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

Gorka Fernández-Eulate; Julian Theuriet; Christopher J Record; Giorgia Querin; Marion Masingue; Sarah Leonard-Louis; Anthony Behin; Nadine Le Forestier; Antoine Pegat; Maud Michaud; Jean-Baptiste Chanson; Aleksandra Nadaj-Pakleza; Celine Tard; Anne-Laure Bedat-Millet; Guilhem Sole; Marco Spinazzi; Emmanuelle Salort-Campana; Andoni Echaniz-Laguna; Vianney Poinsignon; Philippe Latour; Mary M Reilly; Francoise Bouhour; Tanya Stojkovic

doi:10.1212/NXG.0000000000200087

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

Neurol Genet. 2023 Jul 17;9(4):e200087. doi: 10.1212/NXG.0000000000200087. eCollection 2023 Aug.

Authors

Gorka Fernández-Eulate¹, Julian Theuriet¹, Christopher J Record¹, Giorgia Querin¹, Marion Masingue¹, Sarah Leonard-Louis¹, Anthony Behin¹, Nadine Le Forestier¹, Antoine Pegat¹, Maud Michaud¹, Jean-Baptiste Chanson¹, Aleksandra Nadaj-Pakleza¹, Celine Tard¹, Anne-Laure Bedat-Millet¹, Guilhem Sole¹, Marco Spinazzi¹, Emmanuelle Salort-Campana¹, Andoni Echaniz-Laguna¹, Vianney Poinsignon¹, Philippe Latour¹, Mary M Reilly¹, Francoise Bouhour¹, Tanya Stojkovic¹

Affiliation

¹ From the Nord/Est/Ile-de-France Neuromuscular Reference Center (G.F.-E., G.Q., M. Masingue, S.L.-L., A.B., T.S.), Institut de Myologie, Pitié-Salpêtrière Hospital, Paris; Electromyography and Neuromuscular Department (J.T., A.P., F.B.), Hospices Civils de Lyon; Centre for Neuromuscular Diseases (C.J.R., M.M.R.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neurology Department (N.L.F.), Pitié-Salpêtrière Hospital, Paris; Nord/Est/Ile-de-France Neuromuscular Reference Center (M. Michaud), Central Nancy University Hospital; Nord/Est/Ile-de-France Neuromuscular Reference Center (J.-B.C., A.N.-P.), Strasbourg University Hospitals; Nord/Est/Ile-de-France Neuromuscular Reference Center (C.T.), U1172, Lille University Hospital; Nord/Est/Ile-de-France Neuromuscular Reference Center (A.-L.B.-M.), Rouen University Hospital; Neuromuscular Reference Center 'AOC' (G.S.), Bordeaux University Hospitals (Pellegrin Hospital); Neuromuscular Reference Center (M.S.), Angers University Hospital; Neuromuscular and ALS Reference Center (E.S.-C.), La Timone University Hospital, Marseille; French National Center for Rare Neuropathies (A.E.-L.), Neurology Department, Bicêtre University Hospital, INSERM U1195, Paris-Saclay University; Molecular Genetics Lab (V.P.), Bicêtre University Hospital, Le Kremlin Bicêtre; and Center for Biology - East (P.L.), Neurological Hereditary Disorders Unit, Hospices Civils de Lyon, France.

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.