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Digenic Inheritance in Medical Genetics Alejandro a Schäffer

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Digenic Inheritance in Medical Genetics Alejandro a Schäffer Review J Med Genet: first published as 10.1136/jmedgenet-2013-101713 on 19 June 2013. Downloaded from Digenic inheritance in medical genetics Alejandro A Schäffer ▸ Additional material is ABSTRACT The first report of DI in a human disease was in published online only. To view Digenic inheritance (DI) is the simplest form of 1994 for retinitis pigmentosa (RP).7 This report please visit the journal online (http://dx.doi.org/10.1136/ inheritance for genetically complex diseases. By contrast was convincing because it included data from mul- jmedgenet-2013-101713). with the thousands of reports that mutations in single tiple pedigrees, and the protein products of the two genes cause human diseases, there are only dozens of genes had a known interaction. After 1994, there Correspondence to Dr Alejandro A Schäffer, human disease phenotypes with evidence for DI in some was a trickle of additional DI reports until 2001, Computational Biology Branch, pedigrees. The advent of high-throughput sequencing which saw prominent reports of human DI in National Center for (HTS) has made it simpler to identify monogenic disease Bardet–Biedl syndrome (BBS),8 deafness9 and other Biotechnology Information, causes and could similarly simplify proving DI because phenotypes. These discoveries stimulated a trio of National Institutes of Health, fi fl – 10–12 Department of Health and one can simultaneously nd mutations in two genes in in uential reviews in 2002 2003. Since 2002, Human Services, 8600 the same sample. However, through 2012, I could find discoveries of human DI have been appearing at a Rockville Pike, Bethesda, MD only one example of human DI in which HTS was used; steady pace (see Discussion), but were not reviewed 20894, USA; in that example, HTS found only the second of the two systematically, except for specific diseases, such as [email protected] genes. To explore the gap between expectation and deafness13 and Hirschprung’s disease.14 Received 2 April 2013 reality, I tried to collect all examples of human DI with a The three reviews and other contemporaneous Revised 24 May 2013 narrow definition and characterise them according to the papers engaged in a lively but inconclusive debate Accepted 28 May 2013 types of evidence collected, and whether there has been on how to define human DI. Here, I use a narrow, Published Online First replication. Two strong trends are that knowledge of operational definition that inheritance is digenic 19 June 2013 candidate genes and knowledge of protein–protein when the variant genotypes at two loci explain the interactions (PPIs) have been helpful in most published phenotypes of some patients and their unaffected examples of human DI. By contrast, the positional (or more mildly affected) relatives more clearly method of genetic linkage analysis, has been mostly than the genotypes at one locus alone. This unsuccessful in identifying genes underlying human DI. includes cases where both loci determine who is Based on the empirical data, I suggest that combining affected, a substantial change in severity, or a sub- HTS with growing networks of established PPIs may stantial change in age of onset. The definition expedite future discoveries of human DI and strengthen includes cases in which one locus is the primary the evidence for them. locus, and by itself has variable expressivity, as well as cases where the two loci are roughly equal in importance. I generally exclude cases where the INTRODUCTION inheritance is polygenic with many more than two http://jmg.bmj.com/ Digenic inheritance (DI) has fascinated geneticists loci involved. I generally exclude ‘modifier loci’ since the early 20th century. In the early decades of that have a modest effect on the phenotype and for studies on genetics, the term ‘epistatis’ was used by which the evidence is only statistical.15 For diseases some to describe some forms of digenic inherit- whose aetiology involves more than two genes, ance,1 but in recent decades ‘epistasis’ has been formalisms, such as Bayesian networks, may be used to describe a much broader category of locus– needed to describe the role of each gene and its locus interactions in polygenic diseases, including variants in the ‘cause’ of the disease. on September 26, 2021 by guest. Protected copyright. but not limited to interactions of loci identified by In the prominent example of BBS and others in genome-wide association studies.2 This review is a the section on five examples below, a simple deter- synthesis of knowledge about digenic inheritance in ministic model that explained some pedigrees a narrow sense, not about epistatsis in a broad proved to be too simple for all pedigrees. When sense. large collections of pedigrees are available, prob- Defrise–Gussenhoven3 suggested more than abilistic models that assign higher probabilities to 50 years ago that there would be many human patients who have more mutations will likely fit the disease pedigrees showing reduced penetrance collection of data better. The impetus to collect when treated in genetic analysis as monogenic, but hundreds of patients and fit a statistical genotype- that the inheritance could be explained more accur- phenotype model comes after initial observations ately by a two-locus model. The first prediction of one or a few pedigrees that fit simpler models of came true, but few studies of pedigrees with incom- multigenic inheritance. Therefore, this review plete penetrance consider two-locus analysis, even focuses attention on how to find the initial digenic – though good methods have been developed.4 6 In patients and pedigrees. this context, ‘reduced penetrance’ means that while Besides the lack of recent reviews, another stimulus all or almost all affected pedigree members are for this review is the hypothesis that high-throughput modelled as having the mutant genotype at DNAsequencing(HTS)wouldbeanenablingtech- the primary locus, one or more relatives with the nology to accelerate discoveries of human DI. primary mutant genotype are unaffected; genetic Because HTS makes it possible to sequence many To cite: Schäffer AA. J Med modelling allows for the imperfect correspondence genes simultaneously, disease-relevant mutations in – Genet 2013;50:641 652. between genotype and phenotype. two genes can be discovered in a single experiment. Schäffer AA. J Med Genet 2013;50:641–652. doi:10.1136/jmedgenet-2013-101713 641 Review J Med Genet: first published as 10.1136/jmedgenet-2013-101713 on 19 June 2013. Downloaded from HTS does not solve the problem of deciding which mutations are may be hard to find. Therefore, in a few cases, such as Long QT relevant to the phenotype, and doing so is more difficult when the syndrome (LQTS), the evidence accumulates over multiple – inheritance is digenic as compared with monogenic. studies.22 26 Various studies suggested DI based on one or a few There has been one recent example of HTS enabling a proof patients without pedigree evidence. To evaluate whether genetic of DI. The disease is facioscapulohumeral muscular dystrophy linkage analysis (GLA) is useful to find DI, I included studies in (FSHD) type 2.16 The primary locus for both type 1 and type 2 which strong evidence of two loci was found by linkage analysis, FSHD is DUX4, and that had been discovered by pre-HTS without requiring that the two genes have been found. methods. In many pedigrees with type 2 FSHD, the penetrance The data about each study include: the loci and genes, of the DUX4 variant is incomplete. Therefore, Lemmers et al16 whether there was pedigree evidence, whether the study was sought a second locus via HTS. They found that heterozygous, replicated later, had internal replication only, or mostly repli- rare variants in the gene SMCHD1 could explain the inheritance cated a prior study (see online supplementary table S1). Two pattern in 21/26 individuals in various pedigrees. Patients with a additional useful pieces of information are: whether the loci are variant at DUX4 and a variant at SMCHD1 are mostly affected, genetically linked, and whether there is any functional relation- while patients with a variant at DUX4 and wild type at ship between the two genes or their protein products. The func- SMCHD1 are mostly unaffected. SMCHD1 controls epigenetic tional relationships could be: protein–protein interaction (PPI), marks affecting gene expression, so the basis for the DI is likely protein–DNA interaction, or being on a shared pathway without to be a protein–DNA interaction between SMCHD1 and DUX4, a known direct interaction. The importance of whether the loci affecting the expression of DUX4. are linked, and whether the genes have any interaction, is con- I could not find any other studies in which HTS has facili- sidered in the section entitled: ‘Three lessons for future studies tated a discovery of human DI, though a second example was of human digenic inheritance’. published online after this article was submitted.17 To investigate why, I started by building a catalogue of human DI examples. COMMONLY USED STUDY DESIGNS Next, I analysed what study designs had been tried. Then, I con- Two experimental study designs predominate among the sidered some of the more publicised examples to see if there reported cases of human digenic inheritance. These are illu- was anything special about the most replicated cases of human strated abstractly in figure 1. I consider one alternative design in DI. The successes and some not-so-successful examples suggest this section and another alternative design in the Discussion. three lessons that may aid future studies of human DI. In the The majority of examples in table 1 and almost all examples Discussion, I use an epistemological approach to suggest how in which both genes have been identified are based on a candi- HTS and other new technologies may be used to accelerate the date gene (CG) design, proceeding as follows: pace of future discoveries.
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