Nature Medicine | Spoonful of Medicine

Database to help doctors grasp disease risk of duplications the genome

Copy number variations, in which a section of DNA is duplicated or deleted, have been a boon for geneticists hoping to explain the chromosomal causes of everything from autism to schizophrenia to colon cancer. CNVs that are deletions can be helpful in diagnosing a handful of developmental disorders and birth defects such as DiGeorge syndrome, an illness affecting skull formation in which a portion of chromosome 22 is missing. But when doctors find a CNV that is a duplication, they have difficulty knowing exactly which disorder their patient might have as a single duplicated region can cover multiple genes. For example, the clinical significance of rare duplication CNVs of the region including the gene DCLK2, which has been implicated in attention deficit hyperactivity disorder (ADHD), are often missed by lab technicians and physicians.

A new database has begun to change that, allowing doctors to input and access all of the tested mutations within a CNV. The free International Standards for Cytogenomic Arrays (ISCA) database, which currently includes the results of 30,000 CNV tests and is housed at the US National Center for Biotechnology Information in Bethesda, is described in the May issue of Clinical Genetics, and has already drawn more than 800 users. Using the database, “a doctor or lab technician can see all the genes in a CNV,” says geneticist and senior author Christa Martin of Emory University in Atlanta.

What’s more, the database includes a rating system to help physicians estimate how likely genes within an observed CNV are to cause disease. Each CNV is ranked by expert groups on the basis of seven criteria, including the number of mutations reported in people with the CNV, mutational mechanisms and patterns of inheritance. The ratings for CNVs go from 0 (no evidence it causes disease) to 3 (sufficient evidence to predict disease). Surprisingly, “before now, there was not a formal process to rate CNV pathogenicity,” says Martin. “It made analyzing [CNV microarray] data very confusing for doctors. This database begins to fix that problem.”

The ISCA database may become even more important in the future. Preliminary data from a multicenter study presented in February at the Society for Maternal-Fetal Medicine meeting in Dallas indicated that microarray testing detects fetal abnormalities than the current standard karyotype test misses. Helping parents make decisions based on prenatal CNV testing will require the use of a database. “It’s no longer an option for doctors to just avoid CNVs because they’re too complicated to analyze,” says Martin. “Physicians will have to start using the new database tools available to them.”

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