NEW YORK – An international team has tracked down a block of common variants that seem to modify the congenital heart disease risk associated with a chromosome 22 microdeletion syndrome.
Researchers from the US, Chile, Belgium, and elsewhere searched for rare disease modifiers using whole-genome sequence data for more than 1,000 individuals with 22q11.2 deletion syndrome (22q11.2DS), before doing common variant searches with case-control data and genome-wide association meta-analyses. Together, their analyses led to a block of common variants in and around CRKL, including a SNP influencing the expression of that enzyme-coding proto-oncogene.
"Complete sequence data indicate that this association was not driven by rare variants individually or jointly in the same region, suggesting that associated common variants are among the top causal variants," senior editor Bernice Morrow, a genetics researcher at the Albert Einstein College of Medicine, and her co-authors noted in their American Journal of Human Genetics study.
Congenital heart conditions — particularly cardiac outflow defects of the heart known as "conotruncal" defects — arise in some 60 or 70 percent of individuals with 22q11.2 deletion syndrome, which typically stem from de novo non-allelic homologous recombination events involving four low-copy repeats, the team noted. Even so, a subset of individuals who carry the 3-million-base chromosome 22 deletion appear to have normal cardiac anatomy, suggesting additional genetic factors may serve as modifiers.
"Phenotypic variability … cannot be fully explained by the presence of the 22q11.2 deletion or deletion size and is most likely due to the existence of additional genetic and/or environmental modifiers," the authors wrote, noting that modifier identification "can provide insight into the biological mechanism of heart development and disease."
In an effort to find rare or common variants that might modify the deletion syndrome, perhaps by impacting the second copy of the chromosome 22 region, the researchers analyzed whole-genome sequences for 1,053 participants in the International 22q11.2 Brain and Behavior Consortium study.
While the individuals all had 22q11.2DS, more than 40 percent had conotruncal heart defects and almost 56 percent had any type of congenital heart diagnosis, while 469 individuals were not affected by heart disease or other conditions considered.
While the team's analyses did not lead to rare variants with significant disease ties, a common variant analysis focused on 424 individuals with 22q11.2DS and conotruncal heart defects compared with 469 heart disease-free 22q11.2DS individuals led to 45 SNPs in linkage disequilibrium with one another on chromosome 22 that appeared to boost heart defect risk.
When they folded in information from prior GWAS, meanwhile, the researchers validated associations with conotruncal heart defects for four of these common variants — a set that included an apparent enhancer for the CRKL gene, which has been linked to similar heart defects in mice.
"Haploinsufficiency of this region alone is associated with [conotruncal defects]," the authors concluded, "and when taken together with mouse genetic studies, the results presented here implicate, most plausibly, CRKL as a possible target of non-coding putative regulatory variants."