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ACMG Recommends Sequencing as Test for Children With Intellectual Disability, Congenital Anomalies

NEW YORK ­– The American College of Medical Genetics and Genomics strongly recommends the use of exome or genome sequencing as a first- or second-tier test for children with intellectual disability, developmental delay, or multiple congenital anomalies in new guidelines released Thursday.

Congenital anomalies, developmental delay, and intellectual disability are among the top reasons for pediatric genetic referrals, and can affect children's life expectancy, health, learning, and behavior. Globally, there are an estimated 1,982 intellectual disability cases per 100,000 children, and a European analysis found 23.9 major congenital anomalies per 1,000 births there.

According to the developers of the new guidelines, having a diagnosis can lead to changes in patient management that could influence morbidity and mortality as well as end the diagnostic odyssey many patients and their families go through.

To develop their practice guideline, an ACMG working group conducted a systematic review of the literature to gauge whether it supported the use of exome or genome sequencing as an early test among pediatric patients with intellectual disability or multiple congenital anomalies. They found evidence that exome or genome sequencing has clinical utility and desirable effects on the clinical management of patients, with few associated harms, as they reported in Genetics in Medicine.

"We are excited to announce the publication of the first ACMG-endorsed evidence-based guideline on the use of exome and genome sequencing for evaluation of pediatric intellectual disability or multiple congenital anomalies," Fuki Marie Hisama from the University of Washington School of Medicine and Kandamurugu Manickam from Nationwide Children's Hospital, who co-chaired the ACMG working group, said in a statement. "We expect this EBG will help to raise the quality and consistency of healthcare and improve outcomes for patients with rare genetic disorders."

The Pediatric Exome Sequencing/Genome Sequencing Guideline Work Group considered 167 studies in its analysis. The working group focused on both exome sequencing and genome sequencing, as exome sequencing is currently widely available as a clinical tool and as, while genome sequencing is less common, the group expects the number of labs offering it to increase.

They assessed the quality of the studies they considered using the "Grading of Recommendations Assessment, Development and Evaluation" evidence-to-decision framework.

Clinical utility, the panel noted, includes both short-term clinical management changes like alterations to treatment and long-term clinical management changes like specialist referrals, surveillance, or lifestyle modifications. Their literature-based assessment suggested that exome and genome sequencing do lead to changes in clinical management.

For instance, they found that exome and genome sequencing had a short-term clinical management impact of 8 percent and long-term clinical management impact of 10 percent. The Ontario Health Technology Assessment also reported respective impact rates of 6.3 percent and 17.5 percent, the group noted.

The panel additionally found that exome sequencing and genome sequencing had reproductive and family-focused outcomes — such as decisions surrounding pregnancy and prenatal testing and concerning cascade testing — at a rate of 9 percent and 4 percent, respectively.

At the same time, the Ontario HTA has reported a diagnostic yield of 38 percent for genome-wide sequencing, as compared to 21 percent for standard genetic testing. The working group also pointed out that some patients' parents have also found nondiagnostic results helpful if they rule out certain conditions.

Meanwhile, the panel weighed the potential harms of exome or genome sequencing. Most of the studies they analyzed reported few harms, though the ones they did find include cases of misattributed paternity and financial cost of treatment.

On balance, the panel concluded the potential benefits outweigh the potential harms of exome or genome sequencing of children with intellectual disability, developmental delay, or multiple congenital anomalies.