An estimation of the prevalence of genomic disorders using chromosomal microarray data

Abstract

Multiple genomic disorders result from recurrent deletions or duplications between low copy repeat (LCR) clusters, mediated by nonallelic homologous recombination. These copy number variants (CNVs) often exhibit variable expressivity and/or incomplete penetrance. However, the population prevalence of many genomic disorders has not been estimated accurately. A subset of genomic disorders similarly characterized by CNVs between LCRs have been studied epidemiologically, including Williams-Beuren syndrome (7q11.23), Smith-Magenis syndrome (17p11.2), velocardiofacial syndrome (22q11.21), Prader-Willi/Angelman syndromes (15q11.2q12), 17q12 deletion syndrome, and Charcot-Marie-Tooth neuropathy type 1/hereditary neuropathy with liability to pressure palsy (PMP22, 17q11.2). We have generated a method to estimate prevalence of highly penetrant genomic disorders by (1) leveraging epidemiological data for genomic disorders with previously reported prevalence estimates, (2) obtaining chromosomal microarray data on genomic disorders from a large medical genetics clinic; and (3) utilizing these in a linear regression model to determine the prevalence of this syndromic copy number change among the general population. Using our algorithm, the prevalence for five clinically relevant recurrent genomic disorders: 1q21.1 microdeletion (1/6882 live births) and microduplication syndromes (1/6309), 15q13.3 microdeletion syndrome (1/5525), and 16p11.2 microdeletion (1/3021) and microduplication syndromes (1/4216), were determined. These findings will inform epidemiological strategies for evaluating those conditions, and our method may be useful to evaluate the prevalence of other highly penetrant genomic disorders.

Figure 1

DECIPHER coordinates genomic disorders at chromosomes 1q21.1, 15q13.3, and 16p11.2. Region is highlighted in red box along the chromosome. For 15q13.3 microdeletions, larger deletions spanning breakpoint 3 to breakpoint 5 were included, but only breakpoint 4 to breakpoint 5 is shown. Adapted from UCSC Genome Browser.

Figure 2

Linear regressions used to determine prevalence of highly penetrance genomic disorders. Percent of CMA cases at the Baylor Genetics (BG) Laboratories was plotted against known population prevalence. The prevalence of 1q21.1 microdeletion syndrome (red circle), 1q21.1 microduplication syndrome (blue circle), 15q13.3 microdeletion syndrome (red triangle), 16p11.2 microdeletion syndrome (red square), and 16p11.2 microduplication syndrome (blue square) were extrapolated based on the prevalence of Smith-Magenis syndrome (SMS), Williams-Beuren syndrome (WBS), Prader-Willi syndrome/Angelman syndrome (PWS/AS), and Velocardiofacial syndrome (VCFS).