Pathogenic Mechanisms and Clinical Consequences of Chromosomal Aberrations in Man

Abstract

Abstract Structural genome variations (SVs) found in patients with ‘cytogenetic disorders’ are classified as deletions, duplications, translocations, inversions, insertion translocations and complex chromosome rearrangements. Some SVs are phenotypically neutral, but de novo SVs in isolated patients or SVs inherited from a diseased parent are generally considered pathogenic. A phenotypic effect results either from gene dosage‐dependent mechanisms, for example, haploinsufficiency, or mechanisms based on disruption of the genomic architecture, such that genes, parts of genes or regulatory elements are truncated, fused or relocated and their interactions disturbed. This mechanism predominantly affects gene expression. Third, mixed mutational mechanisms in which an SV is combined with a different mutation on the other, homologous chromosome, have been documented. Inferred mechanisms of pathogenicity need corroboration by mRNA sequencing. In addition, future studies with model systems such as inducible pluripotent stem cells from patients and transgenic organisms should substantiate current inferences regarding phenotypic effects of SVs. Key Concepts Structural genome variations (SVs) result either from one or two chromosome breaks; for example, terminal deletions, reciprocal translocations or from more than 2 breaks, that is, complex chromosome rearrangements. The rate of detection and the apparent complexity of the detected SVs increase with improving resolution of detection techniques. SVs may exert pathogenic effects by gene dosage alterations, disruption of genomic architecture and mixed mutational mechanisms. Genes which encode proteins that engage in physical interactions with other proteins may cause phenotypic effects after gene dosage alterations. Disruption of genomic architecture by SVs may provoke phenotypic effects by altering the transcription of genes in the vicinity of the chromosome break. If a deletion on one chromosome is combined with a deletion or a single nucleotide variant in the same deleted segment on the other, homologous chromosome, a mixed mutational mechanism, such as ‘unmasking’, may arise. In counselling families with at least one individual with an SV multiple, possibly pathogenic mechanisms have to be considered.