Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G > C Variant in SMN2
Por:
Blasco-Perez, L, Costa-Roger, M, Leno-Colorado, J, Bernal, S, Alias, L, Codina-Sola, M, Martinez-Cruz, D, Castiglioni, C, Bertini, E, Travaglini, L, Millan, JM, Aller, E, Sotoca, J, Juntas, R, Hoei-Hansen, CE, Moreno-Escribano, A, Guillen-Navarro, E, Costa-Comellas, L, Munell, F, Boronat, S, Rojas-Garcia, R, Povedano, M, Cusco, I, Tizzano, EF
Publicada:
1 ago 2022
Resumen:
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.
Filiaciones:
Blasco-Perez, L:
Univ Autonoma Barcelona UAB, Vall dHebron Res Inst VHIR, Med Genet Grp, Barcelona 08035, Spain
Univ Autonoma Barcelona UAB, Hosp Univ Vall dHebron, Dept Clin & Mol Genet, Barcelona 08035, Spain
Costa-Roger, M:
Univ Autonoma Barcelona UAB, Vall dHebron Res Inst VHIR, Med Genet Grp, Barcelona 08035, Spain
Univ Autonoma Barcelona UAB, Hosp Univ Vall dHebron, Dept Clin & Mol Genet, Barcelona 08035, Spain
Leno-Colorado, J:
Univ Autonoma Barcelona UAB, Vall dHebron Res Inst VHIR, Med Genet Grp, Barcelona 08035, Spain
Univ Autonoma Barcelona UAB, Hosp Univ Vall dHebron, Dept Clin & Mol Genet, Barcelona 08035, Spain
Bernal, S:
Hosp Santa Creu & Sant Pau, Genet Dept, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, St Pau Biomed Res Inst, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain
Alias, L:
Hosp Santa Creu & Sant Pau, Genet Dept, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, St Pau Biomed Res Inst, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain
Codina-Sola, M:
Univ Autonoma Barcelona UAB, Vall dHebron Res Inst VHIR, Med Genet Grp, Barcelona 08035, Spain
Univ Autonoma Barcelona UAB, Hosp Univ Vall dHebron, Dept Clin & Mol Genet, Barcelona 08035, Spain
Martinez-Cruz, D:
Univ Autonoma Barcelona UAB, Vall dHebron Res Inst VHIR, Med Genet Grp, Barcelona 08035, Spain
Univ Autonoma Barcelona UAB, Hosp Univ Vall dHebron, Dept Clin & Mol Genet, Barcelona 08035, Spain
Castiglioni, C:
Clin Las Condes, Dept Neurol Pediat, Santiago 7591047, Chile
Bertini, E:
Osped Pediatr Bambino Gesu, IRCCS, Unit Neuromuscular & Neurodegenerat Dis, I-00165 Rome, Italy
Travaglini, L:
Osped Pediatr Bambino Gesu, IRCCS, Unit Neuromuscular & Neurodegenerat Dis, I-00165 Rome, Italy
Millan, JM:
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain
Hosp La Fe & IIS La Fe, Unidad Genet, Valencia 46026, Spain
Aller, E:
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain
Hosp La Fe & IIS La Fe, Unidad Genet, Valencia 46026, Spain
Sotoca, J:
Hosp Univ Vall dHebron, Neurol Dept, Neuromuscular Dis Unit, Barcelona 08035, Spain
Juntas, R:
Hosp Univ Vall dHebron, Neurol Dept, Neuromuscular Dis Unit, Barcelona 08035, Spain
Hoei-Hansen, CE:
Copenhagen Univ Hosp, Dept Paediat, DK-2100 Copenhagen, Denmark
Univ Copenhagen, Dept Clin Med, DK-1165 Copenhagen, Denmark
Moreno-Escribano, A:
Univ Murcia, Hosp Clin Univ Virgen Arrixaca, IMIB Arrixaca, Neurol Serv, Murcia 30120, Spain
Univ Murcia, Hosp Clin Univ Virgen Arrixaca, IMIB Arrixaca, Med Genet Sect, Murcia 30120, Spain
Guillen-Navarro, E:
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain
Univ Murcia, Hosp Clin Univ Virgen Arrixaca, IMIB Arrixaca, Neurol Serv, Murcia 30120, Spain
Univ Murcia, Hosp Clin Univ Virgen Arrixaca, IMIB Arrixaca, Med Genet Sect, Murcia 30120, Spain
Costa-Comellas, L:
Univ Autonoma Barcelona UAB, Hosp Univ Vall dHebron, Vall dHebron Res Inst VHIR, Pediat Neurol Sect, Barcelona 08035, Spain
Munell, F:
Univ Autonoma Barcelona UAB, Hosp Univ Vall dHebron, Vall dHebron Res Inst VHIR, Pediat Neurol Sect, Barcelona 08035, Spain
Boronat, S:
Hosp Santa Creu & Sant Pau, Pediat Dept, Barcelona 08025, Spain
Rojas-Garcia, R:
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain
Univ Autonoma Barcelona, Dept Neurol, MND Clin, Hosp Santa Creu & St Pau, Barcelona 08025, Spain
Povedano, M:
Hosp Univ Bellvitge, Serv Neurol, Unidad Func Enfermedad Motoneurona, Barcelona 08907, Spain
Cusco, I:
Univ Autonoma Barcelona UAB, Vall dHebron Res Inst VHIR, Med Genet Grp, Barcelona 08035, Spain
Univ Autonoma Barcelona UAB, Hosp Univ Vall dHebron, Dept Clin & Mol Genet, Barcelona 08035, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain
Tizzano, EF:
Univ Autonoma Barcelona UAB, Vall dHebron Res Inst VHIR, Med Genet Grp, Barcelona 08035, Spain
Univ Autonoma Barcelona UAB, Hosp Univ Vall dHebron, Dept Clin & Mol Genet, Barcelona 08035, Spain
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