TM7SF3 – Kallmann Syndrome

Evidence from recent multi‐patient studies has offered preliminary support for an association between TM7SF3 (HGNC:23049) and Kallmann syndrome (MONDO_0018800). In these studies, TM7SF3 was identified among a panel of candidate genes through copy number variation analyses in a cohort of KS patients, including the evaluation of six additional subjects and eight DECIPHER cases (PMID:37563198, PMID:37034680). Notably, one reported variant, c.436G>C (p.Asp146His), was identified in TM7SF3, although its recurrence among unrelated probands is limited. The CNV-based evidence supports a potential dosage effect, yet clear segregation data and comprehensive familial studies remain sparse.

In contrast, functional assessment studies have robustly characterized TM7SF3 in the regulation of TEAD1 alternative splicing and liver fibrosis (PMID:38670107). While these functional insights underscore the biological importance of TM7SF3, they do not directly corroborate its mechanistic involvement in the etiology of Kallmann syndrome. Overall, the genetic evidence, compounded by limited recurrence and unclear segregation, renders the gene–disease association as Limited. Additional evidence is needed to firmly establish TM7SF3 as a diagnostic marker for Kallmann syndrome.

Key Take‑home: TM7SF3 remains a candidate gene for Kallmann syndrome, but further genetic replication and segregation studies are required to support its clinical utility in diagnostic and commercial settings.

References

• Scientific Reports • 2023 • A cryptic microdeletion del(12)(p11.21p11.23) implicates new candidate loci for intellectual disability and Kallmann syndrome PMID:37563198
• Scientific Reports • 2023 • Candidate Gene Screening in Kallmann Syndrome Reveals Novel Dosage Sensitivity PMID:37034680
• Cell Metabolism • 2024 • TM7SF3 controls TEAD1 splicing to prevent MASH-induced liver fibrosis PMID:38670107

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