UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy

Fernández-Eulate, Gorka; Theuriet, Julian; Record, Christopher J; Querin, Giorgia; Masingue, Marion; Leonard-Louis, Sarah; Behin, Anthony; ... Stojkovic, Tanya; + view all (2023) Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy. Neurology Genetics , 9 (4) , Article e200087. 10.1212/NXG.0000000000200087. Green open access

[thumbnail of Record_Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy_VoR.pdf]
Preview
PDF
Record_Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy_VoR.pdf - Published Version

Download (822kB) | Preview

Abstract

BACKGROUND AND OBJECTIVES: Spinal muscular atrophy (SMA) is mainly caused by homozygous SMN1 gene deletions on 5q13. Non-5q SMA patients' series are lacking, and the diagnostic yield of next-generation sequencing (NGS) is largely unknown. The aim of this study was to describe the clinical and genetic landscape of non-5q SMA and evaluate the performance of neuropathy gene panels in these disorders. METHODS: Description of patients with non-5q SMA followed in the different neuromuscular reference centers in France as well as in London, United Kingdom. Patients without a genetic diagnosis had undergone at least a neuropathy or large neuromuscular gene panel. RESULTS: Seventy-one patients from 65 different families were included, mostly sporadic cases (60.6%). At presentation, 21 patients (29.6%) showed exclusive proximal weakness (P-SMA), 35 (49.3%) showed associated distal weakness (PD-SMA), and 15 (21.1%) a scapuloperoneal phenotype (SP-SMA). Thirty-two patients (45.1%) had a genetic diagnosis: BICD2 (n = 9), DYNC1H1 (n = 7), TRPV4 (n = 4), VCP, HSBP1, AR (n = 2), VRK1, DNAJB2, MORC2, ASAH1, HEXB, and unexpectedly, COL6A3 (n = 1). The genetic diagnostic yield was lowest in P-SMA (6/21, 28.6%) compared with PD-SMA (16/35, 45.7%) and SP-SMA (10/15, 66.7%). An earlier disease onset and a family history of the disease or consanguinity were independent predictors of a positive genetic diagnosis. Neuropathy gene panels were performed in 59 patients with a 32.2% diagnostic yield (19/59). In 13 additional patients, a genetic diagnosis was achieved through individual gene sequencing or an alternative neuromuscular NGS. DISCUSSION: Non-5q SMA is genetically heterogeneous, and neuropathy gene panels achieve a molecular diagnosis in one-third of the patients. The diagnostic yield can be increased by sequencing of other neuromuscular and neurometabolic genes. Nevertheless, there is an unmet need to cluster these patients to aid in the identification of new genes.

Type: Article
Title: Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1212/NXG.0000000000200087
Publisher version: https://doi.org/10.1212/NXG.0000000000200087
Language: English
Additional information: © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10174505
Downloads since deposit
48Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item