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This summary outlines the association between TSSK4 (HGNC:19825) and male infertility (MONDO_0005372). Multifaceted evidence from chromosomal breakpoint analysis and exome sequencing studies provides a basis for considering TSSK4 as a candidate gene in the etiology of male infertility. The studies evaluated large cohorts of infertile patients and utilized comprehensive transcriptomic profiling to refine the list of potential infertility-related genes (PMID:39358566). In these analyses, TSSK4 emerged among several genes exhibiting significant differential expression in patients with abnormal spermatogenesis. The consistency of its inclusion across independent studies underscores its relevance in the disorder. The evidence supports its consideration in diagnostic panels where genetic etiology is explored.
The overall clinical validity of the association is best described as Moderate. Although a robust multi-patient study analyzed 198 cases (PMID:39358566) and an exome sequencing investigation further implicated TSSK4 among 12 candidate genes (PMID:36048845), detailed family segregation data or recurrent, functionally disruptive variants have not been reported. This moderate association is reinforced by consistent expression data and the integration of cytogenetic breakpoints with high-throughput sequencing findings across independent cohorts.
Genetic evidence for TSSK4 includes its identification in both large-scale candidate gene screenings and expression studies. Differential expression analyses in azoospermic individuals revealed that TSSK4 is downregulated alongside other key genes involved in spermatogenesis. Although no discrete coding variants following the HGVS nomenclature (for example, a variant starting with a c. notation) were reported for TSSK4 in these publications, its recurrent identification among candidate genes lends moderate support to its genetic involvement. The candidate gene was noted in a study that assessed chromosomal rearrangement breakpoints in 198 infertile subjects (PMID:39358566), while a complementary exome sequencing study further consolidated its candidacy (PMID:36048845).
Functional insights into TSSK4 are currently limited. Although specific in vitro or in vivo assays directly interrogating TSSK4 function were not provided, its inclusion within gene panels associated with abnormal spermatogenesis suggests a plausible role in key signaling or regulatory pathways during testicular development. The absence of detailed functional assays precludes a high functional evidence score; however, supportive expression data and its co-occurrence with other functionally validated infertility candidates offer preliminary but noteworthy experimental support. Future studies focused on targeted functional analysis of TSSK4 may further clarify the mechanistic pathway underlying its association with male infertility.
No compelling conflicting evidence was reported in the available literature. Both cytogenetic studies and next‑generation sequencing efforts consistently place TSSK4 among genes potentially implicated in male infertility. While the lack of segregation data or clearly pathogenic coding variants requires circumspection, the observed expression patterns and cross‑study recurrence strengthen the genetic association. Researchers and clinicians should note that although additional evidence exists, the current ClinGen scoring does not exceed the maximum threshold for gene-disease validity.
In summary, TSSK4 presents as a moderately supported candidate gene for male infertility, with genetic evidence deriving from large-scale patient studies and suggestive, though limited, functional data. The integration of cytogenetic and exome sequencing findings emphasizes its potential utility in clinical diagnostic work‑ups and in guiding further research into the molecular pathogenesis of male infertility.
Key Take‑home sentence: TSSK4 is a promising candidate gene in male infertility diagnostics whose recurrent identification in large patient cohorts merits additional functional studies to fully elucidate its pathogenic role.
Gene–Disease AssociationModerateTSSK4 was recurrently identified in multi‑patient studies involving 198 cases (PMID:39358566) and supported by exome sequencing data (PMID:36048845), despite the absence of explicit segregation and recurrent pathogenic variants. Genetic EvidenceModerateThe gene was consistently nominated in candidate gene panels through large-scale expression and breakpoint analyses, although no explicit HGVS coding variant was reported. Functional EvidenceLimitedWhile expression data and gene panel inclusion support a role for TSSK4 in spermatogenesis, there is a lack of dedicated functional assays confirming its mechanism of action. |