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Mendelian inheritance revisited: dominance and recessiveness in medical genetics

Nature Reviews Genetics volume 24, pages 442–463 (2023)Cite this article

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Abstract

Understanding the consequences of genotype for phenotype (which ranges from molecule-level effects to whole-organism traits) is at the core of genetic diagnostics in medicine. Many measures of the deleteriousness of individual alleles exist, but these have limitations for predicting the clinical consequences. Various mechanisms can protect the organism from the adverse effects of functional variants, especially when the variant is paired with a wild type allele. Understanding why some alleles are harmful in the heterozygous state — representing dominant inheritance — but others only with the biallelic presence of pathogenic variants — representing recessive inheritance — is particularly important when faced with the deluge of rare genetic alterations identified by high throughput DNA sequencing. Both awareness of the specific quantitative and/or qualitative effects of individual variants and the elucidation of allelic and non-allelic interactions are essential to optimize genetic diagnosis and counselling.

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Fig. 1: Genotype and phenotypes — from DNA sequence to clinical manifestation in phenylalanine hydroxylase deficiency.
Fig. 2: Quantitative variant effects.
Fig. 3: Dominant negative effects.
Fig. 4: Protein subfunction and moonlighting-function effects.
Fig. 5: Allelic variants in the fibroblast growth factor receptor 1 gene.
Fig. 6: Multiple steps in tumour predisposition syndromes.
Fig. 7: Gonosomal inheritance.

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Acknowledgements

The authors wish to thank U. Moog and S. Rudnik for helpful comments on earlier drafts of this manuscript, and J. Amberger for help with Online Mendelian Inheritance in Man (OMIM) statistics. A.O.M.W. acknowledges part-funding from NIHR Oxford Biomedical Research Centre.

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Authors and Affiliations

  1. Institute of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

    Johannes Zschocke

  2. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA

    Peter H. Byers

  3. Department of Medicine (Medical Genetics), University of Washington, Seattle, WA, USA

    Peter H. Byers

  4. MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

    Andrew O. M. Wilkie

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  1. Johannes Zschocke
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  2. Peter H. Byers
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  3. Andrew O. M. Wilkie
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All authors contributed to all aspects of the article; J.Z. developed the concept, wrote the initial draft of the manuscript and carried out major revisions.

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Correspondence to Johannes Zschocke.

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Matched Annotation from NCBI and EMBL-EBI (MANE): https://www.ncbi.nlm.nih.gov/refseq/MANE/

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Glossary

Anticipation

The earlier or more severe manifestation of a hereditary disease in the offspring than in the parent.

Allelic series

Different variants in the same gene often acting through different pathogenetic pathways cause a range of phenotypes that may be associated with different inheritance patterns.

Autozygosity mapping

A method to identify disease-causing variants in consanguineous families by focusing on autosomal regions with runs of homozygous genotypes inherited from a shared ancestor (that is, autozygous regions).

Co-dominance

Different alleles of the same autosomal gene yield functionally distinct proteins with alternative phenotypes, both of which can be recognized in the (compound) heterozygous state.

Compound heterozygous

Different pathogenic variants on the two alleles of the same autosomal gene, causing biallelic loss or modification of gene function.

Dominant negative effect

A heterozygous variant codes for a structurally altered protein that interferes with the wild type (WT) protein.

Exome

The transcribed sequences of all protein-coding human genes.

Expressivity

The severity or extent of clinical manifestation in persons with a particular genotype. Variable expressivity indicates that individuals with the same genotype (for example, in the same family) may have quite different phenotypes.

Genotype

The constellation of genetic variants in a particular gene or in the genome.

Gain of function (GoF) variant

A genetic variant that causes inappropriate or novel protein functions such as uncontrolled activation or loss of regulation of the encoded protein, ectopic and/or illegitimate organ and/or cell-specific expression patterns, or novel (including toxic) protein or mRNA functions.

Gonosomal

A gene or variant on one of two sex chromosomes, as opposed to autosomes.

Haplosufficiency

Complete loss of one copy of a particular autosomal gene is usually asymptomatic. Haplosufficiency is a typical feature of recessive diseases and Mendelian wild type (WT) dominance.

Haploinsufficient

Complete loss of one copy of a particular autosomal gene causes noticeable clinical effects; a single (haploid) normal allele does not suffice for normal development or homeostasis. Haploinsufficiency is the central pathogenetic mechanism in semi-dominant diseases caused by loss of function (LoF) variants.

Hypomorphic (Hyp) variants

Genetic variants that reduce but do not completely abolish the function of the encoded protein.

Loss of function (LoF) variant

A genetic variant that causes complete loss of the encoded protein. Also known as a null variant.

Moonlighting-function effects

A multifunctional protein performs two or more autonomous, independent and mechanistically different functions; specific impairment of one function by a pathogenic variant does not necessarily affect the other function(s).

Overdominance

The phenomenon whereby some heterozygous variants have advantageous clinical effects not observed in homozygous wild type (WT) or homozygous variant states.

Penetrance

The probability of clinical manifestation in persons with a particular genotype, which is frequently age-dependent. Penetrance may be complete (100%) or incomplete (reduced).

Phenotype

The measurable consequences of a genetic variant on the protein, cell, organ or clinical level.

Pleiotropy

A protein function is required in two or more different cellular processes or pathways; pathogenic variants in the respective gene cause different seemingly unrelated phenotypic traits.

Pseudo-dominant

The occurrence of an autosomal recessive (biallelic) disease in successive generations.

Semi-dominant

Describes the phenomenon whereby an autsomal genetic variant in its heterozygous state is associated with a less severe, intermediate phenotype than its homozygous state. Most quantitative variants are semi-dominant, but semi-dominance is also commonly observed for variants that have qualitative effects.

Subfunction effects

A protein has successive functions in cellular processes, such as sequential steps in an enzymatic reaction or transport processes, which are differently affected by genetic variants.

Triplosensitive

An additional copy of a particular autosomal gene (for example through a duplication that causes three instead of two gene copies) that has adverse clinical consequences.

Tissue-specific transcript effects

A gene shows functional variability in expression or splicing, which is differently affected by genetic variants.

Underdominance

The phenomenon whereby some heterozygous variants cause a clinically adverse phenotype that is absent or less severe in wild type (WT) or variant homozygotes.

Wild type

(WT). The genetic sequence or function defined as normal.

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Zschocke, J., Byers, P.H. & Wilkie, A.O.M. Mendelian inheritance revisited: dominance and recessiveness in medical genetics. Nat Rev Genet 24, 442–463 (2023). https://doi.org/10.1038/s41576-023-00574-0

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