1 - Unidade de Genética Molecular, Centro de Genética Médica Dr. Jacinto Magalhães, Centro Hospitalar do Porto, Porto, Portugal.
2 - Unidade Multidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.
3 - Prevention Genetics, Marshfield, Wisconsin.
4 - Consulta de Doenças Neuromusculares e Serviço 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 Criança 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 - Serviço de Neurologia Pediátrica, Área da Mulher, Adolescente e Criança, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
10 - Serviço de Genética Médica, Área da Mulher, Adolescente e Criança, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
11 - Consulta de Doenças Neuromusculares, Hospitais da Universidade de Coimbra, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal
12 - Consulta de Doenças Neuromusculares e Serviço de Neuropediatria, Centro Hospitalar do Porto, Porto, Portugal
13 - Departments of Human Genetics and Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
14 - UCIBIO/REQUIMTE, Departamento de Ciências Biológicas, Laboratório de Bioquímica, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
15 - Departamento de Microscopia, Laboratório de Biologia Celular, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
16 - Centro de Genética da Reprodução Prof. Alberto Barros, Porto, Portugal
- Publicação na Hum Mutat. 2018 Oct;39(10):1314-1337
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.
Palavras Chave: LAMA2; congenital; laminin-α2; locus-specific database; muscular dystrophy; mutation update