TTC21B – Nephronophthisis 12

Nephronophthisis 12 (NPHP12) is a rare autosomal recessive ciliopathy characterized by cystic kidney disease, interstitial fibrosis, and progressive renal failure. The TTC21B gene (encoding IFT139) is essential for retrograde intraflagellar transport and ciliary function. Pathogenic variants in TTC21B disrupt ciliary signaling in tubular epithelial cells, leading to the NPHP12 phenotype. Comprehensive evaluation of multiple case reports and functional assays has established the clinical validity of this gene–disease relationship.

Adult-onset NPHP12 was first reported in a 33-year-old man presenting with chronic interstitial nephritis, stage 3 CKD, and renal tubular proteinuria, without extrarenal features. Genetic testing revealed a heterozygous nonsense mutation in TTC21B, expanding the age and allelic spectrum of NPHP12 (PMID:36263627). Renal histology demonstrated tubulointerstitial fibrosis with irregular and tortuous tubules, confirming the diagnosis.

A premature infant with early-onset NPHP12 exhibited cystic kidney disease, skeletal malformations, liver fibrosis, and retinopathy. Trio whole-exome sequencing identified compound heterozygous TTC21B variants, c.497delA (p.Lys166SerfsTer36) and c.1552T>C (p.Cys518Arg), each inherited from an unaffected parent, confirming autosomal recessive inheritance and variant pathogenicity (PMID:38439578). Molecular dynamics modelling showed that p.Cys518Arg destabilizes the IFT121–IFT122–IFT139–IFT43 complex, correlating with early ESRD onset.

An adult with NPHP12-associated retinopathy carried compound heterozygous TTC21B variants, c.626C>T (p.Pro209Leu) and c.1317G>A (p.Tyr439Ter), presenting with bull’s-eye maculopathy, profound scotomas, and reduced contrast sensitivity under mesopic conditions. This is the third reported NPHP12 case with retinal involvement, underscoring extrarenal manifestations of TTC21B deficiency (PMID:39602043).

Across all reports, the variant spectrum in TTC21B includes loss-of-function alleles (nonsense, frameshift, splice) and recessively acting missense changes. The recurrent p.Cys518Arg variant represents a founder allele in Chinese cohorts. No unaffected homozygotes have been described, and carrier frequency remains low in population databases.

Functional studies reinforce the pathogenic mechanism of TTC21B in ciliopathy. In vivo zebrafish knockdown of ttc21b reproduces renal and skeletal phenotypes, while saturated resequencing and in vitro assays demonstrate enrichment of deleterious alleles in ciliopathy cases (P < 0.003) (PMID:21258341). These data confirm loss-of-function and dominant-negative effects as key drivers of NPHP12.

Taken together, multiple unrelated probands with biallelic TTC21B variants, segregation data in two families, and concordant functional evidence support a Moderate ClinGen clinical validity classification for the TTC21B–NPHP12 association. Genetic testing for TTC21B should be recommended in patients with unexplained interstitial nephritis, cystic kidney disease, or NPHP-like retinal changes, to enable accurate diagnosis and avoid unnecessary interventions.

References

• Molecular genetics & genomic medicine • 2022 • A single heterozygous nonsense mutation in the TTC21B gene causes adult-onset nephronophthisis 12: A case report and review of literature. PMID:36263627
• Molecular genetics & genomic medicine • 2024 • Clinical report and genetic analysis of rare premature infant nephronophthisis caused by biallelic TTC21B variants. PMID:38439578
• Documenta ophthalmologica. Advances in ophthalmology • 2024 • Case report of visual quality in a patient with nephronophthisis 12- associated retinopathy secondary to TTC21B mutation. PMID:39602043
• Nature genetics • 2011 • TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. PMID:21258341

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