Doublecortin domain containing protein 2 (DCDC2) genetic variants in primary sclerosing cholangitis

To the Editor

We read with great interest the study by T. Grammatikopoulos et al. that reported an association between neonatal sclerosing cholangitis (NSC) and loss of function mutations in doublecortin domain containing protein 2 (DCDC2).¹ On electron microscopy, the cholangiocytes of these patients lacked primary cilia.

While primary sclerosing cholangitis (PSC) is a different entity than NSC, pathologic similarities, including cilia abnormalities observed in PSC,² suggest that some of the underlying pathogenic mechanisms could be shared between the two diseases. Thus, we were interested to determine whether potentially damaging genetic variants of DCDC2 ([ENST00000378454]) might also play a role in PSC. To this end, we examined available whole exome sequencing data for 67 PSC patients, 30 of whom were diagnosed in childhood (<18 years of age) and 37 as adults (>18 years of age). The median age of PSC diagnosis was 14 years (range 5–17) and 46 years (range 26–69) in these groups, respectively. DCDC2 was covered well in our sequencing data, with read-depth averaging 80–100x across the gene. Following quality control steps and removing extremely common variants (minor allele frequency >0.2) and those located outside of the protein-coding sequence, we identified three missense variants (c.1368A>T_p. Lys456Asn, c.661A>G_p.Ser221Gly, c.454C>G_p.Pro152Ala) among the 67 patients. Importantly, none of these variants were predicted to have a severe impact on the protein and there was no evidence of compound heterozygosity of the missense variants.

To conclude, germ-line genetic variants of DCDC2 do not feature prominently among patients with PSC, consistent with recent genome-wide association studies³ and lack of severe biliary disease in the heterozygous carriers of the NSC-causative DCDC2 alleles. However, a potential role for severe (but not complete) DCDC2 haploinsufficiency, due possibly to unobserved protein-damaging or expression-altering alleles, cannot be dismissed by our present study. Further efforts to establish whether cilia defects in PSC occur prior to disease onset, or are instead the result of cholestasis, will be informative for targeted, mechanism-based genetic inquiry in the evolving era of individualized medicine.