TSPAN11 and Kallmann Syndrome

TSPAN11 is emerging as a candidate gene for Kallmann syndrome (KS). Recent multi‑patient studies have implicated this gene through copy number variation analyses in patients with KS and co‑occurring neurodevelopmental phenotypes, suggesting that alterations in TSPAN11 dosage may influence disease expression (PMID:37563198). These initial findings, derived from comprehensive phenotypic‐genotypic comparisons, provide a preliminary framework supporting TSPAN11’s involvement in KS.

In assessing clinical validity, the gene–disease association currently falls into the Limited category. Although TSPAN11 was identified among a panel of candidate genes in studies employing both array techniques and targeted sequencing (PMID:37563198; PMID:27502037), the evidence is constrained by the modest number of unrelated probands and absent extensive segregation data.

The genetic evidence specifically for TSPAN11 is based on its recurrent nomination in multi‑patient copy number variation studies. Notably, no individual TSPAN11 variant that meets rigorous HGVS criteria has been reported in these studies, limiting the ability to correlate specific alterations with the KS phenotype. As such, while TSPAN11 is consistently highlighted as a candidate, detailed variant-level information remains sparse.

Functional data offer additional, albeit limited, support for TSPAN11’s role in KS. In one study, in silico analyses and expression profiles suggested that TSPAN11 may act as a modifier gene, potentially impacting pathways essential for olfactory and reproductive system development (PMID:35707593). However, direct functional assays validating its pathogenic impact in KS are currently lacking, which further contributes to the Limited classification of its functional evidence.

Integrating the genetic and functional findings, the current narrative supports a role for TSPAN11 in the etiology of Kallmann syndrome, but the overall evidence remains limited pending further case‐level data, segregation studies, and dedicated functional validations. This cautious interpretation underscores the need for additional studies to confirm TSPAN11’s clinical utility in KS diagnostics.

Key Take‑Home Message: TSPAN11 should be considered a candidate gene in Kallmann syndrome; while current data are limited, its inclusion in diagnostic panels could refine patient stratification and stimulate further research in this domain.

References

• Scientific Reports • 2023 • A cryptic microdeletion del(12)(p11.21p11.23) within an unbalanced translocation implicates new candidate loci for intellectual disability and Kallmann syndrome PMID:37563198
• Molecular and Cellular Endocrinology • 2016 • Targeted next generation sequencing approach identifies eighteen new candidate genes in normosmic hypogonadotropic hypogonadism and Kallmann syndrome PMID:27502037
• Molecular Syndromology • 2022 • New Report of a Different Clinical Presentation of CD151 Splicing Mutation: Could TSPAN11 be Considered as a Potential Modifier Gene for CD151? PMID:35707593

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