triplosensitivity

Triplosensitivity is a form of gene dosage sensitivity in which an increase in copy number to three copies (or more) of a gene leads to a pathogenic phenotype. It stands in contrast to haploinsufficiency, where the loss of one gene copy causes disease. Triplosensitivity applies to individual genes as well as to chromosomal regions containing multiple genes.

Pathogenic duplications arise from copy-number variants and can disrupt gene regulation, protein networks, or developmental pathways by producing excess gene product. Whether three copies produce symptoms depends on the gene’s dosage sensitivity, the tissue and developmental timing, and interactions with other genetic or environmental factors. Not all duplicated genes are triplosensitive, and some duplications may be benign depending on context.

Classic examples illustrate the concept. Duplication of the PMP22 gene on chromosome 17p11.2 is a well-known cause of Charcot–Marie–Tooth disease type 1A. MECP2 duplications on the X chromosome (Xq28) lead to MECP2 duplication syndrome, a severe neurodevelopmental disorder in males. The 17p11.2 duplication syndrome, also known as Potocki–Lupski syndrome, results from larger duplications in that region and can produce a broad phenotype including hypotonia, facial features, and developmental delay.

Clinical significance and testing rely on gene- and region-level dosage sensitivity data. ClinGen maintains dosage sensitivity resources, including triplosensitivity assessments, based on case data and segregation analyses. Chromosomal microarray analysis and CNV-aware sequencing are used to detect duplications; interpretation considers whether the implicated genes are among those with established triplosensitivity, as well as the overall phenotype and family testing results. Counseling addresses recurrence risk and the implications of inherited versus de novo duplications.