haploinsuffisiens

Haploinsufficiency, sometimes referred to in languages like Dutch as haploinsuffisiens, is a genetic situation in diploid organisms where a single functional copy of a gene does not produce enough gene product to maintain normal function. As a result, individuals who carry one normal allele and one inactivated or deleted allele (heterozygotes) can display a phenotype despite having one seemingly intact copy. This contrasts with haplosufficiency, where one copy is sufficient for normal function.

The mechanism hinges on gene dosage: for certain genes, especially those involved in development or tightly regulated cellular pathways, the amount of protein produced from one allele is insufficient. Causes include loss-of-function mutations, deletions, or other disruptions to one gene copy. Regulatory and dosage-sensitive genes, such as transcription factors and signaling components, are particularly prone to haploinsufficiency.

Well-established examples include PAX6 haploinsufficiency, which can cause aniridia (absence of the iris), TBX5 haploinsufficiency leading to Holt–Oram syndrome (cardiac and limb anomalies), and SHOX haploinsufficiency associated with short stature and limb abnormalities. Haploinsufficiency is a common mechanism for autosomal dominant diseases and can arise from microdeletions that remove one copy of a critical gene or from point mutations that inactivate the other copy.

Diagnosis typically involves genetic sequencing and copy-number analysis to detect loss-of-function variants or deletions. Clinically, managing haploinsufficiency focuses on addressing the resulting functional deficits. In research, approaches that modulate gene dosage, such as upregulating the remaining allele or gene replacement, are explored as potential strategies.