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Diagnosing missed cases of spinal muscular atrophy in genome, exome, and panel sequencing data sets
B. Weisburd, R. Sharma, V. Pata, T. Reimand, VS. Ganesh, C. Austin-Tse, I. Osei-Owusu, E. O'Heir, M. O'Leary, L. Pais, SA. Stafki, AL. Daugherty, C. Folland, S. Peric, N. Fahmy, B. Udd, M. Horáková, A. Łusakowska, R. Manoj, A. Nalini, V. Karcagi,...
Jazyk angličtina
Typ dokumentu časopisecké články
Grantová podpora
UM1 HG008900
NHGRI NIH HHS - United States
U24 HG011746
NHGRI NIH HHS - United States
T32 HG010464
NHGRI NIH HHS - United States
R01 HG009141
NHGRI NIH HHS - United States
K23 AR083505
NIAMS NIH HHS - United States
U01 HG011755
NHGRI NIH HHS - United States
- MeSH
- algoritmy MeSH
- exom genetika MeSH
- genom lidský genetika MeSH
- genomika metody MeSH
- lidé MeSH
- protein přežití motorických neuronů 1 genetika MeSH
- protein přežití motorických neuronů 2 genetika MeSH
- sekvenční analýza DNA metody MeSH
- sekvenování exomu MeSH
- spinální svalová atrofie * genetika diagnóza MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: We set out to develop a publicly available tool that could accurately diagnose spinal muscular atrophy (SMA) in exome, genome, or panel sequencing data sets aligned to a GRCh37, GRCh38, or T2T reference genome. METHODS: The SMA Finder algorithm detects the most common genetic causes of SMA by evaluating reads that overlap the c.840 position of the SMN1 and SMN2 paralogs. It uses these reads to determine whether an individual most likely has 0 functional copies of SMN1. RESULTS: We developed SMA Finder and evaluated it on 16,626 exomes and 3911 genomes from the Broad Institute Center for Mendelian Genomics, 1157 exomes and 8762 panel samples from Tartu University Hospital, and 198,868 exomes and 198,868 genomes from the UK Biobank. SMA Finder's false-positive rate was below 1 in 200,000 samples, its positive predictive value was greater than 96%, and its true-positive rate was 29 out of 29. Most of these SMA diagnoses had initially been clinically misdiagnosed as limb-girdle muscular dystrophy. CONCLUSION: Our extensive evaluation of SMA Finder on exome, genome, and panel sequencing samples found it to have nearly 100% accuracy and demonstrated its ability to reduce diagnostic delays, particularly in individuals with milder subtypes of SMA. Given this accuracy, the common misdiagnoses identified here, the widespread availability of clinical confirmatory testing for SMA, and the existence of treatment options, we propose that it is time to add SMN1 to the American College of Medical Genetics list of genes with reportable secondary findings after genome and exome sequencing.
Anesthesiology and Intensive Care Clinic Tartu University Hospital Tartu Estonia
Brain and Mind Research Institute University of Ottawa Ottawa ON Canada
Center for Genomic Medicine Massachusetts General Hospital Harvard Medical School Boston MA
Centre for Cancer Biology An SA Pathology and UniSA Alliance Adelaide SA Australia
Centre of Medical Research The University of Western Australia Perth Western Australia Australia
Children's Hospital of Eastern Ontario Research Institute Ottawa ON Canada
Department of Clinical Neurosciences University of Cambridge Cambridge United Kingdom
Department of Neurology Brigham and Women's Hospital Boston MA
Department of Neurology Neuromuscular Center ERN Medical University of Warsaw Warsaw Poland
Department of Neurology Neuromuscular Center ERN University Hospital Brno Brno Czech Republic
Division of Genetics and Genomics Boston Children's Hospital Harvard Medical School Boston MA
Division of Neurology Department of Medicine The Ottawa Hospital Ottawa ON Canada
Faculty of Medicine Masaryk University Brno Czech Republic
Genetics and Personalized Medicine Clinic Tartu University Hospital Tartu Estonia
Harry Perkins Institute for Medical Research Perth Western Australia Australia
Istenhegyi Genetic Diagnostic Centre Molecular Genetic Laboratory Budapest Hungary
National Institute of Mental Health and Neuro Sciences Bengaluru India
Neuromuscular Center Ain Shams University Cairo Egypt
Tampere Neuromuscular Center and Folkhälsan Research Center Helsinki Finland
UC Santa Cruz Genomics Institute UCSC Santa Cruz CA
University Clinical Centre of Serbia Neurology Clinic Belgrade Serbia
Citace poskytuje Crossref.org
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- $a Weisburd, Ben $u Program in Medical and Population Genetics, Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA; Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA. Electronic address: weisburd@broadinstitute.org
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