Diploid organisms such as humans have two copies of each autosomal gene. Loss of both copies often has serious consequences – but what happens if just one copy is lost? For some genes, it matters; for others, it does not. Haploinsufficiency describes the situation where having only a single functioning copy of a gene is not enough for normal function, so that loss‐of‐function mutations cause a dominant phenotype. The reasons why some genes, but not others, show haploinsufficiency are interesting. In a few cases, the gene product is required in such large amounts that a single gene copy cannot satisfy the need. But more often, the reason is that the gene product interacts with something else in the cell in a way that requires the correct relative amounts of the interacting partners: a ligand interacting with its receptor or a transcription factor interacting with its target sequence, for example.

Key Concepts

  • DNA sequence variants in a protein‐coding gene may cause monogenic conditions either by causing a loss of function of the gene product or by causing a gain of function.
  • Conditions caused by a gain of function are normally dominant (a single copy of the variant gene is sufficient to cause the condition). Usually, they are caused by a very limited set of variants.
  • Conditions caused by a loss of function usually show extensive allelic heterogeneity.
  • Loss‐of‐function conditions may be either dominant or recessive, depending whether the 50% overall level of function in a heterozygote is sufficient for a normal phenotype. Haploinsufficiency describes the situation where a 50% level of function is not sufficient. In these cases, loss‐of‐function mutations cause a dominant condition.
  • Haploinsufficiency is sometimes caused due to inability of a single functional copy of a gene to produce a sufficient quantity of an abundant protein, but more often, it is because the gene product is interacting with something else in the cell, and the correct relative amounts are important. Examples would include interaction of a ligand with its receptor or a transcription factor with its target sequence.
  • Haploinsufficiency may be suspected when databases of genome sequences of healthy individuals show a significant deficiency of heterozygous loss‐of‐function mutations in a particular gene.

Keywords: haploinsufficiency; loss of function; dominant; probability of loss of function intolerance; Waardenburg syndrome; Apert syndrome

Figure 1. Effect of mutations that decrease the quantity or function of a gene product. The solid vertical line shows the threshold for clinical effects. (a) For this gene, effects become noticeable only when the combined level of function of both alleles drops below 20% of normal; therefore, loss‐of‐function mutations will be recessive. (b) Haploinsufficiency: for this gene, effects become noticeable when the level of function is below 65% of normal. People with one nonfunctional copy of the gene will be affected and the resulting condition will be dominant.
Figure 2. Contrasting patterns of mutations in patients with Waardenburg and Apert syndromes. (a) The PAX3 gene is mutated in patients with type 1 Waardenburg syndrome. Among unrelated patients, a variety of truncating and nontruncating mutations have been recorded, indicating that this is a loss‐of‐function condition. Missense changes are concentrated in two functional regions (shaded), the paired box and homeobox. As Waardenburg syndrome is dominant, the pathogenic mechanism is haploinsufficiency. (b) The FGFR2 gene is mutated in patients with Apert syndrome. Unrelated patients never have truncating mutations; almost invariably, they have one of the two closely spaced missense changes in exon 7, indicating that this is a gain‐of‐function condition.


Farley EK, Olson KM, Zhang W, et al. (2015) Suboptimization of developmental enhancers. Science 350: 325–328.

Huang N, Lee I, Marcotte EM and Hurles ME (2010) Characterising and predicting haploinsufficiency in the human genome. PLoS Genetics 6: e1001154.

Lek M, Karczewski K, Minikel E, et al. (2016) Analysis of protein‐coding genetic variation in 60,706 humans. Nature 536: 285–291.

Further Reading

Cabelof DC (2012) Haploinsufficiency in mouse models of DNA repair deficiency: modifiers of penetrance. Cellular and Molecular Life Sciences 69: 727–740.

Harrington L (2012) Haploinsufficiency and telomere length homeostasis. Mutation Research 730: 37–42.

Read AP and Donnai D (2015) New Clinical Genetics, 3rd, chap. 6 edn. Banbury: Scion Publishing.

Wilkie AOM (1994) The molecular basis of dominance. Journal of Medical Genetics 31: 89–98.

Web Links

ExAC (Exome Aggregation Consortium), http://exac.broadinstitute.org/

Fibroblast growth factor receptor 2 (FGFR2); MIM number: 176943.



Paired box 3 (PAX3); MIM number: 606597.



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Read, Andrew P(Nov 2017) Haploinsufficiency. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005489.pub2]