Calvin, who was diagnosed
with Pitt-Hopkins Syndrome
via trio-CES
Credit: Lapidus family
A 3-pronged approach to clinical exome sequencing (CES) can provide a higher diagnostic yield than traditional molecular diagnostic methods, results of a new study suggest.
Investigators found that sequencing a patient’s exome together with his or her parents’—a method known as trio-CES—greatly improved the ability to reach a firm diagnosis in children with suspected genetic conditions.
This research was published in JAMA. It was released to coincide with a presentation at the American Society of Human Genetics Annual Meeting in San Diego.
The researchers performed CES on 814 patients with undiagnosed, suspected genetic conditions between January 2012 and August 2014. Sequencing was conducted as trio-CES or as proband-CES (only the affected individual sequenced) when parental samples were not available.
The team funneled the raw data through an informatics pipeline to identify variants from the standard human genome. Next, they applied a series of filters to the data based on the patient’s family history and other relevant aspects of his or her condition.
The investigators then hunted for all genes and mutations linked by medical literature to the patient’s symptoms. And a multidisciplinary team of experts reviewed the findings to reach a diagnosis.
Overall, 26% of patients (213/814) received a molecular diagnosis, with the causative variant(s) identified in a well-established clinical gene.
There was a significantly higher molecular diagnostic yield from cases performed as trio-CES relative to proband-CES—31% (127/410) and 22% (74/338), respectively.
In cases of developmental delay in children younger than 5 years (n=138), the molecular diagnosis rate was 41% (45/ 109) for trio-CES cases and 9% (2/23) for proband-CES cases.
The typical turnaround time for exome sequencing is less than 8 weeks, though test results have been returned to physicians within 10 days in medically urgent situations.
With preauthorization, many insurance providers cover the cost to sequence a child and both parents. If not, the out-of-pocket fee is about $6650.
“All families deserve a clear diagnosis of their child’s condition,” said study author Wayne Grody, MD, PhD, of the University of California, Los Angeles.
“Exome sequencing plays an important role in identifying the precise cause of a child’s illness. This is immediately useful to families and physicians in understanding how the disease occurred, preventing unnecessary testing, and developing the best strategies to treat it.”
The researchers noted, however, that the clinical implications of their findings should be better understood before trio- or proband-CES are routinely adopted.
