Dosagesensitive

Dosage sensitivity refers to the property of certain genes to produce a phenotype that depends on the number of copies present in the genome. In humans, changes in gene copy number—such as deletions or duplications—can disrupt normal function, leading to developmental, neurological, or metabolic disorders. Genes with dosage sensitivity are often studied in the context of copy-number variations (CNVs) and are frequently involved in regulatory networks, signaling pathways, or components of protein complexes.

Key concepts related to dosage sensitivity include haploinsufficiency and triplosensitivity. Haploinsufficiency occurs when a single functional copy of a gene is not sufficient to maintain normal function, so loss of one copy can cause disease. Triplosensitivity describes cases where an extra copy leads to pathology. These phenomena help explain why some CNVs produce consistent clinical effects while others show variable outcomes. Dosage-sensitive genes are commonly enriched among transcription factors, developmental regulators, and genes that participate in multi-subunit complexes, where precise stoichiometry is crucial.

Clinical examples illustrate the importance of dosage sensitivity. The 22q11.2 deletion syndrome can result from haploinsufficiency of TBX1 and related genes, affecting development. MECP2 haploinsufficiency is associated with Rett syndrome, while MECP2 duplication causes MECP2 duplication syndrome. The 16p11.2 region demonstrates dosage sensitivity in both deletions and duplications, with links to neurodevelopmental disorders and body-weight regulation. These cases underscore how changes in gene dosage can translate to distinct clinical phenotypes.

In research and clinical genetics, assessing dosage sensitivity aids in interpreting CNVs, guiding diagnosis, prognosis, and counseling. Ongoing work includes functional studies, model organisms, and approaches to restore or compensate for disrupted gene dosage.