Clinical Implications of Digenic Inheritance and Epistasis in Primary Immunodeficiency Disorders

Abstract

The existence of epistasis in humans was first predicted by Bateson in 1909. Epistasis describes the non-linear, synergistic interaction of two or more genetic loci, which can substantially modify disease severity or result in entirely new phenotypes. The concept has remained controversial in human genetics because of the lack of well-characterized examples. In humans, it is only possible to demonstrate epistasis if two or more genes are mutated. In most cases of epistasis, the mutated gene products are likely to be constituents of the same physiological pathway leading to severe disruption of a cellular function such as antibody production. We have recently described a digenic family, who carry mutations of TNFRSF13B/TACI as well as TCF3 genes. Both genes lie in tandem along the immunoglobulin isotype switching and secretion pathway. We have shown they interact in an epistatic way causing severe immunodeficiency and autoimmunity in the digenic proband. With the advent of next generation sequencing, it is likely other families with digenic inheritance will be identified. Since digenic inheritance does not always cause epistasis, we propose an epistasis index which may help quantify the effects of the two mutations. We also discuss the clinical implications of digenic inheritance and epistasis in humans with primary immunodeficiency disorders.

First Case of Patient With Two Homozygous Mutations in MYD88 and CARD9 Genes Presenting With Pyogenic Bacterial Infections, Elevated IgE, and Persistent EBV Viremia

“…This condition could be depend by the simultaneous presence of both defects that may create the proper context to allow the EBV to replicate, or by the presence of any other gene unknown variants that could increase the susceptibility to EBV. Despite the persistent asymptomatic EBV viremia represents the only new feature as compared to MYD88- and CARD9- deficiency phenotype, we do not feel to define our patient as affected by digenic PID (22, 23), but rather with two monogenic disorders. Accordingly to the patient's age the predominant clinical phenotype is the one associated with MYD88-deficiency (Figure 3).…”

Novel digenic inheritance of PCDH15 and USH1G underlies profound non-syndromic hearing impairment

“…We cannot, confirm epistasis in vitro, i.e. biochemical epistasis [ 31 ]. We hypothesize that the biochemical function of their network is severely affected by these two variants and results in a profound HI, because both proteins function together at the stereocilia tips in the hair cells and are necessary for proper mechanotransduction.…”

Assessing Disease Severity in Common Variable Immunodeficiency Disorders (CVID) and CVID-Like Disorders

“…from those which predispose to CVID ( TNFRSF13B /TACI, BAFFR, TWEAK, MSH5 ) ( 23 ). As seen in the first family, there are substantial differences in the disease severity scores of family members bearing TNFRSF13B /TACI vs. TCF3 mutations, showing effective genotype-phenotype separation ( 9 ). If patients carrying genes predisposing to CVID have a high CDSS, this should prompt a search for a second causative mutation as seen in the first family.…”

“…Her son carrying only the TCF3 mutation has a higher score than other family members bearing either homozygous or heterozygous mutations of the TNFRSF13B /TACI gene. This indicates the TCF3 mutation has a much greater impact on disease severity compared to mutations of TNFRSF13B /TACI ( 9 ).…”

“…In the first family, we have confirmed the existence of quantitative epistasis in humans ( 7 ). Epistasis is the non-linear, synergistic interaction of two or more genetic loci either leading to a much more severe disorder or a novel phenotype ( 8 , 9 ). The existence of epistasis was first predicted by William Bateson in 1909 but has remained highly controversial because of the lack of well characterized examples in humans ( 10 ).…”