Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G>C Variant in SMN2

Fecha de publicación: 01/08/2022 Fecha Ahead of Print: 27/07/2022

Autores de IIS La Fe

José María Millán Salvador

Autor
Elena María Aller Mañas

Autor

Participantes ajenos a IIS La Fe

Blasco-Perez, Laura
Costa-Roger, Mar
Leno-Colorado, Jordi
Bernal, Sara
Alias, Laura
Codina-Sola, Marta
Martinez-Cruz, Desiree
Castiglioni, Claudia
Bertini, Enrico
Travaglini, Lorena
Sotoca, Javier
Juntas, Raul
Engel Hoei-Hansen, Christina
Moreno-Escribano, Antonio
Guillen-Navarro, Encarna
Costa-Comellas, Laura
Munell, Francina
Boronat, Susana
Rojas-Garcia, Ricardo
Povedano, Monica
Cusco, Ivon
Tizzano, Eduardo F.

Grupos

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.

Datos de la publicación

ISSN/ISSNe:: 1661-6596, 1661-6596
Tipo:: Article
Páginas:: -
DOI:: 10.3390/ijms23158289
Factor de Impacto:: 1,176 SCImago ℠
Cuartil:: Q1 SCImago ℠

Documentos

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Métricas

Filiaciones

Blasco-Perez, Laura:: Medicine Genetics Group, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain

Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
Costa-Roger, Mar:: Medicine Genetics Group, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain

Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
Leno-Colorado, Jordi:: Medicine Genetics Group, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain

Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
Bernal, Sara:: Genetics Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain

Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
Alias, Laura:: Genetics Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain

Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
Codina-Sola, Marta:: Medicine Genetics Group, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain

Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
Martinez-Cruz, Desiree:: Medicine Genetics Group, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain

Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
Castiglioni, Claudia:: Departamento de Neurología Pediátrica, Clínica Las Condes, 7591047 Santiago de Chile, Chile
Bertini, Enrico:: Unit of Neuromuscular and Neurodegenerative Disease, Ospedale Pediatrico Bambino Gesu, IRCCS, 00165 Rome, Italy
Travaglini, Lorena:: Unit of Neuromuscular and Neurodegenerative Disease, Ospedale Pediatrico Bambino Gesu, IRCCS, 00165 Rome, Italy
Millan, Jose M.:: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain

Instituto de Investigación. Unidad de Genética, Hospital La Fe and IIS La Fe, 46026 Valencia, Spain
Aller, Elena:: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain

Instituto de Investigación. Unidad de Genética, Hospital La Fe and IIS La Fe, 46026 Valencia, Spain
Sotoca, Javier:: Neuromuscular Diseases Unit, Neurology Department, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain
Juntas, Raul:: Neuromuscular Diseases Unit, Neurology Department, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain
Engel Hoei-Hansen, Christina:: Copenhagen Univ Hosp, Dept Paediat, DK-2100 Copenhagen, Denmark

Univ Copenhagen, Dept Clin Med, DK-1165 Copenhagen, Denmark
Moreno-Escribano, Antonio:: Neurology Service and Medical Genetics Section, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Universidad de Murcia, 30120,Murcia, Spain
Guillen-Navarro, Encarna:: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain

Neurology Service and Medical Genetics Section, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Universidad de Murcia, 30120,Murcia, Spain
Costa-Comellas, Laura:: Pediatric Neurology Section, Vall d'Hebron Research Institute (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
Munell, Francina:: Pediatric Neurology Section, Vall d'Hebron Research Institute (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
Boronat, Susana:: Pediatrics Department, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain
Rojas-Garcia, Ricardo:: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain

MND Clinic, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain
Povedano, Monica:: Unidad Funcional de Enfermedad de Motoneurona, Servicio de Neurología, Hospital Universitario de Bellvitge, 08907 Barcelona, Spain
Cusco, Ivon:: Medicine Genetics Group, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain

Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain

Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
Tizzano, Eduardo F.:: Medicine Genetics Group, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain

Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain

Keywords

spinal muscular atrophy; SMN2 copies; phenotype-genotype correlations; positive modifiers; next-generation sequencing

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