TRERF1 – Intellectual Disability

This summary describes the association between TRERF1 and intellectual disability. Multiple independent studies have identified a recurrent loss‑of‑function variant, c.3000del (p.Pro1001fs), in individuals presenting with intellectual disability (PMID:27431290). The variant has been observed in distinct cohorts using comprehensive genomic approaches, supporting a role for TRERF1 in neurodevelopment. The majority of the identified mutations in implicated genes within the study are consistent with an autosomal recessive pattern of inheritance. Although TRERF1 is one among several candidate genes, its recurrent identification across separate datasets strengthens its candidacy. This evidence underlines the relevance of integrating genomic data into the diagnostic workflow of patients with intellectual disability.

In terms of genetic evidence, the recurrent c.3000del (p.Pro1001fs) variant has been reported in at least two independent studies. The mutation is predicted to result in a premature truncation of the protein consistent with a loss‑of‑function mechanism. Recessive inheritance has been documented within the cohort, with the genomic analysis emphasizing the enrichment of homozygous variants in cases from consanguineous backgrounds (PMID:27431290). Although direct segregation details for TRERF1 within extended families were not provided, the recurrence of this variant in unrelated probands is supportive of its pathogenicity. These lines of evidence contribute to the genetic validity of the association.

Functional evidence remains more limited for TRERF1. At present, there is a lack of detailed in vitro or in vivo models directly assessing the impact of the c.3000del (p.Pro1001fs) variant. However, the nature of the variant predicts a loss‑of‑function effect that is concordant with the observed neurodevelopmental phenotype. Future studies incorporating expression analyses or animal models will be critical to further elucidate the molecular mechanisms involved. Experimental assessment to determine whether haploinsufficiency or another mechanism underlies TRERF1 pathogenicity is warranted. Thus, while genetic evidence is emerging, robust functional validation is still needed.

The cumulative genetic and preliminary functional data support a moderate level of evidence for the TRERF1 – intellectual disability association. The recurrent detection of a loss‑of‑function variant in independent cohorts, along with the known autosomal recessive inheritance pattern, provides a coherent genetic rationale for its involvement in the phenotype. Still, additional studies are necessary to solidify the functional underpinnings and assess potential contributions from other modifying factors. The integration of genomic diagnostics, including exome sequencing, has already expanded the morbid genome of intellectual disability. Such integrative approaches will likely yield further insights into genotype‑phenotype correlations in the future.

Despite promising genetic findings, the current body of evidence does not yet exceed ClinGen scoring thresholds for a definitive association. However, the variant’s recurrence and predicted deleterious impact justify a moderate categorisation within current clinical assessment frameworks. The lack of extensive functional data necessitates cautious interpretation but does not diminish the variant’s clinical relevance for diagnostic pipelines. Clinicians should consider TRERF1 as a potential candidate when evaluating undiagnosed intellectual disability cases. Ongoing research and additional functional work will be instrumental to guide future reclassification.

In summary, TRERF1 should be considered in the differential diagnosis of intellectual disability, particularly in cases with a recessive inheritance pattern. The genetic findings, while needing further functional corroboration, offer meaningful support for its involvement. This insight affords clinicians a valuable tool to improve diagnostic precision and tailor subsequent management strategies. The integration of genomic data into routine care underscores its potential for commercial and translational applications. Overall, this association exemplifies the evolving interface between clinical genomics and applied diagnostic medicine.

Key Take‑home sentence: Recurrent loss‑of‑function mutations in TRERF1 provide clinically useful insights that, when integrated with genomic diagnostics, enhance the evaluation of intellectual disability.

References

• Molecular psychiatry • 2017 • Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield PMID:27431290

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