Whole-exome sequencing (WES) and other genetic tests can shorten the “diagnostic odyssey” in a substantial percentage of cases of suspected pediatric monogenic conditions and early-life epilepsy, according to two studies published online July 31 in JAMA Pediatrics.
Several large-scale studies that have indicated the effectiveness of WES in diagnosing monogenic disorders have focused on patients who have already tested negative for multigene panels. WES earlier in the diagnostic odyssey may be even more valuable, in terms of economics and in preventing suffering from protracted and unnecessary diagnostic procedures.
Tiong Yang Tan, MBBS, PhD, from the Victorian Clinical Genetics Services in Melbourne, Australia, and colleagues used WES prospectively to diagnose 23 of 44 (52%) sequencing-naive children aged 2 to 18 years. Participants enrolled in the Melbourne Genomics Health Alliance demonstration project had had chromosomal microarray analysis (CMA) that had not led to diagnosis. Including older children enabled analysis of individuals with intellectual disability but no congenital anomalies. Parents also underwent WES.
Pediatricians had referred the children in 2015 from outpatient clinics to clinical geneticists because symptoms such as dysmorphic facial features and multiple anomalies suggested monogenic disease. The mean diagnostic odyssey lasted 6 years; each child had undergone a mean 19 tests, four clinical genetics evaluations, and four nongenetics specialist consultations; and 26 (59%) had undergone a diagnostic procedure requiring general anesthesia.
Sanger sequencing was used to follow up on identification of pathogenic or likely pathogenic variants, and geneticists prioritized genes most likely to explain symptoms.
In eight of the 23 cases (35%), the identified gene was not among those the referring geneticist had specified as likely causative. In six cases (26%), the diagnosis led to a change in clinical management, such as surveillance for specific complications, ceasing surveillance for suspected diagnoses that WES excluded, and referrals to appropriate specialists.
Most of the cases (14 of 23; 61%) were de novo heterozygous mutations that therefore do not increase risk to future siblings. As a result of the WES, one couple canceled further diagnostic procedures and another planned preimplantation genetic diagnosis for future conceptions.
Initial tertiary presentation is the optimal time for WES. The cost per patient of standard diagnosis without WES was $7,509 (95% confidence interval [CI] $5,738 – $9,478); for standard diagnosis with WES, $9,792 (95% CI, $8,026 – $11,747); WES at initial tertiary presentation, $3,933 (95% CI, $3,517 – $4,407); and WES at the first genetics appointment, $5,347 (95% CI, $4,580 – $6,290). The researchers calculate the savings of implementation at initial tertiary presentation as $6,840 (95% CI, $11,681 – $3,265).
“Our prospective study provides compelling evidence for the clinical utility and cost-effectiveness of WES at an early point in the diagnostic trajectory,” the researchers conclude. A limitation of the study was exclusion of children whose symptoms did not fit a known Mendelian disorder.
Early-Life Epilepsy
In the second study, Anne T. Berg, PhD, from the Epilepsy Center at the Ann and Robert H. Lurie Children’s Hospital of Chicago, Illinois, and colleagues explored the utility of several types of genetic testing as a frontline diagnostic tool for young children who have epilepsies that might be part of neurodevelopmental syndromes.
The cause of early-life epilepsy (ELE) is unknown in more than half of cases, with neuroimaging the standard of care. Because genetic testing introduces precision, it may shorten time to diagnosis.
In a prospective observational cohort study, the researchers classified the basis of diagnosis (neuroimaging, metabolic, or genetic) for 775 children aged less than 3 years with epilepsy to evaluate the contributions of cytogenetic testing, CMA, panels of specific genes, and WES. Participants were from 17 children’s hospitals in the United States, from 2012 to 2015, with 1-year follow-up. The primary endpoint was discovery of a pathogenic gene variant that could explain symptoms.
After considering history, clinical findings, and results of neuroimaging and metabolic testing, the researchers classified participants’ ELE as the result of acquired brain injury, focal cortical dysplasia, other brain malformations and abnormalities, tuberous sclerosis complex, other neurocutaneous diseases, metabolic diseases, recognizable dysmorphic syndromes such as Down syndrome, other conditions such as brain tumors, or “unexplained” with normal or delayed development.
The total of 725 neuroimaging studies diagnosed a specific etiology or a developmental or progressive brain disorder in 273 (37.7%) cases. Metabolic testing led to diagnosis for only 16 of 384 children (4.2%).
Of the 775 patients in the study, 95 (12.3%) had acquired brain injuries, and 327 (48.1%) of the remaining 680 patients had genetic testing. These tests revealed pathogenic gene variants in 132 cases (40.4%; 95% CI, 37% – 44%): 26 of 59 (44.1%) with karyotyping, 32 of 188 (17.0%) with CMA, 31 of 114 (27.2%) with epilepsy gene panels, 11 of 33 (33.3%) with WES, four of 20 (20.0%) with mitochondrial gene panels, and 28 of 94 (29.8%) with other DNA-based tests. Of the 680, 94 underwent genetic testing before initial epilepsy evaluations, 171 during initial evaluations, and 135 during the next year. Sixty children had more than one genetic test.
Among the 446 children with initially unexplained seizure etiology, diagnostic yield for gene panels was the best (28 of 96 [29.2%]; 95% CI, 17% – 42%; P < .001), then WES (5 of 18 [27.8%]; 95% CI, 3% – 52%; P = .02), and then CMA (8 of 101 [7.9%]; 95% CI, 0% – 16%).
Including 44 cases diagnosed with genetic or chromosomal conditions before seizure evaluation, 132 (40.4%) of the 680 children tested positive. “Genetic testing provided a diagnosis in one-fourth of children whose cause would have otherwise remained unresolved,” the researchers conclude.
Limitations of the study include reliance on medical records, selection for patients presenting at hospitals, and lack of uniformity of genetic testing.
In an accompanying editorial, Johannes R. Lemke, MD, from the Institute of Human Genetics at the University of Leipzig Hospitals and Clinics in Germany, points out the advantages of moving high-throughput DNA sequencing to a first-tier diagnostic test for early-onset conditions. “How much effort and how many nonspecific screening tests are justifiable when searching for a clinical diagnosis, before making a decision toward comprehensive genetic testing, such as trio-WES? Implementing WES early within the diagnostic workup could save an enormous amount of effort, time, costs, and patience.”
The researchers and commentator have disclosed no relevant financial relationships.
JAMA Pediatr. Published online July 31, 2017. Full text; Abstract; Full text
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