By Eric Mallack, MD
Assistant Professor of Pediatrics and Neurology, Division of Child Neurology, Weill Cornell Medical College; Director, Leukodystrophy Center at Weill Cornell Medicine
Dr. Mallack reports no financial relationships relevant to this field of study.
SYNOPSIS: The results of this study indicate that first-line genome sequencing in pediatric patients with suspected genetic white matter disease is more diagnostically efficient, defined as higher diagnostic efficacy and shorter time to diagnosis, than current standard of care approaches.
SOURCE: Vanderver A, Bernard G, Helman G, et al. Randomized clinical trial of first-line genome sequencing in pediatric white matter disorders. Ann Neurol 2020; April 28. doi:10.1002/ana.25757. [Online ahead of print].
Genetic, non-acquired, pediatric white matter disorders are caused by mutations in genes that code for the structural and metabolic components vital to the development and maintenance of cerebral white matter. Despite a growing understanding of these disorders, diagnosis has remained a significant challenge. Next-generation sequencing has been shown to be effective in resolving persistently undiagnosed cases. Genome sequencing (GS) is a particularly promising diagnostic approach given its ability to capture large copy number variants across both the nuclear and mitochondrial genomes in addition to small indels and single nucleotide variants typically detected by exome sequencing. This study prospectively compared the diagnostic yield and time to diagnosis between GS and current standard of care (SoC) approaches in pediatric patients newly identified to have a white matter disorder without a definitive diagnosis by clinical assessment and magnetic resonance imaging (MRI). One-third of the recruited patients were randomized to immediate GS plus SoC (treatment arm). Two-thirds were randomized to SoC followed by a four-month delayed GS (control arm). SoC was defined as routine clinical testing, which included enzymatic and metabolic testing, and non-GS genetic testing, which included chromosomal, targeted gene sequencing, or gene panel testing.
Eighty-four patients met inclusion criteria and 34 ultimately were enrolled. Nine patients were randomized to immediate-GS and 23 to delayed GS. Two cases were resolved by SoC metabolic testing prior to randomization and were not included in the analysis. In the treatment arm, five of nine patients received a diagnosis by immediate GS, whereas zero of nine patients were diagnosed by SoC (P < 0.005). Five of 23 patients were diagnosed by SoC vs. 14 of 23 patients diagnosed by GS introduced after a four-month delay in the control arm (P < 0.005). The diagnostic yield was superior for GS vs. SoC (59% vs. 16%, P < 0.005). Time to diagnosis was significantly shorter in the immediate-GS group (P = 0.04). Overall, 76.5% of the cases were resolved in the study, 73% of which were achieved by GS.
This study by Vanderver et al indicates that first-line GS is a superior diagnostic approach to SoC testing in pediatric white matter disorders. Patients who underwent first-line, agnostic GS received a diagnosis more often, and in less time, than those who received the SoC approach, which included more focused, traditionally first-line genetic testing methodologies (i.e., chromosomal analysis, targeted testing, gene panel testing). The authors placed their findings in the context of imaging and metabolic testing, offering an updated diagnostic algorithm for patients with a suspected white matter disorder. Increasing the efficiency of disease diagnosis has important downstream implications. It addresses the “diagnostic odyssey” characteristic of many children affected by neurogenetic disease. Accordingly, first-line GS may prove to be a viable strategy to streamline resources and healthcare use. Clinically, decreasing the time to accurate diagnosis, especially in presymptomatic or minimally symptomatic patients, leads to the timely delivery of therapy. This is especially important in diseases where invasive treatments are most successful when instituted early in the disease course.1 The molecular insights gained from accurate genetic diagnoses, and potential gene discovery in previously uncharacterized diseases, are the initial steps crucial to the development of novel therapies, including gene therapy.2-5
Important limitations exist in the study. Limited patient enrollment decreases the power of the overall results and limits the generalizability of the conclusions to other diseases. This is a difficulty common to all rare disorders. Additionally, two patients were resolved by SoC metabolic testing after study enrollment but prior to randomization and therefore were excluded from the primary analysis. If those two patients were added back into the study and were randomized to the immediate-GS treatment arm, the results may not have reached statistical significance (5/11 diagnosed by GS vs. 2/11 diagnosed by SoC). Importantly, as noted by the authors, the diagnostic yield by GS would remain superior to SoC despite the addition of the two enrolled cases resolved by SoC (56% [19/34] vs. 21% [7/34], P < 0.001). Given the findings from this study, and the overall progress in the field of pediatric neurogenetics, one can reasonably expect the continued adoption of next-generation sequencing as a diagnostic method for adult-onset neurological disorders. Additionally, as more pediatric patients are tested, more healthy family members will be identified during family screening to have risk alleles for adult-onset neurological disease. This has the potential to evolve the molecular understanding of these diseases and increase the specificity of targeted preventive strategies for presymptomatically identified patients.
- Raymond GV, Aubourg P, Paker A, et al. Survival and functional outcomes in boys with cerebral adrenoleukodystrophy with and without hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2019;25:538-548.
- Eichler F, Duncan C, Musolino PL, et al. Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy. N Engl J Med 2017;377:1630-1638.
- Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med 2017;377:1713-1722.
- Sessa M, Lorioli L, Fumagalli F, et al. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: An ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet 2016;388:476-487.
- Mallack EJ, Turk B, Yan H, Eichler FS. The landscape of hematopoietic stem cell transplant and gene therapy for x-linked adrenoleukodystrophy. Curr Treat Options Neurol 2019;21:61.