Digenic Inheritance

Abstract

Monogenic inheritance refers to genetic control of a phenotype or trait by a single gene. For a monogenic trait, mutations in one (dominant) or both (recessive) copies of the gene are sufficient for the trait to be expressed. Many traits are not determined so simply, and either involve the interaction of many genes with (multifactorial inheritance) or without (polygenic inheritance) environmental effects. Less commonly, the interaction of only two genes is required for expression of a phenotype, a mechanism referred to as digenic inheritance. In this situation, mutations in at least one copy of each gene are required for the expression of a phenotype. A growing number of human diseases with a digenic inheritance pattern are being described, a phenomenon that is likely to increase with more deoxyribonucleic acid (DNA) sequence data being generated through clinical‐based exome and genome sequencing efforts.

Key Concepts:

  • Traditional mendelian patterns of inheritance are controlled by mutations at a single genetic locus.

  • Many human disorders are caused by more complex patterns of inheritance.

  • Digenic inheritance refers to mutation on two genes interacting to cause a genetic phenotype or disease.

  • Triallelic inheritance is a special case of digenic inheritance that requires homozygous mutations at one locus and heterozygous mutations at a second locus to express a phenotype.

  • Digenic inheritance is probably best though of as being on a continuum that includes modifier effects of monogenic inheritance and polygenic or multifactorial inheritance.

Keywords: mendelian inheritance; polygenic inheritance; multifactorial inheritance; gene interactions; penetrance; expressivity; pleiotropy; modifier genes

Figure 1.

Left: Digenic inheritance arises when mutations (represented by the lightning bolt) on at least one allele (copy) of two genes is necessary for the appearance of a phenotype or disease. Right: Triallelic inheritance is a special case of digenic inheritance in which it is necessary to have homozygous mutations on both alleles of one gene plus a mutation on at least one allele of a second gene for a phenotype or disease to manifest.

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References

Abe S, Kelley PM, Kimberling WJ and Usami S (2001) Connexin 26 gene (GJB2) mutation modulates the severity of hearing loss associated with the 1555A→G mitochondrial mutation. American Journal of Medical Genetics 103(4): 334–338.

Adato A, Kalinski H, Weil D et al. (1999) Possible interaction between USH1B and USH3 gene products as implied by apparent digenic deafness inheritance. American Journal of Human Genetics 65(1): 261–265.

Balling R (1994) The undulated mouse and the development of the vertebral column. Is there a human PAX‐1 homologue? Clinical Dysmorphology 3(3): 185–191.

Baulac S, Picard F, Herman A et al. (2001) Evidence for digenic inheritance in a family with both febrile convulsions and temporal lobe epilepsy implicating chromosomes 18qter and 1q25‐q31. Annals of Neurology 49(6): 786–792.

Boughman JA, Conneally PM and Nance WE (1980) Population genetic studies of retinitis pigmentosa. American Journal of Human Genetics 32(2): 223–235.

Bykhovskaya Y, Estivill X, Taylor K et al. (2000) Candidate locus for a nuclear modifier gene for maternally inherited deafness. American Journal of Human Genetics 66(6): 1905–1910.

Chiang PW, Spector E and McGregor TL (2009) Evidence suggesting digenic inheritance of Waardenburg syndrome type II with ocular albinism. American Journal of Medical Genetics A 149A(12): 2739–2744.

Cox KB, Hamm DA, Millington DS et al. (2001) Gestational, pathologic and biochemical differences between very long‐chain acyl‐CoA dehydrogenase deficiency and long‐chain acyl‐CoA dehydrogenase deficiency in the mouse. Human Molecular Genetics 10(19): 2069–2077.

Fauser S, Munz M and Besch D (2003) Further support for digenic inheritance in Bardet‐Biedl syndrome. Journal of Medical Genetics 40(8): e104.

Finsterer J and Fellinger J (2005) Nuclear and mitochondrial genes mutated in nonsyndromic impaired hearing. International Journal of Pediatric Otorhinolaryngology 69(5): 621–647.

Hardelin JP and Dode C (2008) The complex genetics of Kallmann syndrome: KAL1, FGFR1, FGF8, PROKR2, PROK2, et al. Sex Development 2(4–5): 181–193.

Helwig U, Imai K, Schmahl W et al. (1995) Interaction between undulated and Patch leads to an extreme form of spina bifida in double‐mutant mice. Nature Genetics 11(1): 60–63.

Ikeda A, Zheng QY, Rosenstiel P et al. (1999) Genetic modification of hearing in tubby mice: evidence for the existence of a major gene (moth1) which protects tubby mice from hearing loss. Human Molecular Genetics 8(9): 1761–1767.

Kajiwara K, Berson EL and Dryja TP (1994) Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci. Science 264(5165): 1604–1608.

Katsanis N, Ansley SJ, Badano JL et al. (2001) Triallelic inheritance in Bardet‐Biedl syndrome, a Mendelian recessive disorder. Science 293(5538): 2256–2259.

Kelley RI, Kratz LE, Glaser RL et al. (2002) Abnormal sterol metabolism in a patient with Antley‐Bixler syndrome and ambiguous genitalia. American Journal of Medical Genetics 110(2): 95–102.

Kurtz DM, Rinaldo P, Rhead WJ et al. (1998) Targeted disruption of mouse long‐chain acyl‐CoA dehydrogenase gene reveals crucial roles for fatty acid oxidation. Proceedings of the National Academy of Sciences of the USA 95(26): 15592–15597.

Lerer I, Sagi M, Ben‐Neriah Z et al. (2001) A deletion mutation in GJB6 cooperating with a GJB2 mutation in trans in non‐syndromic deafness: A novel founder mutation in Ashkenazi Jews. Human Mutatation 18(5): 460.

Liu XZ, Yuan Y, Yan D et al. (2009) Digenic inheritance of non‐syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31. Human Genetics 125(1): 53–62.

Morak M, Massdorf T, Sykora H, Kerscher M and Holinski‐Feder E (2010) First evidence for digenic inheritance in hereditary colorectal cancer by mutations in the base excision repair genes. European Journal of Cancer. S0959‐8049(10)01120‐2 [pii], doi:10.1016/j.ejca.2010.11.016.

Morell R, Spritz RA, Ho L et al. (1997) Apparent digenic inheritance of Waardenburg syndrome type 2 (WS2) and autosomal recessive ocular albinism (AROA). Human Molecular Genetics 6(5): 659–664.

Moser AR, Shoemaker AR, Connelly CS et al. (1995) Homozygosity for the Min allele of Apc results in disruption of mouse development prior to gastrulation. Developmental Dynamics 203(4): 422–433.

Muntoni F, Bonne G, Goldfarb LG et al. (2006) Disease severity in dominant Emery Dreifuss is increased by mutations in both emerin and desmin proteins. Brain 129(Pt 5): 1260–1268.

Reardon W, Smith A, Honour JW et al. (2000) Evidence for digenic inheritance in some cases of Antley‐Bixler syndrome? Journal of Medical Genetics 37(1): 26–32.

Rodriguez‐Paris J and Schrijver I (2009) The digenic hypothesis unraveled: the GJB6 del(GJB6‐D13S1830) mutation causes allele‐specific loss of GJB2 expression in cis. Biochemistry and Biophysics Research Communication 389(2): 354–359.

Roy HK, Iversen P, Hart J et al. (2004) Down‐regulation of SNAIL suppresses MIN mouse tumorigenesis: modulation of apoptosis, proliferation, and fractal dimension. Molecualr Cancer Therapy 3(9): 1159–1165.

Savage DB, Agostini M, Barroso I et al. (2002) Digenic inheritance of severe insulin resistance in a human pedigree. Nature Genetics 31(4): 379–384.

Schuler AM, Gower BA, Matern D et al. (2005) Synergistic heterozygosity in mice with inherited enzyme deficiencies of mitochondrial fatty acid beta‐oxidation. Molecular Genetics & Metabolism 85(1): 7–11.

Suliman SG, Stanik J, McCulloch LJ et al. (2009) Severe insulin resistance and intrauterine growth deficiency associated with haploinsufficiency for INSR and CHN2: new insights into synergistic pathways involved in growth and metabolism. Diabetes 58(12): 2954–2961.

Truslove GM (1977) A new allele at the patch locus in the mouse. Genetic Research 29(2): 183–186.

Vincent AL, Billingsley G, Buys Y et al. (2002) Digenic inheritance of early onset glaucoma: CYP1B1, a potential modifier gene. American Journal of Human Genetics 70(2): 448–460.

Wine JJ (1992) No CFTR: are CF symptoms milder? Nature Genetics 1(1): 10.

Yang T, Gurrola JG 2nd, Wu H et al. (2009) Mutations of KCNJ10 together with mutations of SLC26A4 cause digenic nonsyndromic hearing loss associated with enlarged vestibular aqueduct syndrome. American Journal of Human Genetics 84(5): 651–657.

Zheng QY, Yan D, Ouyang XM et al. (2005) Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans. Human Molecualr Genetics 14(1): 103–111.

Further Reading

Gropman AL and Adams DR (2007) Atypical patterns of inheritance. Seminars in Pediatric Neurology 14: 34–45.

Vockley J, Rinaldo P, Bennett MJ, Matern D and Vladutiu GD (2000) Synergistic heterozygosity: disease resulting from multiple partial defects in one or more metabolic pathways. Molecular Genetics and Metabolism 71(1‐2): 10–18.

Web Links

Deafness, autosomal recessive 26 (DFNB26); Locus ID: 23714. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=23714

Deafness, autosomal recessive 26 (DFNB26); MIM number: 605428. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?605428

Protein phosphatase 1, regulatory (inhibitor) subunit 3A (glycogen and sarcoplasmic reticulum binding subunit, skeletal muscle) (PPP1R3A); Locus ID: 5506. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=5506

Protein phosphatase 1, regulatory (inhibitor) subunit 3A (glycogen and sarcoplasmic reticulum binding subunit, skeletal muscle) (PPP1R3A); MIM number: 600917. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?600917

Peroxisome proliferative activated receptor, gamma (PPARG); Locus ID: 5468. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=5468

Peroxisome proliferative activated receptor, gamma (PPARG); MIM number: 601487. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?601487

Retinal degeneration, slow (retinitis pigmentosa 7) (RDS); Locus ID: 5961. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=5961

Retinal degeneration, slow (retinitis pigmentosa 7) (RDS); MIM number: 179605. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?179605

Retinal outer segment membrane protein 1 (ROM1); Locus ID: 6094. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=6094

Retinal outer segment membrane protein 1 (ROM1); MIM number: 180721. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?180721

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How to Cite close
Vockley, Jerry(Apr 2011) Digenic Inheritance. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005560.pub2]