2026-04-17T12:49:47Zhttps://recercat.cat/oai/request

oai:recercat.cat:11351/118022025-10-24T10:22:10Zcom_2072_378070com_2072_378040col_2072_378092

Complex SMN Hybrids Detected in a Cohort of 31 Patients With Spinal Muscular Atrophy Costa Roger, Mar Blasco Pérez, Laura Gerin, Lorène Codina Solà, Marta Leno Colorado, Jorge Gómez-García de la Banda, Marta TIZZANO, EDUARDO F. Institut Català de la Salut [Costa Roger M, Blasco Pérez L, Codina Solà M, Leno Colorado J, Tizzano EF] Grup de Recerca de Medicina Genètica, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Gerin L] Neuromuscular Unit, Pediatric Neurology and ICU Department, Raymond Poincaré Hospital (UVSQ), AP-HP Université ParisSaclay, Garches, France. [Gómez-García De la Banda M] Neuromuscular Unit, Pediatric Neurology and ICU Department, Raymond Poincaré Hospital (UVSQ), AP-HP Université ParisSaclay, Garches, France Vall d'Hebron Barcelona Hospital Campus Atròfia muscular espinal - Aspectes genètics Fenotip Anomalies cromosòmiques DISEASES::Nervous System Diseases::Central Nervous System Diseases::Spinal Cord Diseases::Muscular Atrophy, Spinal Other subheadings::Other subheadings::Other subheadings::/genetics PHENOMENA AND PROCESSES::Genetic Phenomena::Phenotype PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation::Mutation ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, DNA::DNA Mutational Analysis ENFERMEDADES::enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades de la médula espinal::atrofia muscular espinal Otros calificadores::Otros calificadores::Otros calificadores::/genética FENÓMENOS Y PROCESOS::fenómenos genéticos::fenotipo FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética::mutación TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::técnicas de investigación::técnicas genéticas::análisis de secuencias::análisis de secuencias de ADN::análisis de mutaciones del ADN Spinal muscular atrophy Atròfia muscular espinal Atrofia muscular espinal Background and Objectives Spinal muscular atrophy (SMA) is a recessive neuromuscular disorder caused by the loss or presence of point pathogenic variants in the SMN1 gene. The main positive modifier of the SMA phenotype is the number of copies of the SMN2 gene, a paralog of SMN1, which only produces around 10%–15% of functional SMN protein. The SMN2 copy number is inversely correlated with phenotype severity; however, discrepancies between the SMA type and the SMN2 copy number have been reported. The presence of SMN2-SMN1 hybrids has been proposed as a possible modifier of SMA disease. Methods We studied 31 patients with SMA, followed at a single center and molecularly diagnosed by Multiplex Ligand-Dependent Probe Amplification (MLPA), with a specific next-generation sequencing protocol to investigate their SMN2 genes in depth. Hybrid characterization also included bioinformatics haplotype phasing and specific PCRs to resolve each SMN2-SMN1 hybrid structure. Results We detected SMN2-SMN1 hybrid genes in 45.2% of the patients (14/31), the highest rate reported to date. This represents a total of 25 hybrid alleles, with 9 different structures, of which only 4 are detectable by MLPA. Of particular interest were 2 patients who presented 4 SMN2-SMN1 hybrid copies each and no pure SMN2 copies, an event reported here for the first time. No clear trend between the presence of hybrids and a milder phenotype was observed, although 5 of the patients with hybrid copies showed a better-than-expected phenotype. The higher hybrid detection rate in our cohort may be due to both the methodology applied, which allows an in-depth characterization of the SMN genes and the ethnicity of the patients, mainly of African origin. Discussion Although hybrid genes have been proposed to be beneficial for patients with SMA, our work revealed great complexity and variability between hybrid structures; therefore, each hybrid structure should be studied independently to determine its contribution to the SMA phenotype. Large-scale studies are needed to gain a better understanding of the function and implications of SMN2-SMN1 hybrid copies, improving genotype-phenotype correlations and prediction of the evolution of patients with SMA. This work was partially funded by grants from Biogen (ESP-SMG-17-11256), Roche, GaliciAME and the Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias and co-funded with ERDF funds (FIS PI18/000687). 2024-07-31T08:22:32Z 2024-07-31T08:22:32Z 2024-07-16 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Costa-Roger M, Blasco-Pérez L, Gerin L, Codina-Solà M, Leno-Colorado J, Gómez-García De la Banda M, et al. Complex SMN Hybrids Detected in a Cohort of 31 Patients With Spinal Muscular Atrophy. Neurol Genet. 2024 Jul 16;10(4):e200175. 2376-7839 https://hdl.handle.net/11351/11802 10.1212/NXG.0000000000200175 39035824 http://hdl.handle.net/11351/11802 eng Neurology Genetics;10(4) https://doi.org/10.1212/NXG.0000000000200175 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess application/pdf Wolters Kluwer Health Scientia