Mutations in DCDC2 (doublecortin domain containing protein 2) in neonatal sclerosing cholangitis

Abstract

Background & Aims Neonatal sclerosing cholangitis (NSC) is a severe neonatal-onset cholangiopathy commonly leading to liver transplantation (LT) for end-stage liver disease in childhood. Liver-biopsy findings histopathologically resemble those in biliary atresia (BA); however, in NSC extrahepatic bile ducts are patent, whilst in BA their lumina are obliterated. NSC is commonly seen in consanguineous kindreds, suggesting autosomal recessive inheritance. Methods From 29 NSC patients (24 families) identified, DNA was available in 24 (21 families). Thirteen (7 male) patients (12 families) of consanguineous parentage were selected for whole exome sequencing. Sequence variants were filtered for homozygosity, pathogenicity, minor allele frequency, quality score, and encoded-protein expression pattern. Results Four of 13 patients were homozygous and two were compound heterozygous for mutations in DCDC2, encoding doublecortin domain containing 2 (DCDC2), expressed in cholangiocyte cilia. Another 11 patients were sequenced: one (with one sibling pair) was compound heterozygous for DCDC2 mutations. All mutations were protein-truncating. In available liver tissue from patients with DCDC2 mutations, immunostaining for human DCDC2 and the ciliary protein acetylated alpha-tubulin (ACALT) showed no expression (n=6) and transmission electron microscopy found that cholangiocytes lacked primary cilia (n=5). DCDC2 and ACALT were expressed in NSC patients without DCDC2 mutations (n=22). Of the DCDC2, one patient died awaiting LT; five came to LT, of whom one died 2 years later. The other 4 are well. Conclusion Among 24 NSC patients with available DNA, 7 had mutations in DCDC2 (6 of 19 families). NSC patients in substantial proportion harbour mutations in DCDC2. Their disease represents a novel liver-based ciliopathy.

Intrahepatic bile duct primary cilia in biliary atresia

“…26 Interestingly, NSC patients lacking DCDC2 protein showed a total absence of BEC cilia by both optic microscopy and transmission electron microscopy, where the presence of BEC cilia was shown in the remaining NSC patients, ruling out the possibility that cilia abnormalities were induced by severe jaundice and/or inflammation. 26 The results are clearly indicative of the existence of genetic heterogeneity at the base of one clinical pathological disorder with no genotype-phenotype correlation. The same might be speculated to be true for isolated BA.…”

“…The genetic deficiency of doublecortin domain‐containing protein 2 (DCDC2), a BEC cilia‐associated protein, has been recently found in a subgroup of patients affected by neonatal sclerosing cholangitis (NSC), a rare progressive cholangiopathy of infancy that might resemble BA in terms of severe intrahepatic biliary tract inflammation and fibrosis requiring liver transplantation early in life . Interestingly, NSC patients lacking DCDC2 protein showed a total absence of BEC cilia by both optic microscopy and transmission electron microscopy, where the presence of BEC cilia was shown in the remaining NSC patients, ruling out the possibility that cilia abnormalities were induced by severe jaundice and/or inflammation . The results are clearly indicative of the existence of genetic heterogeneity at the base of one clinical pathological disorder with no genotype–phenotype correlation.…”

Recessive Mutations in KIF12 Cause High Gamma‐Glutamyltransferase Cholestasis

“…Of note, recessive mutations in doublecortin domain containing protein 2 encoded by DCDC2 , a microtubule‐associated protein, are known to cause neonatal sclerosing cholangitis (which presents with high GGT) . Other well‐characterized genetic disorders presenting with high GGT cholestasis in children comprise MDR3 deficiency and Alagille syndrome.…”

“…Undiagnosed liver disease remains an unmet medical need in pediatric and adult hepatology, including cholestasis of unknown etiology. We and others have shown the utility of unbiased whole‐exome sequencing (WES) in diagnosing patients with atypical presentations of known liver disorders as well as in identifying novel Mendelian forms of liver diseases. Identification of underlying genetic defects provides new insight into the role of specific genes in the maintenance of normal liver function as well as disease pathogenesis; this finding also identifies potential new therapeutic options for affected patients.…”

Nephronophthisis due to a novel DCDC2 variant in a patient from African‐Caribbean descent: A case report

“…This syndrome has only previously been identified in two patients; an adolescent male from the UK who had a homozygous variant with a history of parental consanguinity and a male of Czech origin who had two compound heterozygous variants (a frameshift mutation and a splice site mutation) without parental consanguinity (Schueler et al, ). Other variants in the DCDC2 gene have also been associated with dyslexia (Meng et al, , ) and two other disorders: Neonatal Sclerosing Cholangitis (MIM #617394) (Girard et al, ; Grammatikopoulos et al, ) and Autosomal Recessive Deafness 66 (MIM #610212) (Grati et al, ). Here, we report the third ever published case of NPHP19, due to a novel variant in DCDC2 , and the first case in a patient of African‐Caribbean decent.…”