Waldrop MA, Pastore M, Schrader R, Sites E, Bartholomew D, Tsao CY, Flanigan KM. u. Neuropediatrics. 2019 Jan 21. doi: 10.1055/s-0039-1677734. [Epub ahead of print]
Next-generation sequencing is a powerful diagnostic tool, yet it has proven inadequate to establish a diagnosis in all cases of congenital hypotonia or childhood onset weakness. We sought to describe the impact of whole exome sequencing (WES), which has only recently become widely available clinically, on molecular diagnosis in the Nationwide Children's Hospital Neuromuscular clinics. We reviewed records of all patients in our clinic with pediatric onset of symptoms who had WES done since 2013. Patients were included if clinical suspicion was high for a neuromuscular disease. Clinical WES was performed in 30 families, representing 31 patients, all of whom were seen for hypotonia, weakness, or gait disturbance. Probands had between 2 and 12 genetic diagnostic tests prior to obtaining WES. A genetic diagnosis was established in 11 families (37%), and in 12 patients (39%), with mutations in 10 different genes. Five of these genes have only been associated with disease since 2013, and were not previously represented on clinically available disease gene panels. Our results confirm the utility of WES in the clinical setting, particularly for genetically heterogeneous syndromes. The availability of WES can provide an end to the diagnostic odyssey for parents and allow for expansion of phenotypes.
Traditionally, diagnosis of neuromuscular disorders follows a pattern: review the clinical phenotype and narrow down the likely options; run a targeted test for the suspected disorder; diagnose. In cases with challenging phenotypes or unresolved diagnoses after these initial assessments, many neuromuscular clinics resort to a range of additional tests, including microarray, electromyography, a muscle or nerve biopsy and next generation gene panel testing — a broader genetic screen capturing more of the possible single-gene neuromuscular diseases.
For patient families with inconclusive results throughout this battery of tests, it used to be the end of the road. Over the past several years, however, whole exome sequencing (WES) has become a clinically available test, offering physicians the chance to cast a much broader net in the search for genetic alterations at the root of a child’s symptoms. To find out whether the test offers clinically meaningful diagnostic utility, physician-scientists at Nationwide Children’s Hospital reviewed the results of four years of WES testing among patients in their Neuromuscular Disorders Clinic.,,
Twelve of the patients (39%) received a confirmed diagnosis based on WES findings, most commonly for genetic syndromes associated with myopathy or congenital myopathy (n=8), including three children (including two siblings) with the ultra-rare Vici syndrome. Two patients were diagnosed with central nervous system disorders. WES led to changes in the clinical management of numerous patients, including one who had had a long-standing presumptive diagnosis of mitochondrial disease.
“These were patients in whom our standard genetic testing algorithm did not show a result,” says Kevin Flanigan, MD, director of the Neuromuscular Disorders program at Nationwide Children’s and senior author on the paper. “WES is now a mature technology, and we think that, when it’s properly applied, WES can rapidly and economically shorten the diagnostic odyssey for parents and add to our understanding of the range of clinical phenotypes associated with mutations in given genes.”
Drs. Flanigan and Waldrop also suspect that using WES after initial failed gene panel tests, rather than moving on to invasive tests in between, is likely more cost-effective and beneficial for families. It should be noted, however, that WES is only useful in cases of single-gene disorders, rather than for broad syndromes that result in similar phenotypes. This may account for the substantial proportion of children who remain undiagnosed even after WES.
For some of these patients, Drs. Flanigan and Waldrop request whole genome sequencing — an expanded genomic screen analyzing billions of pieces of genetic code instead of the thousands studied by WES. The test is extremely resource intensive both in manpower and computational technology. While not yet available clinically due to its expense and experimental nature, it is offered through the Institute for Genomic Medicine as part of a research program for children who remain undiagnosed after exhausting all other options.