| Title: | Diagnosing missed cases of spinal muscular atrophy in genome, exome, and panel sequencing data sets |
| Journal: | Genetics in Medicine |
| Published: | 9 Dec 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39670433/ |
| DOI: | https://doi.org/10.1016/j.gim.2024.101336 |
Publication 14687
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
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.</p>
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.</p>
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.</p>
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.</p>
11 Keywords
- Algorithms
- Exome
- Exome Sequencing
- Genome, Human
- Genomics
- High-Throughput Nucleotide Sequencing
- Humans
- Muscular Atrophy, Spinal
- Sequence Analysis, DNA
- Survival of Motor Neuron 1 Protein
- Survival of Motor Neuron 2 Protein
39 Authors
- 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
- Seth A Stafki
- Audrey L Daugherty
- Chiara Folland
- Stojan Peric
- Nagia Fahmy
- Bjarne Udd
- Magda Horáková
- Anna Łusakowska
- Rajanna Manoj
- Atchayaram Nalini
- Veronika Karcagi
- Kiran Polavarapu
- Hanns Lochmüller
- Rita Horvath
- Carsten G Bönnemann
- Sandra Donkervoort
- Göknur Haliloğlu
- Ozlem Herguner
- Peter B Kang
- Gianina Ravenscroft
- Nigel Laing
- Hamish S Scott
- Ana Töpf
- Volker Straub
- Sander Pajusalu
- Katrin Õunap
- Grace Tiao
- Heidi L Rehm
- Anne O'Donnell-Luria
Enabling scientific discoveries that improve human health