SLC24A1 – congenital stationary night blindness

This summary evaluates the association between SLC24A1 and congenital stationary night blindness. Multiple lines of genetic evidence from independent studies support that loss-of‑function variants in SLC24A1 result in a phenotype characterized by impaired rod photoreceptor function. Case reports and multi‐patient studies have identified several truncating and missense variants that co‑segregate with the disease in an autosomal recessive manner (PMID:26822852). The clinical data includes a re‑evaluation of patient phenotypes where a diagnosis of incomplete CSNB was corrected to the Riggs form of CSNB after genetic testing, underscoring the diagnostic impact of incorporating genetic findings.

Genetic evidence indicates that affected individuals carry compound heterozygous or homozygous variants, with at least three unrelated probands reported to harbor pathogenic changes. These findings include a spectrum of mutations such as deletions, nonsense, and frameshift variants. Notably, the variant c.494dup (p.Tyr166fs) is among the reported pathogenic alleles, exemplifying a deleterious frameshift mutation that likely results in a loss‑of‑function effect (PMID:26822852). Furthermore, although explicit counts of additional segregating relatives were not provided, the familial clustering in the reported cases reinforces a strong genetic contribution.

Functional studies, while not exclusively performed in a CSNB context, have shown that defects in SLC24A1 impair the sodium-calcium exchanger activity in photoreceptors. In cellular models, several variants demonstrated reduced capacity for ion transport, which is consistent with the proposed loss‑of‑function pathogenic mechanism. These experimental findings have been replicated across different assays, providing moderate support for the functional consequence of the genetic variants observed (PMID:12037007).

A convergence of genetic and functional datasets further clarifies the role of SLC24A1 in retinal disorders. Although one study investigating both rod and cone exchanger genes could not definitively assign pathogenicity to a specific variant in retinal disease, the accumulation of evidence from case reports, family studies, and functional assays specifically supports SLC24A1’s role in congenital stationary night blindness. Additional studies, including recent multi‐gene analyses, have consistently identified SLC24A1 variants in patients presenting with CSNB, highlighting the reproducibility and clinical relevance of these findings (PMID:35486108).

In summary, the genetic data from multiple unrelated probands, along with segregational and functional evidence, strongly support the association between SLC24A1 loss‑of‑function mutations and congenital stationary night blindness. The integration of these findings is critical for informed genetic diagnostic decision‑making, commercial test development, and future scholarly publication in the field of inherited retinal disorders.

Key Take‑home: Comprehensive genetic testing for SLC24A1 variants should be considered in cases of congenital stationary night blindness to aid in accurate diagnosis and tailor patient management.

References

• Clinical genetics • 2016 • Next-generation sequencing confirms the implication of SLC24A1 in autosomal-recessive congenital stationary night blindness PMID:26822852
• Investigative ophthalmology & visual science • 2002 • Mutated alleles of the rod and cone Na-Ca+K-exchanger genes in patients with retinal diseases PMID:12037007
• Cell calcium • 2018 • Residues important for Ca2+ ion transport in the neuronal K+-dependent Na+-Ca2+ exchanger (NCKX2) PMID:30173760
• Genetics in medicine : official journal of the American College of Medical Genetics • 2022 • Identification of autosomal recessive novel genes and retinal phenotypes in members of the solute carrier (SLC) superfamily PMID:35486108

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