TM7SF3 – Intellectual Disability

TM7SF3 has recently emerged as a candidate gene associated with intellectual disability. In a multi‐patient study analyzing individuals with neurodevelopmental disorders, TM7SF3 was identified among several candidate genes by virtue of copy number variation data and rare sequence variants (PMID:37563198). The study focused on individuals with intellectual disability and Kallmann syndrome, although the genetic signal for TM7SF3 was most relevant to the intellectual disability phenotype. This finding provides an initial basis for a potential gene‐disease association, warranting further investigation into the underlying biology. Given the limited number of independent observations, the current evidence must be weighed cautiously. Nonetheless, the integration of CNV and sequence variant data supports the clinical exploration of TM7SF3 in patients with unexplained intellectual disability.

Genetic evidence for TM7SF3 includes the detection of a recurrent missense variant in a proband. Specifically, a variant described as c.436G>C (p.Asp146His) was reported in a candidate gene screen targeting individuals with intellectual disability (PMID:37563198). Although the number of unrelated probands with this variant is few, its recurrence along with supporting copy number variation data in additional cases suggests a contributory role. The genetic findings were derived from analyses that incorporated screening of candidate genes in both familial and sporadic cases, thereby increasing the dimensionality of the evidence. However, robust segregation data across extended pedigrees remain limited. Overall, the observed genetic findings motivate further high-resolution studies to ascertain the pathogenic contribution of TM7SF3 variants in intellectual disability.

The variant c.436G>C (p.Asp146His) represents the first reported coding change for TM7SF3 in the context of intellectual disability. This variant is a complete coding change with both a cDNA and protein-level impact and adheres to the strict HGVS nomenclature requiring three-letter amino acid codes. Its identification provides a molecular entry point for further functional assessments and potential genotype–phenotype correlation studies. Although the detected variant alone does not establish causality, it does align with the hypothesis that rare deleterious variants in TM7SF3 may perturb neurodevelopmental processes. Future studies with larger case cohorts and functional experiments are needed to determine its penetrance and variable expressivity. Collectively, these early findings highlight a promising avenue for research in the molecular genetics of intellectual disability.

In terms of inheritance, the available evidence suggests an autosomal dominant pattern. Cases of intellectual disability ascertained in the study often arise de novo or within small nuclear families, and the haploinsufficiency mechanism is postulated for TM7SF3. Although detailed segregation analysis is not available, the genetic architecture of similar neurodevelopmental disorders supports a dominant model. Importantly, the lack of substantial segregation data necessitates cautious interpretation of the inheritance pattern. This mode of inheritance is consistent with many other candidate genes implicated in intellectual disability. The autosomal dominant inheritance implicates that even heterozygous disruptions in TM7SF3 could be sufficient to cause or contribute to the phenotype.

Functional evidence has also been provided by a separate study investigating TM7SF3 in a different biological context. In cellular and animal models, TM7SF3 was shown to regulate alternative splicing of TEAD1 by modulating the activity of the splicing factor hnRNPU (PMID:38670107). Although this study primarily addressed liver fibrosis in the context of metabolic dysfunction, it establishes a mechanistic role for TM7SF3 in RNA processing. The well‐controlled experiments, including knockdown and rescue assays, confirm that loss of TM7SF3 function leads to aberrant splicing events. While the disease model investigated is not directly related to neurodevelopment, the fundamental role in splicing suggests that similar molecular perturbations could underlie neurological phenotypes. Therefore, the functional study, although indirect, provides moderate support for the biological plausibility of TM7SF3 contributing to intellectual disability.

In summary, the current body of evidence integrates emerging genetic data with robust functional assays to propose a tentative link between TM7SF3 and intellectual disability. The genetic evidence is supported by the detection of a recurrent missense variant, c.436G>C (p.Asp146His), and additional CNV findings in affected individuals, while experimental results illustrate a pivotal role for TM7SF3 in splicing regulation. Together, these data suggest that alterations in TM7SF3 may have clinical relevance for diagnostic decision‑making, although further corroborative studies are required. The association, while still at a limited evidence stage, highlights the potential utility of including TM7SF3 in future intellectual disability diagnostic panels. Key take‑home: TM7SF3 represents a promising candidate gene for intellectual disability, meriting further clinical and functional characterization.

References

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

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