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Study Explores Basis for Clinical Variability in Conditions Linked to Rare CNVs

NEW YORK (GenomeWeb News) – A subset of genomic disorders stemming from rare copy number variants involve one or more additional CNVs that combine to contribute to the variability observed in these conditions, according to a study appearing online last night in the New England Journal of Medicine.

By looking at the nature and frequency of additional rare CNVs in individuals with developmental delay who were known to carry at least one suspicious rare rearrangement, an international team led by investigators at the University of Washington found clues to understanding the range of phenotypes associated with potentially pathogenic CNVs.

Their analyses suggests that conditions characterized by very variable phenotypes are more apt to involve rare, disease-associated CNVs acting in concert with other rare de novo or inherited rearrangements, while so-called "syndromic disorders" typically involve fewer rearrangements overall.

"Our data are consistent with locus heterogeneity and a modest number of high-impact variants contributing to a spectrum of disease severity within families," senior author Evan Eichler, a genome sciences researcher at the University of Washington, and his colleagues explained.

"The interpretation of clinical variants associated with phenotypic variation remains challenging at the clinical level," they added, "but our study provides a step toward understanding factors that contribute to the phenotypic outcome, which may be used for counseling."

Although several recent studies have shown that rare, recurrent copy number alterations can contribute to human diseases — particularly conditions with a neurodevelopmental component — the wide variation with which these genomic disorders present themselves can make it tricky to use CNV patterns in a clinical setting.

"[C]omparatively recent discoveries of potentially pathogenic copy-number variants have broadened the phenotypic range associated with a given variant to include entirely distinct diseases," the study authors explained, noting that "[h]igh-throughput analyses of patient populations have implicated the same copy-number variants in diseases such as schizophrenia, autism, cardiac disease, epilepsy, and intellectual disability."

To look at the basis of this variability in more detail, the researchers started from data on almost 33,000 children who had been diagnosed with intellectual disability and/or congenital abnormalities at various sites in the US between 2008 and 2010.

To root out genome-wide CNV patterns in these cases, samples from each of the 32,587 children had been assessed by array-CGH at Signature Genomic Laboratories, a company co-founded by University of Washington researcher and study co-author Lisa Shaffer.

For 2,312 of the children with intellectual disability, developmental delays, and/or congenital malformation, the aCGH analyses uncovered one of 72 CNVs known or suspected to cause a genomic disorder.

But the researchers suspected that there might be rare copy number changes beyond these apparently pathogenic CNVs that were contributing to some of the children's clinical phenotypes. Indeed, when they delved into the data further, they found that just over 10 these children carried at least one additional, rare CNV.

Compared to more than 8,300 control individuals without detectable neurological disorders, the team reported, children carrying at least two large CNVs were roughly eight times as likely to be diagnosed with developmental delay.

The team analyzed CNV patterns for 841 children with autism spectrum disorder and found that that the median IQ crossed the threshold for intellectual disability among subjects with 18 or more disrupted genes compared with those who had fewer such genes.

Results of the study hint that conditions stemming from multiple rare CNVs are more likely to include individuals with a wide range of phenotypes than are primary CNVs linked to a specific genetic syndrome. Moreover, boys were more likely than girls to be affected by these non-syndromic, phenotypically variable conditions.

Whereas many of the syndromic variants detected in the study seem to have arisen spontaneously in affected children, researchers reported, conditions involving multiple rare copy number changes were more likely to include at least one inherited CNV — more often than not passed on by mothers.

"Multiple, large copy-number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation," Eichler and his co-authors wrote, "and secondary copy-number variants are preferentially transmitted from maternal carriers."

In an accompanying editorial appearing in the same issue of NEJM, Radboud University human genetics researcher Han Brunner credited the team with providing genetic evidence to explain the range of features associated with some genomic disorders.

"We can look forward to further improvements in our understanding of the variation in genetic disease, which will in turn permit physicians to better inform their patients about the cause of their condition, its prognosis, and the therapy that is most likely to benefit them," Brunner concluded.

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