and kidney malformations (13%, 3 of 24 carriers; P = 0.030) were associated with arginine-for-cysteine substitutions. Two of the six patients, originating from different p.Cys620Arg families, harbored both Hirschsprung’s disease and kidney malformations. Hirschsprung’s disease and kidney malformations are the more penetrant, the closer the cysteine mutations are located to the transmembrane domain (codon 636–657) of the RET kinase receptor.