Evidence map›Paper›PMID 39670433›Full record

ArticleGenetics in medicine : official journal of the American College of Medical Genetics2025

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

Ben Weisburd, Rakshya Sharma, Villem Pata, Tiia Reimand, Vijay S Ganesh, Christina Austin-Tse, Ikeoluwa Osei-Owusu, Emily O'Heir, Melanie O'Leary, Lynn Pais and 29 more

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Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed.

  1. Article
  2. Article
  3. Article
  4. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

39 authors.

Ben WeisburdProgram 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.
Rakshya SharmaProgram 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.
Villem PataDepartment of Genetic and Personalized Medicine, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia; Anesthesiology and Intensive Care Clinic, Tartu University Hospital, Tartu, Estonia.
Tiia ReimandDepartment of Genetic and Personalized Medicine, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia; Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia.
Vijay S GaneshProgram 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.
Christina Austin-TseProgram 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.
Ikeoluwa Osei-OwusuProgram 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.
Emily O'HeirProgram 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.
Melanie O'LearyProgram in Medical and Population Genetics, Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA.
Lynn PaisProgram 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.
Seth A StafkiGreg Marzolf Jr. Muscular Dystrophy Center, Department of Neurology, and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN.
Audrey L DaughertyGreg Marzolf Jr. Muscular Dystrophy Center, Department of Neurology, and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN.
Chiara FollandCentre of Medical Research, The University of Western Australia, Perth, Western Australia, Australia.
Stojan PericUniversity of Belgrade, Faculty of Medicine, Belgrade, Serbia; University Clinical Centre of Serbia, Neurology Clinic, Belgrade, Serbia.
Nagia FahmyNeuromuscular Center, Ain Shams University, Cairo, Egypt.
Bjarne UddTampere Neuromuscular Center and Folkhälsan Research Center, Helsinki, Finland.
Magda HorákováDepartment of Neurology, Neuromuscular Center ERN, University Hospital Brno, Brno, Czech Republic; Faculty of Medicine, Masaryk University, Brno, Czech Republic.
Anna ŁusakowskaDepartment of Neurology, Neuromuscular Center ERN, Medical University of Warsaw, Warsaw, Poland.
Rajanna ManojNational Institute of Mental Health and Neuro Sciences, Bengaluru, India.
Atchayaram NaliniNational Institute of Mental Health and Neuro Sciences, Bengaluru, India.
Veronika KarcagiIstenhegyi Genetic Diagnostic Centre, Molecular Genetic Laboratory, Budapest, Hungary.
Kiran PolavarapuChildren's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
Hanns LochmüllerChildren'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.
Rita HorvathDepartment of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
Carsten G BönnemannNeuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD.
Sandra DonkervoortNeuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD.
Göknur HaliloğluNeuromuscular 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.
Ozlem HergunerÇukurova University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Neurology, Adana, Turkey.
Peter B KangGreg Marzolf Jr. Muscular Dystrophy Center, Department of Neurology, and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN.
Gianina RavenscroftCentre of Medical Research, The University of Western Australia, Perth, Western Australia, Australia; Harry Perkins Institute for Medical Research, Perth, Western Australia, Australia.
Nigel LaingCentre of Medical Research, The University of Western Australia, Perth, Western Australia, Australia; Harry Perkins Institute for Medical Research, Perth, Western Australia, Australia.
Hamish S ScottCentre for Cancer Biology, An SA Pathology & UniSA Alliance, Adelaide, SA, Australia.
Ana TöpfJohn Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
Volker StraubJohn Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
Sander PajusaluDepartment of Genetic and Personalized Medicine, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia; Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia.
Katrin ÕunapDepartment of Genetic and Personalized Medicine, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia; Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia.
Grace TiaoProgram in Medical and Population Genetics, Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA.
Heidi L RehmProgram 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.
Anne O'Donnell-LuriaProgram 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.

Funding

The Human Genome Sequencing CenterU54HG003273 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI GIBBS, RICHARD A · 2004 to 2015
$341.3M
Joint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5M
P30 Core Grant for Vision ResearchP30EY014104 · NEI · MASSACHUSETTS EYE AND EAR INFIRMARY · PI Eric A Pierce · 2002 to 2026
$15.1M
University of Washington (UW) Mendelian Genomics Data Coordinating CenterU24HG011746 · NHGRI · UNIVERSITY OF WASHINGTON · PI Susanne May, ALI SHOJAIE · 2021 to 2026
$14.8M
Broad Institute Mendelian Genomic Research CenterU01HG011755 · NHGRI · BROAD INSTITUTE, INC. · PI Anne O'Donnell-Luria, MICHAEL E TALKOWSKI · 2021 to 2026
$14.6M
Baylor-Johns Hopkins Center for Mendelian GeneticsUM1HG006542 · NHGRI · JOHNS HOPKINS UNIVERSITY · PI VALLE, DAVID · 2016 to 2020
$14.5M
MEDICAL GENETICS RESEARCH FELLOWSHIP PROGRAMT32GM007526 · NIGMS · BAYLOR COLLEGE OF MEDICINE · PI Brendan Lee · 1985 to 2026
$11.4M
STRUCTURAL VARIATION IN NEUROLOGICAL DISEASER35NS105078 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI LUPSKI, JAMES R. · 2018 to 2025
$6.0M
Partners Healthcare Training Program in Precision and Genomic MedicineT32HG010464 · NHGRI · MASSACHUSETTS GENERAL HOSPITAL · PI HEIDI L REHM, JORDAN W SMOLLER · 2019 to 2026
$3.1M
A powerful web-based discovery platform for rare disease geneticsR01HG009141 · NHGRI · BROAD INSTITUTE, INC. · PI QUINLAN, AARON R, REHM, HEIDI L · 2017 to 2020
$2.9M
Integrating multiomic analyses for gene discovery andgenetic diagnosis of Mendelian myopathiesK23AR083505 · NIAMS · BRIGHAM AND WOMEN'S HOSPITAL · PI Vijay S Ganesh · 2024 to 2026
$522k
Medical Research Council MR/V009346/1NEI NIH HHS P30 EY014104NHGRI NIH HHS R01 HG009141NHGRI NIH HHS T32 HG010464NHGRI NIH HHS U01 HG011755NHGRI NIH HHS U24 HG011746NHGRI NIH HHS U54 HG003273NHGRI NIH HHS UM1 HG006542NHGRI NIH HHS UM1 HG008900NIAMS NIH HHS K23 AR083505NIGMS NIH HHS T32 GM007526NINDS NIH HHS R35 NS105078Wellcome TrustWellcome Trust 226653/Z/22/Z
6 · The paper itself

Abstract

purposeWe 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.

methodsThe 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.

resultsWe 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.

conclusionOur 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.

Indexed as

Muscular Atrophy, SpinalAlgorithmsExomeExome SequencingGenome, HumanGenomicsHigh-Throughput Nucleotide SequencingHumansSequence Analysis, DNASurvival of Motor Neuron 1 ProteinSurvival of Motor Neuron 2 ProteinSMN1 protein, humanSMN2 protein, humanSurvival of Motor Neuron 1 ProteinSurvival of Motor Neuron 2 ProteinAnalysis toolMuscle diseaseSegmental duplicationSMASpinal muscular atrophy

Identifiers

PMID39670433
PMCPMC11985284

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.