TTC26 – Biliary, Renal, Neurologic, and Skeletal (BRENS) Syndrome

Biallelic variants in TTC26 are associated with biliary, renal, neurologic, and skeletal syndrome (BRENS syndrome), a rare autosomal recessive ciliopathy characterized by hexadactyly, neonatal cholestasis, and multi-organ involvement. Two unrelated patients have been reported: one with a homozygous intronic splice acceptor variant c.1006-5>C affecting canonical splicing (PMID:38135897), and a Chinese case with compound heterozygous variants c.511>G (p.Ile171Val) and c.1099>C (p.Ser367Pro) plus a maternal c.1069+?>A intronic change (PMID:39514123). Both individuals exhibited nephropathy (HP:0000112), hepatopathy (HP:0001392), congenital heart defects (HP:0001627), hypopituitarism (HP:0040075) and additional features such as facial clefts or hexadactyly. No segregation in additional relatives has been described, supporting an autosomal recessive inheritance model.

Functional studies corroborate a loss-of-function mechanism: the hop-sterile mouse mutant in Ttc26 displays polydactyly, hydrocephalus, and impaired Hedgehog signalling due to defective Gli–Sufu dissociation (PMID:25340710), while zebrafish crispants for ttc26 recapitulate ciliary transition zone defects analogous to the human phenotype (PMID:36533556). These in vivo models provide moderate experimental support. In summary, TTC26 meets criteria for a Limited clinical validity classification with Moderate functional evidence. Key Take-home: TTC26 genetic testing enables definitive diagnosis of ultra-rare BRENS syndrome, guiding clinical management and genetic counseling.

References

• American journal of medical genetics. Part A • 2024 • A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip-palate cleft: A case report and expansion of the phenotype. PMID:38135897
• Pediatric nephrology • 2025 • Biliary, Renal, Neurological, and Skeletal syndrome in a Chinese boy. PMID:39514123
• PLoS genetics • 2014 • A mutation in the mouse ttc26 gene leads to impaired hedgehog signaling. PMID:25340710
• Disease models & mechanisms • 2022 • Variable phenotypes and penetrance between and within different zebrafish ciliary transition zone mutants. PMID:36533556

Evidence Based Scoring (AI generated)