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CNV Complication: Duplication at 22q11.2 Masks Effect of Deletion

3 April 2009. A deletion on chromosome 22 that caused velocardiofacial syndrome in an infant girl appeared to be a classic de novo copy-number variation (CNV), because the baby had two healthy parents. But a closer look revealed that the deletion was inherited after all. That was possible because the father turned out to carry not one but two CNVs: the deletion on one chromosome was balanced by a duplication on the other. A clear-cut case of genetic compensation, the family is described by Elisabeth Flori of the Strasbourg University Hospital in France and colleagues in a paper published in the New England Journal of Medicine on March 19. Such compensation could contribute to the incomplete penetrance of disease-causing mutations, a situation that clouds the connections between CNVs and disease in schizophrenia and other disorders.

Deletions and duplications in the 22q11.2 region cause velocardiofacial syndrome, and about one-third of children affected go on to develop schizophrenia. Many of the deletions appear to occur de novo, but some are inherited. In this case, first author Nadege Carelle-Calmels led the analysis of the healthy parents, and cytological analysis using fluorescent in situ hybridization (FISH) revealed the unusual genetic constellation in the father. A check on gene expression in blood cells confirmed that the mRNA levels of affected genes were halved in the affected child, but not in the father, suggesting that the duplication compensated for the deletion to maintain normal expression levels.

“Considering the density of copy-number variations in the human genome, the presence of compensatory copy-number variations may explain why some loss-of-function mutations have low penetrance,” the authors write. This could apply to a growing number of CNVs, mostly deletions, that have been linked to schizophrenia, many of which are inherited from healthy parents (see SRF related news story and SRF news story).

The authors also point out that the deletion and duplication in the father readily appeared on FISH cytogenetic analysis.—such a balanced change would have registered normal on arrays measuring gene copy number. The data thus serve as a cautionary lesson about arrays. They are only one tool, and may not always tell the whole story.—Pat McCaffrey.

Carelle-Calmels N, Saugier-Veber P, Girard-Lemaire F, Rudolf G, Doray B, Guérin E, Kuhn P, Arrivé M, Gilch C, Schmitt E, Fehrenbach S, Schnebelen A, Frébourg T, Flori E. Genetic compensation in a human genomic disorder. N Engl J Med. 2009 Mar 19;360(12):1211-6. Abstract

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