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Multi-gene testing is useful in genetically heterogeneous conditions, including inherited cardiac pathologies. Increasing the number of genes analysed increases diagnostic yield of variants of certain, likely, or uncertain pathogenicity. Concerns exist regarding management of variants of uncertain/likely pathogenicity in conditions of oligogenic inheritance or variable expressivity. We surveyed a sample of colleagues across different specialties and departments internationally to compare management of patients with class 3 or class 4 variants in genes associated with non-syndromic cardiomyopathy or arrhythmia. An electronic survey regarding clinical management of variants ( www.surveymonkey.com/r/cardiacvariants ) was designed and distributed to colleagues internationally via professional bodies and direct email. 150 respondents (88 centres, 27 countries) completed the survey, most of whom were Clinical Geneticists or Genetic Counsellors. Most respondents offer pre-symptomatic testing to asymptomatic relatives of an individual with class 4 or class 5 variants. A minority of respondents offer pre-symptomatic testing for class 3 variants. Considering class 4 variants, 22 (15%) are fully reassuring that the patient with a negative predictive test would not develop the familial phenotype, while 123 (82%) counselled patients about the possibility of variant reclassification. Variability existed between and within centres and specialties. Multiple "free text" comments were provided. Recurring themes including need for multidisciplinary input, technical concerns, and concern regarding duty to review variants of uncertain significance. This study demonstrates that variability in management of likely pathogenic/uncertain variants exists. Close multi-disciplinary input is essential. The development of disorder or gene-specific evidence-based guidelines might ameliorate uncertainty in management.

Genetic generalized epilepsies (GGE) (childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME) and epilepsy with generalized tonic-clonic seizures (GTCS)) are mainly determined by genetic factors. Since few mutations were identified in rare families with autosomal dominant GGE, a polygenic inheritance was suspected in most patients. Recent studies on large American or European cohorts of sporadic cases showed that susceptibility genes were numerous although their variants were rare, making their identification difficult. Here, we reported clinical and genetic characteristics of 30 Tunisian GGE families, including 71 GGE patients. The phenotype was close to that in sporadic cases. Nineteen pedigrees had a homogeneous type of GGE (JME-CAE-CGTS), and 11 combined these epileptic syndromes. Rare non-synonymous variants were selected in probands using a targeted panel of 30 candidate genes and their segregation was determined in families. Molecular studies incriminated different genes, mainly CACNA1H and MAST4. The segregation of at least two variants in different genes in some pedigrees was compatible with the hypothesis of an oligogenic inheritance, which was in accordance with the relatively low frequency of consanguineous probands. Since at least 2 susceptibility genes were likely shared by different populations, genetic factors involved in the majority of Tunisian GGE families remain to be discovered. Their identification should be easier in families with a homogeneous type of GGE, in which an intra-familial genetic homogeneity could be suspected.

Bardet-Biedl syndrome (BBS) is a model disease for ciliopathy in humans. The remarkable genetic heterogeneity that characterizes this disease is consistent with accumulating data on the interaction between the proteins encoded by the 14 BBS genes identified to date. Previous reports suggested that such interaction may also extend to instances of oligogenic inheritance in the form of triallelism which defies the long held view of BBS as an autosomal recessive disease. In order to investigate the magnitude of triallelism in BBS, we conducted a comprehensive analysis of all 14 BBS genes as well as the CCDC28B-modifier gene in a cohort of 29 BBS families, most of which are multiplex. Two in trans mutations in a BBS gene were identified in each of these families for a total of 20 mutations including 12 that are novel. In no instance did we observe two mutations in unaffected members of a given family, or observe the presence of a third allele that convincingly acted as a modifier of penetrance and supported the triallelic model of BBS. In addition to presenting a comprehensive genotype/phenotype overview of a large set of BBS mutations, including the occurrence of nonsyndromic retinitis pigmentosa in a family with a novel BBS9 mutation, our study argues in favor of straightforward autosomal recessive BBS in most cases.

The admixture test of linkage heterogeneity is the most often and most successfully applied oligogenic-model linkage and/or LD analysis method. Full two-locus model linkage analysis is possible, but can be computationally intensive and difficult to interpret because of the need to specify so many indeterminate parameters. A novel, computationally efficient method is proposed for combining single locus lod scores which can allow for varying degrees of epistatic interaction. This method can be applied to two-point or multipoint (using complex-valued recombination fractions) linkage and/or linkage disequilibrium analysis to jointly test for multiple unlinked disease loci. Unlike the traditional admixture test, this algorithm permits joint analysis of multiple disease loci with different modes of inheritance for each, and can be applied to 'model-free' analysis as well through the use of 'pseudomarkers'. Software is available for computation of the various likelihood ratio tests described, for comparison of a variety of possible hypotheses regarding locus homogeneity, locus heterogeneity, and epistasis.

The melon (Cucumis melo) plant introduction PI 414723 was observed to segregate for resistance after inoculation with a highly virulent non-aphid-transmissible strain of zucchini yellow mosaic potyvirus (ZYMV-NAT). By self-pollination of selected resistant plants, the percentage of resistant plants increased in successive generations until nearly 100% in the S7 progeny. A reciprocal cross was made between a resistant S5 plant of PI 414723 and a plant of the susceptible cultivar Dulce. Parental-, filial-, and backcross- generation plants were inoculated with ZYMV-NAT. One-half of the F1 plants, regardless of the direction of the cross, were resistant, indicating that the PI 414723 individual used for crossing was heterozygous. The F2 generation obtained by self-pollination of resistant F1 plants segregated to resistant and susceptible in accordance with a 27:37 ratio, indicating that, in this cross, three complementary dominant genes are needed for resistance to be expressed. The resistance to ZYMV carried by PI 414723 is oligogenic with the number of genes observed to segregate in crossing depending on the genotype of the susceptible parent.

Breeding for host resistance to coffee berry disease (CBD) in arabica coffee (Coffea arabica) was initiated some 35–40 years ago in Kenya, Ethiopia and Tanzania in response to severe CBD epidemics. The release of CBD resistant cultivars to the coffee growers has been in progress since 1985. The resistance of cultivars like Ruiru 11 (Kenya) and Ababuna (and other cvs in Ethiopia) appears to be of a durable nature, since confirmed cases of a breakdown of host resistance under field conditions have not been reported over the past 20 years. Host resistance to the hemibiotrophic fungus Colletotrichum kahawae is of a quantitative nature, but nevertheless can be practically complete in some genotypes of arabica coffee. There is still no consensus on the genetics of CBD resistance, some claiming convincing evidence for oligogenes (1–3 major genes) and others for polygenes determining CBD resistance. Results from genetic studies with germplasm from the centre of genetic diversity for C. arabica in Ethiopia are presented here. These together with the recent identification of molecular markers associated with and the mapping of one major gene, provides additional evidence for oligogenic inheritance of CBD resistance. The development of cultivars combining yield and quality with durable host resistance to CBD has contributed greatly to increased sustainability of arabica coffee production in Africa. It has also considerable relevance to arabica coffee in Latin America and Asia, where CBD is still a quarantine disease but with a risk of becoming endemic one day, just as has happened earlier with coffee leaf rust (Hemileia vastatrix).

Nonsyndromic Hirschsprung disease, hitherto assumed to be a multifactorial disease with a threshold effect due to an unknown number of genes, has been genetically dissected and shown to result from an interaction between just three loci, two of which have not previously been associated with the disease. Oligogenic inheritance can explain the main aspects of its genetic epidemiology.