Implications of copy number variation in people with chromosomal abnormalities: potential for greater variation in copy number state may contribute to variability of phenotype

Abstract

Copy number variation is common in the human genome with many regions, overlapping thousands of genes, now known to be deleted or amplified. Aneuploidies and other forms of chromosomal imbalance have a wide range of adverse phenotypes and are a common cause of birth defects resulting in significant morbidity and mortality. "Normal" copy number variants (CNVs) embedded within the regions of chromosome imbalance may affect the clinical outcomes by altering the local copy number of important genes or regulatory regions: this could alleviate or exacerbate certain phenotypes. In this way CNVs may contribute to the clinical variability seen in many disorders caused by chromosomal abnormalities, such as the congenital heart defects (CHD) seen in ~40% of Down's syndrome (DS) patients. Investigation of CNVs may therefore help to pinpoint critical genes or regulatory elements, elucidating the molecular mechanisms underlying these conditions, also shedding light on the aetiology of such phenotypes in people without major chromosome imbalances, and ultimately leading to their improved detection and treatment.

Keywords: Aneuploidy; Chromosomal abnormalities; Copy number variation; Phenotypic variability.

Fig. 1

Mechanisms of phenotypic variability in trisomy resulting from copy number variation. Amplification of gene copy number during non-disjunction (NDJ) can result in a range of copy number states. Where dosage-sensitive genes are involved, this may result in a wide range of associated phenotypes. This figure illustrates a number of different potential outcomes for a single gene which is susceptible to duplication and/or deletion. a illustrates the difference between meiosis I (MI) and meiosis II (MII) NDJ occurring in parent A; b–d illustrate just three of the possible scenarios resulting from NDJ in parent A if gene duplications are present in one or both parents, each of which could result in over-expression of a dosage-sensitive gene; e illustrates how a deletion on parent B and MII NDJ in parent A, however, that leads to a total of two copies of the gene in the trisomic child which could potentially ameliorate the pathological effects of trisomy

Fig. 2

Copy number variation on chromosome 21. This shows the penetrance plot of aberration calls on chromosome 21 from array CGH data from 50 apparently healthy French Caucasian males (de Smith et al.2007), generated using ADM-2 algorithm with threshold 4 in CGH Analytics 3.4. This displays the percentage of the 50 arrays that have an aberration at each probe position along the chromosome: deletion aberrations point downwards from 0, and amplifications point upwards. The box shows the position of the CNV within DSCAM