haploinsufficiency

Haploinsufficiency is a gene dosage effect observed in diploid organisms, in which a heterozygous loss-of-function mutation or deletion in one allele reduces the amount of gene product below the level needed for normal function. The remaining functional copy cannot fully compensate, producing an abnormal phenotype.

Many genes tolerate one normal copy, but haploinsufficiency occurs when the single copy lacks the capacity to sustain normal development or physiology. It is driven by insufficient expression, regulatory disruption, or the gene’s dosage sensitivity. Haploinsufficiency is distinct from dominant-negative or gain-of-function mutations, which alter protein activity rather than total quantity.

Examples include PAX6 haploinsufficiency causing aniridia, SHOX haploinsufficiency contributing to short stature, TBX1 haploinsufficiency in features of 22q11.2 deletion syndrome, and RPS19 haploinsufficiency in Diamond-Blackfan anemia. MECP2 haploinsufficiency in females can underlie Rett syndrome, reflecting X-linked dosage sensitivity.

Clinically, haploinsufficiency often underlies autosomal dominant disorders with variable expressivity and penetrance. Carriers may be affected to different degrees, and phenotype depends on tissue context and other genetic factors. Diagnosis relies on sequencing and copy-number analysis to detect loss-of-function alleles and deletions.

Research uses haploinsufficiency to study gene dosage effects and to identify genes with critical dosage requirements. Computational measures of intolerance to loss-of-function, such as pLI, help predict haploinsufficient genes and interpret rare variants in patients.