{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T14:50:55Z","timestamp":1781103055178,"version":"3.54.1"},"reference-count":38,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,7,27]],"date-time":"2022-07-27T00:00:00Z","timestamp":1658880000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Biogen","award":["(ESP-SMG-17-11256)"],"award-info":[{"award-number":["(ESP-SMG-17-11256)"]}]},{"name":"Biogen","award":["(grant no. FIS PI18\/000687)"],"award-info":[{"award-number":["(grant no. FIS PI18\/000687)"]}]},{"name":"Roche","award":["(ESP-SMG-17-11256)"],"award-info":[{"award-number":["(ESP-SMG-17-11256)"]}]},{"name":"Roche","award":["(grant no. FIS PI18\/000687)"],"award-info":[{"award-number":["(grant no. FIS PI18\/000687)"]}]},{"name":"GaliciAME and Spanish Instituto de Salud Carlos III","award":["(ESP-SMG-17-11256)"],"award-info":[{"award-number":["(ESP-SMG-17-11256)"]}]},{"name":"GaliciAME and Spanish Instituto de Salud Carlos III","award":["(grant no. FIS PI18\/000687)"],"award-info":[{"award-number":["(grant no. FIS PI18\/000687)"]}]},{"name":"Fondo de Investigaciones Sanitarias and co-funded with ERDF funds","award":["(ESP-SMG-17-11256)"],"award-info":[{"award-number":["(ESP-SMG-17-11256)"]}]},{"name":"Fondo de Investigaciones Sanitarias and co-funded with ERDF funds","award":["(grant no. FIS PI18\/000687)"],"award-info":[{"award-number":["(grant no. FIS PI18\/000687)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u2013phenotype correlation is not absolute. We present eleven unrelated SMA patients with milder phenotypes carrying the c.859G&gt;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&gt;C. Two other cases with the c.859G&gt;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&gt;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&gt;C, as well as accurately assessing the SMN2 region in SMA patients to gain insight into the complex genotype\u2013phenotype correlations and improve prognostic outcomes.<\/jats:p>","DOI":"10.3390\/ijms23158289","type":"journal-article","created":{"date-parts":[[2022,7,27]],"date-time":"2022-07-27T21:11:05Z","timestamp":1658956265000},"page":"8289","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G&gt;C Variant in SMN2"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6483-5742","authenticated-orcid":false,"given":"Laura","family":"Blasco-P\u00e9rez","sequence":"first","affiliation":[{"name":"Medicine Genetics Group, Vall d\u2019Hebron Research Institute (VHIR), Universitat Aut\u00f2noma de Barcelona (UAB), 08035 Barcelona, Spain"},{"name":"Department of Clinical and Molecular Genetics, Hospital Universitari Vall d\u2019Hebron, Universitat Aut\u00f2noma de Barcelona (UAB), 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8949-9466","authenticated-orcid":false,"given":"Mar","family":"Costa-Roger","sequence":"additional","affiliation":[{"name":"Medicine Genetics Group, Vall d\u2019Hebron Research Institute (VHIR), Universitat Aut\u00f2noma de Barcelona (UAB), 08035 Barcelona, Spain"},{"name":"Department of Clinical and Molecular Genetics, Hospital Universitari Vall d\u2019Hebron, Universitat Aut\u00f2noma de Barcelona (UAB), 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi","family":"Leno-Colorado","sequence":"additional","affiliation":[{"name":"Medicine Genetics Group, Vall d\u2019Hebron Research Institute (VHIR), Universitat Aut\u00f2noma de Barcelona (UAB), 08035 Barcelona, Spain"},{"name":"Department of Clinical and Molecular Genetics, Hospital Universitari Vall d\u2019Hebron, Universitat Aut\u00f2noma de Barcelona (UAB), 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4427-0574","authenticated-orcid":false,"given":"Sara","family":"Bernal","sequence":"additional","affiliation":[{"name":"Genetics Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Alias","sequence":"additional","affiliation":[{"name":"Genetics Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5382-413X","authenticated-orcid":false,"given":"Marta","family":"Codina-Sol\u00e0","sequence":"additional","affiliation":[{"name":"Medicine Genetics Group, Vall d\u2019Hebron Research Institute (VHIR), Universitat Aut\u00f2noma de Barcelona (UAB), 08035 Barcelona, Spain"},{"name":"Department of Clinical and Molecular Genetics, Hospital Universitari Vall d\u2019Hebron, Universitat Aut\u00f2noma de Barcelona (UAB), 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desir\u00e9e","family":"Mart\u00ednez-Cruz","sequence":"additional","affiliation":[{"name":"Medicine Genetics Group, Vall d\u2019Hebron Research Institute (VHIR), Universitat Aut\u00f2noma de Barcelona (UAB), 08035 Barcelona, Spain"},{"name":"Department of Clinical and Molecular Genetics, Hospital Universitari Vall d\u2019Hebron, Universitat Aut\u00f2noma de Barcelona (UAB), 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1981-7550","authenticated-orcid":false,"given":"Claudia","family":"Castiglioni","sequence":"additional","affiliation":[{"name":"Departamento de Neurolog\u00eda Pedi\u00e1trica, Cl\u00ednica Las Condes, 7591047 Santiago de Chile, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Bertini","sequence":"additional","affiliation":[{"name":"Unit of Neuromuscular and Neurodegenerative Disease, Ospedale Pediatrico Bambino Gesu, IRCCS, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena","family":"Travaglini","sequence":"additional","affiliation":[{"name":"Unit of Neuromuscular and Neurodegenerative Disease, Ospedale Pediatrico Bambino Gesu, IRCCS, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7211-9129","authenticated-orcid":false,"given":"Jos\u00e9 M.","family":"Mill\u00e1n","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain"},{"name":"Unidad de Gen\u00e9tica, Hospital La Fe and IIS La Fe, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Aller","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain"},{"name":"Unidad de Gen\u00e9tica, Hospital La Fe and IIS La Fe, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3400-1434","authenticated-orcid":false,"given":"Javier","family":"Sotoca","sequence":"additional","affiliation":[{"name":"Neuromuscular Diseases 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Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francina","family":"Munell","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Section, Vall d\u2019Hebron Research Institute (VHIR), Hospital Universitari Vall d\u2019Hebron, Universitat Aut\u00f2noma de Barcelona (UAB), 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"Boronat","sequence":"additional","affiliation":[{"name":"Pediatrics Department, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Rojas-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain"},{"name":"MND Clinic, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Aut\u00f2noma de Barcelona, 08025 Barcelona, 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