Whole exome sequencing in neurogenetic odysseys: An effective, cost- and time-saving diagnostic approach

Abstract

BackgroundDiagnostic trajectories for neurogenetic disorders frequently require the use of considerable time and resources, exposing patients and families to so-called “diagnostic odysseys”. Previous studies have provided strong evidence for increased diagnostic and clinical utility of whole-exome sequencing in medical genetics. However, specific reports assessing its utility in a setting such as ours- a neurogeneticist led academic group serving in a low-income country—are rare.ObjectivesTo assess the diagnostic yield of WES in patients suspected of having a neurogenetic condition and explore the cost-effectiveness of its implementation in a research group located in an Argentinean public hospital.MethodsThis is a prospective study of the clinical utility of WES in a series of 40 consecutive patients selected from a Neurogenetic Clinic of a tertiary Hospital in Argentina. We evaluated patients retrospectively for previous diagnostic trajectories. Diagnostic yield, clinical impact on management and economic diagnostic burden were evaluated.ResultsWe demonstrated the clinical utility of Whole Exome Sequencing in our patient cohort, obtaining a diagnostic yield of 40% (95% CI, 24.8%-55.2%) among a diverse group of neurological disorders. The average age at the time of WES was 23 (range 3–70). The mean time elapsed from symptom onset to WES was 11 years (range 3–42). The mean cost of the diagnostic workup prior to WES was USD 1646 (USD 1439 to 1853), which is 60% higher than WES cost in our center.ConclusionsWES for neurogenetics proved to be an effective, cost- and time-saving approach for the molecular diagnosis of this heterogeneous and complex group of patients.

Systematic evidence-based review: outcomes from exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability

“…A change of patient medication, either initiation of a new treatment or halting of an existing one, was specifically reported in 22 studies. 8,[15][16][17][18]20,22,23,[26][27][28][29][30][31][32][33][34][35][36][37][38][39] For example, Anazi et al reported a patient with ID who was homozygous for a truncating pathogenic variant in SLC39A14 that causes a potentially treatable form of hypermanganesemia, who was started on chelation therapy, resulting in improved manganese levels. 17 In a case series of patients with presumed neurogenetic disorders and DD/ID from Argentina, 10% (4/ 40) underwent a trial of new medication following ES, including a trial of L-Dopa in a patient with paraplegia and ID who had pathogenic variants in SPG11 and a trial of acetazolamide and fampridine in a patient with a pathogenic variant in KCNA2.…”

“…17 In a case series of patients with presumed neurogenetic disorders and DD/ID from Argentina, 10% (4/ 40) underwent a trial of new medication following ES, including a trial of L-Dopa in a patient with paraplegia and ID who had pathogenic variants in SPG11 and a trial of acetazolamide and fampridine in a patient with a pathogenic variant in KCNA2. 39 In the same study, physicians made recommendations to avoid statins in a patient with a pathogenic variant in DMD and to avoid drugs (unspecified) with mitochondrial toxicity in a patient with a MT-ATP6 pathogenic variant causing DD and epilepsy. 39 Alterations to a patient's existing diet were mentioned in nine studies.…”

“…39 In the same study, physicians made recommendations to avoid statins in a patient with a pathogenic variant in DMD and to avoid drugs (unspecified) with mitochondrial toxicity in a patient with a MT-ATP6 pathogenic variant causing DD and epilepsy. 39 Alterations to a patient's existing diet were mentioned in nine studies. 8,23,26,27,30,31,33,40,41 In a case series of 43 French patients with dysmorphic features and neurodevelopmental disorders including severe to profound ID, a patient diagnosed with compound heterozygous pathogenic variants in ADCK3 was diagnosed with coenzyme Q10 deficiency.…”

The Financial Impact of Genetic Diseases in a Pediatric Accountable Care Organization

“…WGS/WES has led to an increased diagnostic yield in patients with suspected rare genetic conditions and in some cases, molecular diagnosis results in better prognosis and recommendations for surveillance of disease-related complications (17,26,27). Although the financial implications associated with WGS/WES may be costly, utilizing this technology in patients with undiagnosed or suspected genetic diseases, who may otherwise go through lengthy, costly, and unfruitful diagnostic tests, may be expected to not only improve quality of patient care but also yield cost-saving returns in the long term, given the exceptionally high cost of these patients as is (28,29). Pediatric ACOs should be in position to drive the reimbursement policies of WGS/WES and the guidance on the best practice on the utilization of WGS/WES.…”

Genetics and genomic medicine in Argentina

“…Finally, we would like to remark that several research/ clinical groups are using genomic approaches for the study and diagnosis of genetic disorders such as neurological disorders (Cordoba et al, 2018;Rodriguez-Quiroga et al, 2015), Duchenne/Becker muscular dystrophy (Luce et al, 2018), breast cancer (Solano et al, 2017, ovarian cancer (Cardoso et al, 2018), and endocrine/immune diseases (Gutierrez et al, 2018), among others.…”