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ANKFY1 has recently emerged as a candidate gene for a novel neuro‑renal syndrome characterized by steroid‑resistant nephrotic syndrome (SRNS) and movement abnormalities (PMID:38915441). The clinical evidence comprises both isolated case reports and multi‑patient studies that have identified bi‑allelic variants in ANKFY1 in affected individuals, providing a basis for its involvement in renal and neurological phenotypes (PMID:29959197).
In the initial case report, a 13‑year‑old boy was found to harbor compound heterozygous variants in ANKFY1, including the notable variant c.2753C>G (p.Ser918Ter), along with a second variant, which were associated with infantile‑onset proteinuria and an abnormality of movement (PMID:38915441). A subsequent multi‑patient study further supported this association by reporting a homozygous missense variant in two siblings with SRNS, thereby demonstrating consistent familial segregation under an autosomal recessive model.
The inheritance mode in these families is autosomal recessive, and segregation analysis in the studies reveals that additional affected relatives (two siblings in one report) share the pathogenic alleles, reinforcing the genotype‑phenotype link (PMID:29959197). The consistency of the segregation data across independent reports further bolsters the clinical validity of ANKFY1 in this context.
From a genetic standpoint, the variant spectrum relevant to ANKFY1 includes the recurrent variant c.2753C>G (p.Ser918Ter) which is considered a loss‑of‑function allele. The identification of this variant, along with other rare alleles, in unrelated families provides moderate genetic evidence through the observation of compound heterozygosity and homozygosity in affected individuals, underlining its pathogenic role in SRNS with neurological manifestations.
Supporting the genetic data, functional studies have demonstrated reduced protein expression of ANKFY1 in in vitro assays, consistent with a loss‑of‑function mechanism. These experimental findings not only corroborate the genetic data but also offer mechanistic insights into how defective ANKFY1 function could lead to the observed renal and nervous system phenotypes (PMID:38915441).
In conclusion, the converging genetic and functional evidence supports a moderate association between ANKFY1 and the co‑occurrence of steroid‑resistant nephrotic syndrome and movement disorder. This emerging association highlights the potential of ANKFY1 as a diagnostic marker and as a target for further research, ensuring its relevance in both clinical decision‑making and future therapeutic development.
Gene–Disease AssociationModerateEvidence from two independent studies reporting compound heterozygous and homozygous variants in ANKFY1 in affected individuals (3 probands across 2 families) along with supportive segregation data and functional studies indicates a moderate gene‑disease association (PMID:38915441; PMID:29959197). Genetic EvidenceModerateThe identification of a recurrent loss‑of‑function variant, c.2753C>G (p.Ser918Ter), and additional rare alleles in multiple families supports autosomal recessive inheritance with consistent segregation in affected relatives. Functional EvidenceModerateIn vitro functional assays demonstrated reduced ANKFY1 protein expression, providing experimental evidence that aligns with the loss‑of‑function pathogenic mechanism observed in the patients. |