KIF13A – Fuchs' Endothelial Dystrophy

Recent multi‐patient studies have identified altered RNA splicing patterns of KIF13A in the corneal endothelium of patients with Fuchs’ endothelial dystrophy (MONDO_0005321). In these studies, patients carrying a CTG trinucleotide repeat expansion in TCF4, a well‐established contributor to FECD, were assessed for the splicing profiles of several candidate genes. Notably, KIF13A, along with MBNL1 and AKAP13, exhibited aberrant splicing in patients with the FECD phenotype, while individuals with the repeat expansion but without FECD maintained normal splicing patterns (PMID:31469403). This observation suggests that mis‐splicing in KIF13A may contribute to disease susceptibility.

The genetic evidence in support of a role for KIF13A in FECD remains preliminary. Although no recurrent pathogenic coding changes have been reported in FECD cases, one reported variant—c.2357dupA (p.Asn786LysfsTer18)—has been described in KIF13A from a functional assessment study linking the gene to a neuroectodermal syndrome (Ito hypomelanosis). This frameshift variant illustrates the gene’s dosage sensitivity and potential for haploinsufficiency; however, its direct implication in Fuchs’ endothelial dystrophy has not been established.

Mechanistically, the data point to a model where dysregulation of RNA splicing in KIF13A may alter downstream pathways critical for corneal endothelial cell integrity. At present, functional studies directly examining the consequences of aberrant KIF13A splicing in corneal endothelial cells are lacking. Indirect insights from studies in alternative clinical contexts (e.g., Ito hypomelanosis) provide supportive evidence for the functional importance of KIF13A, yet they also underscore the need for targeted experiments in FECD models (PMID:33526817).

There is no extensive segregation data or case‐level mutation reports specific for FECD related to variants in KIF13A, thereby limiting the strength of the association. Consequently, the overall gene–disease association is currently classified as Limited. Further genetic studies, including the identification of recurrent variants and detailed family segregation analyses, are required to substantiate KIF13A’s role in the pathogenesis of Fuchs’ endothelial dystrophy.

Overall, while transcriptomic data provide intriguing evidence that altered splicing of KIF13A correlates with the FECD phenotype, definitive functional validation and robust genetic findings are needed. Additional studies could eventually enhance diagnostic precision and inform therapeutic strategies.

Key Take‑home: Alterations in KIF13A splicing patterns may modulate the risk of Fuchs’ endothelial dystrophy, but further evidence is necessary to support its routine use in clinical genetic diagnostics.

References

• Investigative Ophthalmology & Visual Science • 2019 • Gene Expression and Missplicing in the Corneal Endothelium of Patients With a TCF4 Trinucleotide Repeat Expansion Without Fuchs' Endothelial Corneal Dystrophy PMID:31469403
• Journal of Human Genetics • 2021 • Postzygotic Inactivating Mutation of KIF13A Located at Chromosome 6p22.3 in a Patient With a Novel Mosaic Neuroectodermal Syndrome PMID:33526817

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