DCDC2 – Ciliopathy

DCDC2 encodes doublecortin domain–containing protein 2, which localizes to primary cilia and is critical for cholangiocyte and renal epithelial function. Biallelic pathogenic variants in DCDC2 have been implicated in a spectrum of hepatic and renal ciliopathies, most notably neonatal sclerosing cholangitis (NSC), portal fibrosis, and nephronophthisis, establishing DCDC2 as a disease gene for MONDO:0005308. The inheritance is autosomal recessive, with affected individuals harboring two loss-of-function or splice-altering alleles and exhibiting early-onset cholestatic liver disease with variable kidney involvement.

Genetic evidence arises from multiple cohorts. Two unrelated infants with neonatal cholestasis and renal disorders were described with biallelic DCDC2 mutations (PMID:35570614). Another report detailed two independent patients presenting with NSC plus microcephaly, global developmental delay, and axial hypotonia (PMID:34155636). A subsequent Polish series identified six patients from three unrelated families and, including prior cases, recognized 34 individuals with DCDC2-related hepatic ciliopathy (PMID:37296768). Collectively, these 34 probands across at least three families support a robust gene–disease link.

The variant spectrum is dominated by protein-truncating and splice-site alleles, consistent with loss-of-function. Examples include the canonical splice alteration c.426-2A>G and the termination variant c.890T>A (p.Leu297Ter), both abolishing DCDC2 function. Missense changes appear less common, and no recurrent founder alleles have been documented in these cohorts.

Functional studies corroborate the pathogenic mechanism. In NSC patient cholangiocytes, mutant DCDC2 accumulates in the cytoplasm, is absent from cilia, and disrupts ciliogenesis consistent with a loss-of-function mechanism (PMID:27319779). Rescue experiments in zebrafish demonstrate genetic interaction between DCDC2 and other ciliary genes, confirming the role of DCDC2 in cilia assembly and function, and reflecting the hepatic and renal phenotypes observed in humans.

No studies have refuted the DCDC2–ciliopathy association. The available data integrate strong genetic segregation, a consistent autosomal recessive inheritance pattern, and concordant functional assays. Additional reports, including a broader spectrum of nephronophthisis and non-syndromic deafness, exceed the current focus on hepatic ciliopathy but further underscore DCDC2’s pleiotropic role in ciliary biology.

Key take-home: Biallelic loss-of-function variants in DCDC2 cause an autosomal recessive ciliopathy characterized by neonatal sclerosing cholangitis and renal involvement; genetic testing for DCDC2 should be included in the diagnostic evaluation of early-onset cholangiopathies with or without kidney disease.

References

• Experimental and clinical transplantation • 2022 • Two Cases With Neonatal Cholestasis and Renal Disorders Due to DCDC2 Mutation. PMID:35570614
• Clinical genetics • 2021 • Two cases of DCDC2-related neonatal sclerosing cholangitis with developmental delay and literature review. PMID:34155636
• Diagnostics (Basel, Switzerland) • 2023 • DCDC2-Related Ciliopathy: Report of Six Polish Patients, Novel DCDC2 Variant, and Literature Review of Reported Cases. PMID:37296768
• Human mutation • 2016 • DCDC2 Mutations Cause Neonatal Sclerosing Cholangitis. PMID:27319779

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