Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G>C Variant in SMN2
Blasco-Pérez, Laura (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Costa-Roger, Mar (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Leno Colorado, Jordi (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Bernal, Sara (Institut d'Investigació Biomèdica Sant Pau)
Alías, Laura (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Codina Solà, Marta (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Martínez-Cruz, Desirée (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Castiglioni, Claudia (Departamento de Neurología Pediátrica. Clínica Las Condes)
Bertini, Enrico (Unit of Neuromuscular and Neurodegenerative Disease. Ospedale Pediatrico Bambino Gesu. IRCCS)
Travaglini, Lorena (Unit of Neuromuscular and Neurodegenerative Disease. Ospedale Pediatrico Bambino Gesu. IRCCS)
Millán, José (Instituto de Investigación Sanitaria La Fe)
Aller, Elena (Instituto de Investigación Sanitaria La Fe)
Sotoca Fernández, Javier (Hospital Universitari Vall d'Hebron)
Juntas, Raúl (Hospital Universitari Vall d'Hebron)
Hoei-Hansen, Christina Engel (University of Copenhagen. Department of Clinical Medicine)
Moreno-Escribano, Antonio (Hospital Clínico Universitario Virgen de la Arrixaca (El Palmar, Múrcia))
Guillén-Navarro, E. (Clínico Universitario Virgen de la Arrixaca. IMIB-Arrixaca. Universidad de Murcia)
Costa-Comellas, Laura (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Munell Casadesus, Francina (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Boronat, Susanna (Institut d'Investigació Biomèdica Sant Pau)
Rojas-García, Ricardo (Institut d'Investigació Biomèdica Sant Pau)
Povedano, Mónica (Hospital Universitari de Bellvitge)
Cusco, Ivon (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Tizzano, Eduardo F. (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Universitat Autònoma de Barcelona

Date:	2022
Abstract:	Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by biallelic loss or pathogenic variants in the SMN1 gene. Copy number and modifier intragenic variants in SMN2, an almost identical paralog gene of SMN1, are known to influence the amount of complete SMN proteins. Therefore, SMN2 is considered the main phenotypic modifier of SMA, although genotype-phenotype correlation is not absolute. We present eleven unrelated SMA patients with milder phenotypes carrying the c. 859G>C-positive modifier variant in SMN2. All were studied by a specific NGS method to allow a deep characterization of the entire SMN region. Analysis of two homozygous cases for the variant allowed us to identify a specific haplotype, Smn2-859C. 1, in association with c. 859G>C. Two other cases with the c. 859G>C variant in their two SMN2 copies showed a second haplotype, Smn2-859C. 2, in cis with Smn2-859C. 1, assembling a more complex allele. We also identified a previously unreported variant in intron 2a exclusively linked to the Smn2-859C. 1 haplotype (c. 154-1141G>A), further suggesting that this region has been ancestrally conserved. The deep molecular characterization of SMN2 in our cohort highlights the importance of testing c. 859G>C, as well as accurately assessing the SMN2 region in SMA patients to gain insight into the complex genotype-phenotype correlations and improve prognostic outcomes.
Grants:	Instituto de Salud Carlos III FIS PI18/000687
Note:	Altres ajuts: Biogen (ESP-SMG-17-11256); Roche; GaliciAME; Fondo Europeo de Desarrollo Regional (FEDER); Horizon 2020 IMI2 Screen4Care.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Spinal muscular atrophy ; SMN2 copies ; Phenotype-genotype correlations ; Positive modifiers ; Next-generation sequencing
Published in:	International journal of molecular sciences, Vol. 23 Núm. 15 (august 2022) , p. 8289, ISSN 1422-0067

DOI: 10.3390/ijms23158289
PMID: 35955418

13 p, 1.2 MB

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Articles > Research articles
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