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.

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

Centre of Medical Research The University of Western Australia Perth Western Australia Australia; Harry Perkins Institute for Medical Research Perth Western Australia Australia

Children's Hospital of Eastern Ontario Research Institute Ottawa ON Canada

Children's Hospital of Eastern Ontario Research Institute Ottawa ON Canada; Division of Neurology Department of Medicine The Ottawa Hospital Ottawa ON Canada; Brain and Mind Research Institute University of Ottawa Ottawa ON Canada

Çukurova University Faculty of Medicine Department of Pediatrics Division of Pediatric Neurology Adana Turkey

Department of Clinical Neurosciences University of Cambridge Cambridge United Kingdom

Department of Genetic and Personalized Medicine Institute of Clinical Medicine University of Tartu Tartu Estonia; Anesthesiology and Intensive Care Clinic Tartu University Hospital Tartu Estonia

Department of Genetic and Personalized Medicine Institute of Clinical Medicine University of Tartu Tartu Estonia; Genetics and Personalized Medicine Clinic Tartu University Hospital Tartu Estonia

Department of Neurology Neuromuscular Center ERN Medical University of Warsaw Warsaw Poland

Department of Neurology Neuromuscular Center ERN University Hospital Brno Brno Czech Republic; Faculty of Medicine Masaryk University Brno Czech Republic

Greg Marzolf Jr Muscular Dystrophy Center Department of Neurology and Institute for Translational Neuroscience University of Minnesota Minneapolis MN

Istenhegyi Genetic Diagnostic Centre Molecular Genetic Laboratory Budapest Hungary

John Walton Muscular Dystrophy Research Centre Newcastle University and Newcastle Hospitals NHS Foundation Trust Newcastle upon Tyne United Kingdom

National Institute of Mental Health and Neuro Sciences Bengaluru India

Neuromuscular and Neurogenetic Disorders of Childhood Section Neurogenetics Branch National Institute of Neurological Disorders and Stroke NIH Bethesda MD

Neuromuscular and Neurogenetic Disorders of Childhood Section Neurogenetics Branch National Institute of Neurological Disorders and Stroke NIH Bethesda MD; Division of Pediatric Neurology Department of Pediatrics Hacettepe University Faculty of Medicine Ankara Turkey

Neuromuscular Center Ain Shams University Cairo Egypt

Program in Medical and Population Genetics Broad Center for Mendelian Genomics Broad Institute of MIT and Harvard Cambridge MA

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

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; Department of Neurology Brigham and Women's Hospital Boston MA; Division of Genetics and Genomics Boston Children's Hospital Harvard Medical School Boston MA

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; Division of Genetics and Genomics Boston Children's Hospital Harvard Medical School Boston MA

Program in Medical and Population Genetics Broad Center for Mendelian Genomics Broad Institute of MIT and Harvard Cambridge MA; Division of Genetics and Genomics Boston Children's Hospital Harvard Medical School Boston MA

Program in Medical and Population Genetics Broad Center for Mendelian Genomics Broad Institute of MIT and Harvard Cambridge MA; UC Santa Cruz Genomics Institute UCSC Santa Cruz CA

Tampere Neuromuscular Center and Folkhälsan Research Center Helsinki Finland

University of Belgrade Faculty of Medicine Belgrade Serbia; University Clinical Centre of Serbia Neurology Clinic Belgrade Serbia

medRxiv. 2024 Jun 29:2024.02.11.24302646. doi: 10.1101/2024.02.11.24302646. PubMed

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Hail Team. Hail 0.2 https://github.com/hail-is/hail