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Newswise Audrey Lapidus adored her babys sunny smile and irresistible dimples, but grew worried when Calvin did not roll over or crawl by 10 months and suffered chronic digestive problems. Four neurologists dismissed his symptoms and a battery of tests proved inconclusive. Desperate for answers, Audrey and her husband agreed to have their son become UCLAs first patient to undergo a powerful new test called exome sequencing.

Using DNA collected from Calvins and his parents blood, a sophisticated sequencing machine rapidly scanned the boys genome, compared it to his parents and flagged a variant on his 18th chromosome. Calvin was diagnosed with Pitt-Hopkins Syndrome, a rare genetic disorder affecting only 250 children worldwide. At last Audrey and her husband had a concrete diagnosis and clear direction for seeking the best treatment for their son.

Now a landmark UCLA study makes a persuasive argument for the routine clinical use of exome sequencing as a valuable tool for diagnosing children like Calvin with rare genetic disorders. Published in the Oct. 18 online edition of the Journal of the American Medical Association, the findings show that exome sequencing produced a definitive diagnosis in 40 percent of UCLAs most complex cases a quantum leap from the fields 5-percent success rate two decades ago.

Our study is the first to show that sequencing a childs genome together with his or her parents dramatically improves geneticists ability to reach a firm diagnosis in rare disorders, said corresponding author Dr. Stan Nelson, vice chair of human genetics and a professor of pathology and laboratory medicine at David Geffen School of Medicine at UCLA. We discovered a genetic cause for the conditions affecting 40 percent of the hundreds of young children who come to UCLA for exome sequencing due to developmental delays or intellectual disabilities.

The UCLA Clinical Genomics Center was established in 2011 as one of three facilities in the world (including Baylor and Harvard) to put DNA sequencing to clinical use. Unlike earlier diagnostics that study one gene at a time, this test rapidly sifts through all of the 37-million base pairs in a persons 20,000 genes to tease out the single DNA change causing a rare genetic disorder. It focuses on the exome, the protein-coding portions of genes that account for only 1 percent of DNA but nearly 85 percent of the glitches known to cause human diseases.

In this two-year study, Nelson worked with first author Hane Lee, an assistant adjunct professor of pathology, to sequence and analyze the exomes of 814 children whose symptoms had baffled previous clinicians despite exhaustive genetic, biochemical and imaging tests.

Heres how it worked. The UCLA center funneled the raw data from sequencing the genomes of each child and their parents through its informatics pipeline to identify variants from the standard human genome. The average persons exome contains more than 20,000 variants, nearly all benign.

Next the team applied a series of filters to the data based on the patients family history and other relevant aspects of his or her condition. The researchers hunted for all genes and mutations linked by medical literature to the patients symptoms. Finally UCLAs Genomics Data Board, a multidisciplinary team of experts, reviewed the findings to reach a diagnosis.

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New Test Scans All Genes Simultaneously to Identify Single Mutation Causing Child's Rare Genetic Disease