Triplosensitive

Triplosensitive describes genes or genomic regions for which an extra copy, resulting in three copies of the gene rather than the usual two, produces a deleterious phenotype. It is the counterpart to haploinsufficiency, where loss of one copy causes disease. Triplosensitivity is evaluated in the context of copy-number variation (CNV) analyses; duplications encompassing triplosensitive genes may contribute to developmental disorders, congenital anomalies, or neurodevelopmental conditions, though phenotypic effects are variable and depend on the gene and the size of the duplicated segment.

Clinical interpretation relies on accumulating evidence. ClinGen maintains a Dosage Sensitivity Map that curates genes and regions with sufficient evidence for triplosensitivity. Evidence types include case reports of individuals with pure duplications and functional data from model systems or cell studies showing dosage-dependent effects. Not all duplications cause disease; pleiotropy and variable expressivity are common.

Implications include counseling about recurrence risk, assessment of the specific duplicated content, and consideration of whether the duplication is inherited or de novo. Laboratories use array-based CNV tools to identify CNVs; interpretation must consider the presence of additional variants and overall clinical context.

Research interest continues in understanding the mechanisms of triplosensitive effects, including gene dosage–balance, regulatory networks, and developmental timing. Knowledge of triplosensitivity informs diagnosis, prognosis, and potential future therapies targeting dosage effects. See also haploinsufficiency, dosage sensitivity, and copy-number variation.