2009; Vassos et al. 2010; Breckpot et al. ` 2011; Ciuladaite et al. 2011; Hosak et al. 2012; Klopocki et al. 2012; Rosenfeld et al. 2013; Vaags et al. 2012; Weischenfeldt et al. 2013; Dabell et al. 2013; Carvill and Mefford 2013; Tropeano et al. 2013). In their study of youngsters recognized to carry a CNV associated with intellectual disability and congenital abnormalities, Girirajan et al. (2012) reported synergy in between various significant CNVs top to a especially extreme clinical presentation. Such a two-hit model, or `oligogenic heterozygosity’ because it has been termed, also seems to be characteristic of autism (Pinto et al. 2010; Schaaf et al. 2011b; Klei et al. 2012; Gau et al. 2012). The penetrance of a provided CNV may also be influenced by genetic variants within the vicinity. Thus, a submicroscopic deletion of 1q21.1 (encompassing the RBM8A gene) has been reported to interact having a low-frequency functional SNP in the regulatory area from the wild-type RBM8A allele to lead to thrombocytopaenia with absent radii (Albers et al. 2012).Allele dosage and its influence on penetrance Formally, use in the term `autosomal dominant’ implies that the homozygotes exhibit the identical or possibly a equivalent clinical phenotype for the heterozygotes, as will be the case in Huntington disease exactly where the length on the expanded HTT CAG triplet repeat seems to be predictive from the age of onset irrespective with the presence or absence of a second expanded HTT allele (Lee et al. 2012a). On the other hand, in practice, for most `dominant’ human problems in which homozygotes have already been reported, their clinical symptoms tend to be TAPI-2 custom synthesis drastically a lot more serious than within the heterozygotes (Vogel and Motulsky 1997). This would appear to be especially true within the context of low-penetrance mutations for instance those identified in the SCN4A and CLCN1 genes, causing muscle channelopathies, circumstances which are typically held to be transmitted in an autosomal dominantHum Genet (2013) 132:1077Several papers have now recommended that CNVs can also act as genetic modifiers of phenotype severity within a selection of distinct disease contexts (Beckmann et al. 2007; Chaudru et al. 2009; El-Hattab et al. 2010; Mulley et al. 2011; Jiang et al. 2011; Carvalho et al. 2012; Shen et al. 2013b). CNVs may possibly influence the penetrance of a clinical phenotype indirectly also as directly. As an example, a mutant gene could be `covered’ by a CNV inside a offered individual, so that the anticipated clinical phenotype will be masked by the presence of an additional wild-type copy in cis towards the gene in question. Constant with this postulate, Ng et al. (2008) reported that 30 of nonsense SNPs occur in genes residing within segmental duplications, a proportion some threefold bigger than that noted for synonymous SNPs. Genes harbouring nonsense SNPs had been also discovered to belong to larger gene households (Ng et al. 2008) suggesting that some functional redundancy could also exist among paralogous human genes. In support of this thought, Hsiao and Vitkup (2008) reported that these human genes which have a homologue with [90 sequence similarity are three times much less most likely to harbour disease-causing mutations than genes with significantly less closely connected homologues. Hsiao and Vitkup (2008) interpreted their findings in terms of `genetic robustness’ against null mutations, with all the duplicated sequences supplying `backup’ by pote.