Adding Insult to Injury, Complexity to Intricacy

Mundlos, 2016]. Third, mixed mutational mechanisms in which CNVs, chromosome disruptions and gene mutations may occur simultaneously. A particular type of mixed mutational mechanism, namely unmasking of a recessive disease allele by an overlapping loss in the other chromosome, known from studies of SVs, in particular CNVs, has recently been confirmed by diagnostic whole exome sequencing of a cohort of 2,076 patients [Flipsen-ten Berg et al., 2007; Hochstenbach et al., 2012; Poot and Haaf, 2015; Posey et al., 2017]. In 3 out of 101 patients exhibiting symptoms pertaining to 2 syndromes, homozygous intragenic deletions of 1–3 exons of a single gene were found [Posey et al., 2017]. This study shows that intragenic deletions may occur more often than thus far thought and highlights their relevance as a pathogenic mechanism [Poot, 2017; Posey et al., 2017]. These data are in agreement with the impression from a review of 27 literature reports that patients with “double syndromes” are more likely to harbor unmasking of recessive alleles than those with apparently random assortments of symptoms [Flipsen-ten Berg et al., 2007; Hochstenbach et al., 2012; Poot and Haaf, 2015; Posey et al., 2017]. Digenic disorders, such as retinitis pigmentosa, Bardet-Biedl and Joubert syndrome, some forms of deafness, some blood-clotting disorders, and Hirschprung disease, are well-known, while patients with dual or even multiple molecular diagnoses are rarely reported in the literature [Schäffer, 2013; Wallis et al., 2016]. In 101 cases out of 2,076 diagnostic whole exome sequencing (4.9%), this underrecognized phenomenon has been documented [Posey et al., 2017]. The single nucleotide variants (SNVs) In general, medical genetics tries to classify the phenotypes of a patient as manifestations of a syndrome; i.e., a correlated set of symptoms with a common cause. In genetic terms, this cause is supposed to be either “mendelian”, “chromosomal”, or de novo. Mendelian refers to a specific mode of transmission; e.g., recessive, dominant, or X-linked, of the disease allele(s) of a gene and the risk of recurrence of the disease within the family depending on the specific mode of transmission. Complex phenotypes that cannot be subsumed under a single gene are generally thought to be of “chromosomal” origin. This means that the organization of genomic elements, such as genes, promoters, enhancers, etc. has been altered such that a structural variation (SV) resulted [Poot and Haaf, 2015]. SVs may exert a phenotypic effect by changing the copy number of dosage-dependent genes leading to a loss or gain of one or several genes. In the latter case, a contiguous gene syndrome arises typified by a complex set of phenotypes consistent with several mendelian syndromes in a single patient. By comparison of patients with overlapping deletions, candidate genes within the contiguous gene syndrome can be pinpointed and their potential contribution to individual symptoms ascertained [Boland et al., 2007; Caliebe et al., 2010; Baliff et al., 2012; Depienne et al., 2017]. Second, an SV may disrupt the genomic architecture such that genes, parts of genes, and regulatory elements are relocated and their interactions perturbed. The phenotypic effects of the latter are mediated by alteration of gene expression patterns rather than changes in the structure of the encoded protein(s) [Reymond et al., 2007; Henrichsen et al., 2009; Klopocki and Mundlos, 2011; Lupiáñez et al., 2015; Spielmann and Accepted: March 29, 2017 by M. Schmid Published online: June 9, 2017