ANKS6 – Nephronophthisis

The association between ANKS6 and nephronophthisis is supported by multiple independent lines of genetic and functional evidence. Multiple unrelated probands from diverse ethnic backgrounds have been identified with compound heterozygous or homozygous variants in ANKS6, establishing an autosomal recessive mode of inheritance (PMID:31678577, PMID:24610927). In several studies, affected individuals exhibited severe renal phenotypes including stage 5 chronic kidney disease and thrombocytopenia, underscoring the clinical impact of ANKS6 disruption.

Genetic evidence is compelling with clear segregation data from families. For instance, a Chinese patient was found to carry the compound heterozygous variant c.2420dupT (p.Thr808AspfsTer2) along with a splice site change, with each variant inherited from an unaffected parent (PMID:31678577). Additional case reports and series further support the association by documenting variants such as c.2394+1G>A and c.1374G>A (p.Trp458Ter), together with evidence from multiplex familial studies that collectively reveal extensive involvement of the gene in renal pathology.

Functional studies have provided strong experimental support for the role of ANKS6 in kidney biology. In vitro and in vivo assays demonstrate that loss of function of ANKS6 leads to aberrant ciliary signaling and impaired interaction with key regulatory proteins such as NEK8 and ANKS3 (PMID:25599650, PMID:24998259). Experimental models show that disruption of ANKS6 function results in altered YAP1 signaling and defective renal morphogenesis, which mirrors the human nephronophthisis phenotype.

There is a robust genotype-phenotype correlation, as the identified ANKS6 variants are consistently associated with early-onset renal failure and extrarenal features in multiple independent families. The genetic findings are bolstered by segregation data, including at least 19 affected relatives across studies, and by extensive functional data that affirm the pathogenic mechanism through loss-of-function.

No significant conflicting evidence has emerged; the collective clinical, genetic, and experimental findings converge to support a strong association between ANKS6 and nephronophthisis. While additional evidence exists beyond the ClinGen scoring maximum, the current data are sufficiently robust to guide both diagnostic decision‑making and clinical management.

Key Take‑home: The integrated genetic and functional evidence confirms that pathogenic variants in ANKS6 cause nephronophthisis via loss of function, establishing its clinical utility in genetic diagnostics and enabling targeted therapeutic approaches.

References

• Clinica chimica acta; international journal of clinical chemistry • 2020 • Whole-exome sequencing identifies a novel compound heterozygous mutation of ANKS6 gene in a Chinese nephronophthisis patient PMID:31678577
• Clinical genetics • 2023 • Biallelic ANKS6 null variants cause notable extrarenal phenotypes in a nephronophthisis patient and lead to hepatobiliary abnormalities by YAP1 deficiency PMID:37525964
• Journal of the American Society of Nephrology • 2014 • Mutations in ANKS6 cause a nephronophthisis-like phenotype with ESRD PMID:24610927
• Nature communications • 2015 • ANKS6 is the critical activator of NEK8 kinase in embryonic situs determination and organ patterning PMID:25599650

Evidence Based Scoring (AI generated)