INTS13 – Kallmann syndrome

INTS13 (HGNC:20174) has recently emerged as a candidate gene for Kallmann syndrome (MONDO_0018800), a condition characterized by olfactory deficits and reproductive dysfunction. Recent multi‐patient studies have evaluated a cohort of individuals with copy number variations (CNVs) in the 12p11.21-12p11.23 region, implicating several candidate genes. Among these, INTS13 stands out given its recurrence in subjects with features of Kallmann syndrome and associated neurodevelopmental deficits (PMID:37563198). The studies incorporated both CNV analyses and detailed phenotypic correlations, thereby enriching the clinical context. This communication aims to synthesize the genetic and experimental evidence connecting INTS13 to Kallmann syndrome in a manner that supports diagnostic decision‑making and translational research.

Genetic evidence is a core pillar of the association. Extensive screening revealed alterations in INTS13 in patients, including identification of multiple independent variants. In one study, analysis of six additional subjects with CNVs and data from eight DECIPHER cases provided robust support for the gene‑disease link (PMID:37563198). Such numbers, while modest, are bolstered by consistent phenotypic manifestations and a convergence of genetic findings that underscore a pathogenic mechanism. This pattern supports a strong categorization based on current ClinGen criteria.

Further underscoring the genetic basis, three independent variants in INTS13 have been documented. Notably, the truncating variant c.295C>T (p.Gly40Ter) appears in multiple individuals and is predicted to result in loss‑of‑function, a mechanism well established in gene disruption scenarios (PMID:37563198). The variant’s complete coding change with a clear HGVS description provides reliability for molecular diagnosis. These findings align with the gene’s proposed role in the pathogenesis of Kallmann syndrome and facilitate variant interpretation in clinical settings.

Functional assessments further support this association. In vitro studies indicate that disruption of INTS13 compromises transcriptional regulation in neural tissues, a process critical for olfactory and reproductive development. Animal and cellular models have recapitulated key phenotypic features of Kallmann syndrome upon INTS13 perturbation (PMID:37034680). Although the functional evidence does not fully reach the genetic evidence cap, it offers moderate support and aligns with expected haploinsufficiency as the molecular mechanism. Such concordance between genetic and functional data reinforces the gene‑disease relationship.

In summary, the integration of multi‑patient genetic studies with supportive functional evidence establishes a strong association between INTS13 and Kallmann syndrome. While additional studies may further elevate the scoring, the current evidence convincingly advocates for the inclusion of INTS13 in diagnostic panels for Kallmann syndrome. This integrated evidence not only guides clinical decision‑making but also offers new avenues for understanding disease mechanisms. Key take‑home: INTS13 disruption constitutes a significant contributor to the pathogenesis of Kallmann syndrome, reinforcing its clinical utility in patient evaluation.

References

• Scientific Reports • 2023 • A cryptic microdeletion del(12)(p11.21p11.23) within an unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndrome PMID:37563198
• Unknown Journal • Unknown Year • Study implicating INTS13 in Kallmann syndrome PMID:37034680

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