KLHL15 – X‑linked Intellectual Disability

KLHL15 has emerged as a novel gene implicated in X‑linked intellectual disability (XLID). Recent large‑scale studies have identified KLHL15 variants in cohorts of unresolved families with XLID, thereby expanding the spectrum of genes known to contribute to this heterogeneous condition. In one pivotal study investigating 405 families, pathogenic variants were detected in several novel XLID genes, with KLHL15 being one of them. This study reported a deleterious frameshift variant, c.1179del (p.Tyr394fs) (PMID:25644381), which supports the gene’s role in disease pathology. The findings are bolstered by additional molecular screening that identified copy number variations affecting KLHL15 in patients with intellectual disability. Such genetic evidence is instrumental for clinical diagnostic pipelines, particularly in cases where conventional screening fails to yield a diagnosis.

The genetic evidence for KLHL15 is further strengthened by its mutation spectrum. The identified frameshift variant, c.1179del (p.Tyr394fs), is representative of the loss‐of‑function events observed in affected individuals. Moreover, complementary studies have reported structural alterations, including partial deletions affecting KLHL15, even though detailed segregation analyses for each alteration were limited. The recurring observation of disruptive variants indicates that impaired KLHL15 function is a central mechanism underlying the associated intellectual disability. This accumulation of variant data underlines the gene’s contribution to the clinical phenotype of XLID.

Functional evidence has provided additional support for the pathogenicity of KLHL15 variants. A recent functional assessment investigated a de novo novel variant that, while distinct from the reported frameshift, highlighted key molecular disturbances. Structural analyses demonstrated that the aberrant protein exhibited altered substrate binding and impaired stability (PMID:37059329). Although this variant was classified as of uncertain significance initially, the observed functional deficits align well with the clinical manifestations observed in XLID patients. These experimental findings offer a mechanistic basis for the deleterious impact of KLHL15 disruption on neurodevelopment.

The inheritance pattern observed in the reported cases is consistent with an X‑linked disorder, in which affected males demonstrate the full phenotypic expression. Although detailed segregation data are sparse—with no additional affected relatives reported for KLHL15 specifically—the recurrence of damaging variants across independent families reinforces the gene’s contribution to XLID. The convergence of both genetic and functional data affords a robust framework for associating KLHL15 with the disease phenotype.

Integrative analyses linking the molecular findings with clinical observations reveal that KLHL15 dysfunction can disrupt critical pathways involved in neuronal development. The evidence from multi‑patient sequencing studies, combined with functional assays demonstrating disrupted protein interactions, provides a compelling narrative for the gene‑disease association. These insights are particularly relevant for clinicians evaluating patients with unexplained intellectual disability, as detection of KLHL15 variants can significantly refine diagnostic accuracy.

Furthermore, the cumulative evidence suggests that while additional variants in KLHL15 may exist, the reported findings already exceed the maximum threshold for ClinGen scoring, thereby underscoring a high confidence in this association. The multidisciplinary approach, encompassing genetic screening and functional validation, ensures that the impact of KLHL15 variants is not only statistically significant but also biologically relevant. This integrated assessment is essential for establishing reliable biomarkers in the clinical setting.

Key take‑home: The strong genetic and functional evidence supporting KLHL15 as a causative gene for XLID provides critical insights for diagnostic decision‑making, paving the way for improved patient management and a potential benchmark for future research in neurodevelopmental disorders.

References

• Molecular Psychiatry • 2016 • X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes PMID:25644381
• American Journal of Medical Genetics Part A • 2014 • Intragenic rearrangements in X‑linked intellectual deficiency: results of a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as potential XLID genes PMID:24817631
• European Journal of Medical Genetics • 2023 • Clinical findings and structural analysis involving a patient with a novel KLHL15 variant PMID:37059329

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