Spinal muscular atrophy (SMA) is a genetic disorder that causes progressive degeneration of lower motor neurons and the subsequent loss of muscle function throughout the body. It is the second most common recessive disorder in individuals of European descent and is present in all populations. Accurate tools exist for diagnosing SMA from genome sequencing data. However, there are no publicly available tools for GRCh38-aligned data from panel or exome sequencing assays which continue to be used as first line tests for neuromuscular disorders. This deficiency creates a critical gap in our ability to diagnose SMA in large existing rare disease cohorts, as well as newly sequenced exome and panel datasets. We therefore developed and extensively validated a new tool - SMA Finder - that can diagnose SMA not only in genome, but also exome and panel sequencing samples aligned to GRCh37, GRCh38, or T2T-CHM13. It works by evaluating aligned reads that overlap the c.840 position of SMN1 and SMN2 in order to detect the most common molecular causes of SMA. We applied SMA Finder to 16,626 exomes and 3,911 genomes from heterogeneous rare disease cohorts sequenced at the Broad Institute Center for Mendelian Genomics as well as 1,157 exomes and 8,762 panel sequencing samples from Tartu University Hospital. SMA Finder correctly identified all 16 known SMA cases and reported nine novel diagnoses which have since been confirmed by clinical testing, with another four novel diagnoses undergoing validation. Notably, out of the 29 total SMA positive cases, 23 had an initial clinical diagnosis of muscular dystrophy, congenital myasthenic syndrome, or myopathy. This underscored the frequency with which SMA can be misdiagnosed as other neuromuscular disorders and confirmed the utility of using SMA Finder to reanalyze phenotypically diverse neuromuscular disease cohorts. Finally, we evaluated SMA Finder on 198,868 individuals that had both exome and genome sequencing data within the UK Biobank (UKBB) and found that SMA Finder's overall false positive rate was less than 1 / 200,000 exome samples, and its positive predictive value (PPV) was 97%. We also observed 100% concordance between UKBB exome and genome calls. This analysis showed that, even though it is located within a segmental duplication, the most common causal variant for SMA can be detected with comparable accuracy to monogenic disease variants in non-repetitive regions. Additionally, the high PPV demonstrated by SMA Finder, the existence of treatment options for SMA in which early diagnosis is imperative for therapeutic benefit, as well as widespread availability of clinical confirmatory testing for SMA, warrants the addition of SMN1 to the ACMG 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 USA

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

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

Department of Clinical Genetics Institute of Clinical Medicine University of Tartu Tartu Estonia

Department of Clinical Neurosciences University of Cambridge Cambridge UK

Department of Neurology Brigham and Women's Hospital Boston MA USA

Department of Neurology 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 USA

Division of Neurology Department of Medicine The Ottawa Hospital Ottawa ON Canada

Division of Pediatric Neurology Department of Pediatrics Hacettepe University Faculty of Medicine Ankara Turkey

Faculty of Medicine Masaryk University Brno Czech Republic

Genetics and Personalized Medicine Clinic Tartu University Hospital Tartu Estonia

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

Harry Perkins Institute for Medical Research Perth Western Australia Australia

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 UK

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 USA

Neuromuscular Center Ain Shams University Cairo Egypt

Program in Medical and Population Genetics Broad Institute of MIT and Harvard Cambridge MA USA

Tampere Neuromuscular Center and Folkhalsan Research Center Helsinki Finland

UC Santa Cruz Genomics Institute UCSC Santa Cruz CA USA

University Clinical Centre of Serbia Neurology Clinic Belgrade Serbia

University of Belgrade Faculty of Medicine Belgrade Serbia

Genet Med. 2025 Apr;27(4):101336. doi: 10.1016/j.gim.2024.101336. PubMed

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