. 2025 Apr;27(4):101336.

doi: 10.1016/j.gim.2024.101336. Epub 2024 Dec 9.

Diagnosing missed cases of spinal muscular atrophy in genome, exome, and panel sequencing data sets

Ben Weisburd¹, Rakshya Sharma², Villem Pata³, Tiia Reimand⁴, Vijay S Ganesh⁵, Christina Austin-Tse⁶, Ikeoluwa Osei-Owusu⁷, Emily O'Heir⁷, Melanie O'Leary⁸, Lynn Pais⁷, Seth A Stafki⁹, Audrey L Daugherty⁹, Chiara Folland¹⁰, Stojan Peric¹¹, Nagia Fahmy¹², Bjarne Udd¹³, Magda Horáková¹⁴, Anna Łusakowska¹⁵, Rajanna Manoj¹⁶, Atchayaram Nalini¹⁶, Veronika Karcagi¹⁷, Kiran Polavarapu¹⁸, Hanns Lochmüller¹⁹, Rita Horvath²⁰, Carsten G Bönnemann²¹, Sandra Donkervoort²¹, Göknur Haliloğlu²², Ozlem Herguner²³, Peter B Kang⁹, Gianina Ravenscroft²⁴, Nigel Laing²⁴, Hamish S Scott²⁵, Ana Töpf²⁶, Volker Straub²⁶, Sander Pajusalu⁴, Katrin Õunap⁴, Grace Tiao⁸, Heidi L Rehm⁶, Anne O'Donnell-Luria²⁷

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ 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 & Women's Hospital, Boston, MA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA.
⁶ 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.
⁷ 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.
⁸ Program in Medical and Population Genetics, Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA.
⁹ Greg Marzolf Jr. Muscular Dystrophy Center, Department of Neurology, and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN.
¹⁰ Centre of Medical Research, The University of Western Australia, Perth, Western Australia, Australia.
¹¹ University of Belgrade, Faculty of Medicine, Belgrade, Serbia; University Clinical Centre of Serbia, Neurology Clinic, Belgrade, Serbia.
¹² Neuromuscular Center, Ain Shams University, Cairo, Egypt.
¹³ Tampere Neuromuscular Center and Folkhälsan Research Center, Helsinki, Finland.
¹⁴ Department of Neurology, Neuromuscular Center ERN, University Hospital Brno, Brno, Czech Republic; Faculty of Medicine, Masaryk University, Brno, Czech Republic.
¹⁵ Department of Neurology, Neuromuscular Center ERN, Medical University of Warsaw, Warsaw, Poland.
¹⁶ National Institute of Mental Health and Neuro Sciences, Bengaluru, India.
¹⁷ Istenhegyi Genetic Diagnostic Centre, Molecular Genetic Laboratory, Budapest, Hungary.
¹⁸ Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
¹⁹ 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.
²⁰ Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
²¹ Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD.
²² 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.
²³ Çukurova University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Neurology, Adana, Turkey.
²⁴ Centre of Medical Research, The University of Western Australia, Perth, Western Australia, Australia; Harry Perkins Institute for Medical Research, Perth, Western Australia, Australia.
²⁵ Centre for Cancer Biology, An SA Pathology & UniSA Alliance, Adelaide, SA, Australia.
²⁶ John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
²⁷ 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. Electronic address: odonnell@broadinstitute.org.

PMID: 39670433
PMCID: PMC11985284 (available on 2026-04-01)
DOI: 10.1016/j.gim.2024.101336

Diagnosing missed cases of spinal muscular atrophy in genome, exome, and panel sequencing data sets

Ben Weisburd et al. Genet Med. 2025 Apr.

. 2025 Apr;27(4):101336.

doi: 10.1016/j.gim.2024.101336. Epub 2024 Dec 9.

Authors

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ 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 & Women's Hospital, Boston, MA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA.
⁶ 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.
⁷ 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.
⁸ Program in Medical and Population Genetics, Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA.
⁹ Greg Marzolf Jr. Muscular Dystrophy Center, Department of Neurology, and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN.
¹⁰ Centre of Medical Research, The University of Western Australia, Perth, Western Australia, Australia.
¹¹ University of Belgrade, Faculty of Medicine, Belgrade, Serbia; University Clinical Centre of Serbia, Neurology Clinic, Belgrade, Serbia.
¹² Neuromuscular Center, Ain Shams University, Cairo, Egypt.
¹³ Tampere Neuromuscular Center and Folkhälsan Research Center, Helsinki, Finland.
¹⁴ Department of Neurology, Neuromuscular Center ERN, University Hospital Brno, Brno, Czech Republic; Faculty of Medicine, Masaryk University, Brno, Czech Republic.
¹⁵ Department of Neurology, Neuromuscular Center ERN, Medical University of Warsaw, Warsaw, Poland.
¹⁶ National Institute of Mental Health and Neuro Sciences, Bengaluru, India.
¹⁷ Istenhegyi Genetic Diagnostic Centre, Molecular Genetic Laboratory, Budapest, Hungary.
¹⁸ Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
¹⁹ 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.
²⁰ Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
²¹ Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD.
²² 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.
²³ Çukurova University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Neurology, Adana, Turkey.
²⁴ Centre of Medical Research, The University of Western Australia, Perth, Western Australia, Australia; Harry Perkins Institute for Medical Research, Perth, Western Australia, Australia.
²⁵ Centre for Cancer Biology, An SA Pathology & UniSA Alliance, Adelaide, SA, Australia.
²⁶ John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
²⁷ 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. Electronic address: odonnell@broadinstitute.org.

PMID: 39670433
PMCID: PMC11985284 (available on 2026-04-01)
DOI: 10.1016/j.gim.2024.101336

Abstract

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.

Keywords: Analysis tool; Muscle disease; SMA; Segmental duplication; Spinal muscular atrophy.

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Conflict of interest statement

Conflict of Interest Heidi L. Rehm receives research funding from Microsoft and previously received funding from Illumina to support rare disease gene discovery and diagnosis. Anne O’Donnell-Luria has consulted for Tome Biosciences, Ono Pharma USA Inc, and Addition Therapeutics and was a member of the scientific advisory board for Congenica Inc and the Simons Foundation SPARK for Autism study. Anna Łusakowska received honoraria for speaking at educational events for Biogen, PTC, and Roche, is a subinvestigator in clinical trials by Roche and PTC, and is involved in a project supported by Biogen (POL-SMA-17-11166). Peter B. Kang has received research support from ML Bio and Sarepta Therapeutics and has consulted for Lupin, Neurogene, NS Pharma, and Teneofour.

Update of

Diagnosing missed cases of spinal muscular atrophy in genome, exome, and panel sequencing datasets.
Weisburd B, Sharma R, Pata V, Reimand T, Ganesh VS, Austin-Tse C, Osei-Owusu I, O'Heir E, O'Leary M, Pais L, Stafki SA, Daugherty AL, Folland C, Perić S, Fahmy N, Udd B, Horakova M, Łusakowska A, Manoj R, Nalini A, Karcagi V, Polavarapu K, Lochmüller H, Horvath R, Bönnemann CG, Donkervoort S, Haliloğlu G, Herguner O, Kang PB, Ravenscroft G, Laing N, Scott HS, Töpf A, Straub V, Pajusalu S, Õunap K, Tiao G, Rehm HL, O'Donnell-Luria A. Weisburd B, et al. medRxiv [Preprint]. 2024 Jun 29:2024.02.11.24302646. doi: 10.1101/2024.02.11.24302646. medRxiv. 2024. Update in: Genet Med. 2025 Apr;27(4):101336. doi: 10.1016/j.gim.2024.101336. PMID: 38405995 Free PMC article. Updated. Preprint.

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Diagnosing missed cases of spinal muscular atrophy in genome, exome, and panel sequencing data sets

Affiliations

Diagnosing missed cases of spinal muscular atrophy in genome, exome, and panel sequencing data sets

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical