LAMA2 gene mutation update: Toward a more comprehensive picture of the laminin‐α2 variome and its related phenotypes |
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| Authors: | Jorge Oliveira Angela Gruber Márcio Cardoso Ricardo Taipa Isabel Fineza Ana Gonçalves Andreas Laner Thomas L. Winder Jocelyn Schroeder Julie Rath Márcia E. Oliveira Emília Vieira Ana Paula Sousa José Pedro Vieira Teresa Lourenço Luciano Almendra Luís Negrão Manuela Santos Manuel Melo‐Pires Teresa Coelho Johan T. den Dunnen Mário Sousa |
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| Affiliation: | 1. Unidade de Genética Molecular, Centro de Genética Médica Dr. Jacinto Magalh?es, Centro Hospitalar do Porto, Porto, Portugal;2. Unidade Multidisciplinar de Investiga??o Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal;3. PreventionGenetics, Marshfield, Wisconsin;4. Consulta de Doen?as Neuromusculares e Servi?o de Neurofisiologia, Departamento de Neurociências, Centro Hospitalar do Porto, Porto, Portugal;5. Unidade de Neuropatologia, Centro Hospitalar do Porto, Porto, Portugal;6. Unidade de Neuropediatria, Centro de Desenvolvimento da Crian?a Luís Borges, Hospital Pediátrico de Coimbra, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal;7. MGZ ‐ Center of Medical Genetics, Munich, Germany;8. Invitae Corporation, San Francisco, California;9. Servi?o de Neurologia, Hospital de Dona Estefania, Centro Hospitalar de Lisboa Central, Lisboa, Portugal;10. Servi?o de Genética Médica, Hospital de Dona Estefania, Centro Hospitalar de Lisboa Central, Lisboa, Portugal;11. Consulta de Doen?as Neuromusculares, Hospitais da Universidade de Coimbra, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal;12. Consulta de Doen?as Neuromusculares e Servi?o de Neuropediatria, Centro Hospitalar do Porto, Porto, Portugal;13. Departments of Human Genetics and Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands |
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| Abstract: | Congenital muscular dystrophy type 1A (MDC1A) is one of the main subtypes of early‐onset muscle disease, caused by disease‐associated variants in the laminin‐α2 (LAMA2) gene. MDC1A usually presents as a severe neonatal hypotonia and failure to thrive. Muscle weakness compromises normal motor development, leading to the inability to sit unsupported or to walk independently. The phenotype associated with LAMA2 defects has been expanded to include milder and atypical cases, being now collectively known as LAMA2‐related muscular dystrophies (LAMA2‐MD). Through an international multicenter collaborative effort, 61 new LAMA2 disease‐associated variants were identified in 86 patients, representing the largest number of patients and new disease‐causing variants in a single report. The collaborative variant collection was supported by the LOVD‐powered LAMA2 gene variant database ( https://www.LOVD.nl/LAMA2 ), updated as part of this work. As of December 2017, the database contains 486 unique LAMA2 variants (309 disease‐associated), obtained from direct submissions and literature reports. Database content was systematically reviewed and further insights concerning LAMA2‐MD are presented. We focus on the impact of missense changes, especially the c.2461A > C (p.Thr821Pro) variant and its association with late‐onset LAMA2‐MD. Finally, we report diagnostically challenging cases, highlighting the relevance of modern genetic analysis in the characterization of clinically heterogeneous muscle diseases. |
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| Keywords: | congenital LAMA2 laminin‐α 2 locus‐specific database muscular dystrophy mutation update |
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