Interim analysis of an integrated interdisciplinary diagnostic pathway in a cohort of unsolved pediatric neuromuscular disorders


Topic:

Other

Poster Number: P309

Author(s):

Sandra Donkervoort, MS, CGC, National Institutes of Health, Göknur Haliloğlu, MD, Division of Pediatric Neurology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Sibel Öz Yıldız, MD, Division of Pediatric Neurology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Erhan Özel, Division of Pediatric Neurology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Lynn Pais, MS, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Vijay Ganesh, MD, PhD, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Anne O’Donnell-Luria, MD, PhD, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Carsten G Bönnemann, National Institute of Neurological Disorders and Stroke

Accurate genetic diagnoses in neuromuscular disorders (NMDs) requires an iterative clinical genomic approach. Despite advanced genomic sequencing technologies, it is estimated that about half of the patients do not receive a confirmed molecular diagnosis after initial genetic work-up. Here we evaluated 66 families with pediatric neuromuscular disorders of unsolved genetic etiology recruited from a tertiary neuromuscular center in Turkey, in whom initial exome sequencing (ES) had been unrevealing. Diagnostic algorithm included research-based ES complemented by clinical phenotype reassessment-driven prioritization of data analysis and the addition of bioinformatic pipelines that include copy number variants (CNV), SMA Finder and mitochondrial analysis, followed by genome sequencing (GS) and RNA sequencing (RNA seq) in 14 and 4 families respectively. At data cut-off, ES of our cohort of all 66 families was completed. Copy number variant analysis is pending on 11. Most patients (n = 45) were sequenced as trios, followed by singleton (n=10), quartet (n=8), duos (n=2) other (n=1). Nine families had more than one affected individual included in sequencing. Interim diagnostic yield was 40/66 (61%) which included ES (n = 32); ES and CNV analysis (n = 1); ES and mitochondrial filter (n = 1); ES and SMA Finder (n = 1); GS (n = 1); GS and RNAseq (n = 2); GS, RNAseq and CNV analysis (n = 2) as diagnostic pathways. Further analysis in families with a missing pathogenic allele in recessive gene candidates, variants of uncertain significance that require further validation, or a novel candidate gene is currently ongoing. The initial analysis of our highly selected cohort highlights the value of an iterative phenotype driven approach to research-based sequencing data analyses with the integration of additional bioinformatics tools to improve the genetic diagnostic yield.