- To collect biological material (muscle and/or skin biopsies) and the phenotype of patients with mutations in the LMNA gene (within large families with variable clinical presentation or within cohorts of patients with recurrent mutations in the LMNA gene.
- To grade the severity of the muscle phenotype of these patients (severe, moderate, mild).
- Perform "omics" analysis on their biological material.
Mutations in the LMNA gene, which codes for lamins A and C, proteins of the nuclear lamina, are responsible for a wide spectrum of pathologies, including a group specifically affecting striated skeletal and cardiac muscles, with cardiac involvement being life-threatening. At the skeletal muscle level, a wide phenotypic spectrum has been described, ranging from severe forms of congenital muscular dystrophy to less severe forms of limb-girdle muscular dystrophy. The great clinical variability of striated muscle laminopathies, both inter- and intra-familial, can be observed in the age of onset, severity of signs and progression of muscle and heart involvement. To date, more than 400 LMNA mutations have been associated with striated muscle laminopathies (www.umd.be/LMNA/), highlighting strong clinical and genetic heterogeneity. A few recurrent mutations linked to a difference in severity have been identified. However, these genotype-phenotype relationships and the rare cases of digenism reported do not explain all the clinical variability of laminopathies. Therefore, there are probably other factors of severity than the causative mutation, called "modifier genes".
Identification of such modifier genes has been initiated by studying a large family with significant clinical variability in the age of onset of muscle signs. A segregation analysis within this family identified 2 potential modifier loci. High-throughput sequencing restricted to these 2 regions according to phenotypic subgroups did not led to meaningful results so far. In addition, an international retrospective study of the natural history of early muscle laminopathies has allowed the investigators to highlight a strong inter-family clinical variability in patients carrying recurrent mutations. The investigators thus have strong preliminary data that could allow them to identify modifying genetic factors in a cohort of patients carrying a mutation in the LMNA gene.
In order to identify these factors that modulate the clinical severity of laminopathies, the investigators wish to collect biological material (muscle and/or skin biopsies) from patients carrying a mutation in the LMNA gene. The study of this biological material using multi OMICs technics will allow the investigators to identify and functionally validate the action of these modifying genes.
OMIICs is a set of techniques for characterising biological molecules using high-throughput approaches such as DNA sequencing, RNA sequencing and/or chromatin conformation (ATACseq...), proteins.
Skeletal muscle severity outcome [ Time Frame: 5 years ] Will be a composite scale combining maximal motor acquisitions (sitting, walking, running) and what remains as motor skills with disease course (still running, only walking, only sitting, inability to sit)). In details:
The maximal motor acquisitions (M2A) : no motor acquisitions = 0, only rolling = 1, only sitting = 2, only walking = 3, running = 4.
The remaining motor skills (RMS) with disease course: still running = 3, only walking = 2, only sitting = 1, inability to sit = 0.
The composite scale for a given patient will be M2A + RMS.
Cardiac muscle severity outcome [ Time Frame: 5 years ]
Will be a composite scale according to left ventricle ejection fraction (normal>55%, moderate <55% and >45%, severe<45%) and the presence or absence of conduction defects and arrhythmias.
Protective structural variant outcome [ Time Frame: 5 years ]
Structural gene variants identified on patient biological materials by Whole Genome Sequencing (WGS), associated with the mild disease severity.
Protective differential gene expression outcome [ Time Frame: 5 years ]
differential gene expression identified on patient biological materials by RNA sequencing (RNA-seq) associated with the mild disease severity.
Protective 3D chromatin conformation outcome [ Time Frame: 5 years ]
3D conformation of chromatin identified on patient biological materials by Chromatin Immuno-Precipitaiton Sequencing (CHIP Seq) associated with the mild disease severity.
Aggravating structural variant outcome [ Time Frame: 5 years ]
Structural gene variants identified on patient biological materials by Whole Genome Sequencing (WGS), associated with the worse disease severity.
Aggravating differential gene expression outcome [ Time Frame: 5 years ]
Differential gene expression identified on patient biological materials by RNA sequencing (RNA-seq) associated with the worse disease severity.
Aggravating 3D chromatin conformation outcome outcome [ Time Frame: 5 years ] 3D conformation of chromatin identified on patient biological materials by Chromatin Immuno-Precipitaiton Sequencing (CHIP Seq) associated with the worse disease severity.
Ages Eligible for Study: 2 Years and older (Child, Adult, Older Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
Patient with an LMNA mutation that has led to the diagnosis of laminopathy affecting striated muscle
Presenting the symptoms of the disease, whether they are index cases or related to this index case (muscle weakness, tendon retractions with or without respiratory or cardiac involvement)
Have no contraindication to muscle or skin biopsy, i.e., 1) presence of a history of allergy to latex, antiseptics, local anesthetics and adhesive dressings, 2) Current oral or parenteral anticoagulant therapy (anti-vitamin K, heparins, anti-platelet agents, anti-factor X, anti-thrombin), 3) History of inherited (haemophilias, platelet diseases) or acquired (vitamin K deficiency, liver failure) coagulation disorders.
Patients (adult participant) or both holders of parental authority (minor participant) must sign a free and informed consent. If a minor has only 1 legal representative, the latter must attest to this on the consent form.
Patients affiliated to the general French social security system, to the French Universal Medical Coverage (CMU) or to any French equivalent scheme.
Pregnant or breastfeeding women
Adult subject to legal protection measures (safeguard of justice, curatorship and guardianship).
Centre de référence maladies neuromusculaires, Hôpital Femme Mère Enfant, CHU Lyon
Bron, Auvergne-Rhône-Alpes, France, 69677
Contact: Françoise Bouhour, MD françoise.firstname.lastname@example.org
Contact: Véronique Manel, MD email@example.com
Service de Neuropédiatrie, Centre de Référence Maladies Neuromusculaires, CHU de Montpellier
Montpellier, Hérault, France, 34295
Contact: François Rivier, MD +33467330182 firstname.lastname@example.org
Service de Neurologie, Réanimation Pédiatriques, Hôpital Raymond Poincaré, Hôpitaux Universitaires, Paris-Ile-de-France-Ouest
Garches, Ile De France, France, 92380
Contact: Susana Quijano-Roy, MD +33147417890 email@example.com
Service de Génétique médicale, CHU Rennes
Rennes, Ille-et-Vilaine, France, 35000
Contact: Melanie Fradin, MD +33299266744 firstname.lastname@example.org
Laboratoire d'Explorations Fonctionnelles - Centre de Référence Maladies Neuromusculaires Rares, CHU Nantes
Nantes, Loire-Atlantique, France, 44093
Contact: Yann Pereon, MD +33240083617 Yann.Pereon@univ-nantes.fr
Contact: Sandra Mercier, MD +33240083245 email@example.com
Service de cardiologie & Service de Neurophysiologie - CHU de Rouen
Rouen, Normandie, France, 76031
Contact: Frédéric Anselme, MD +33232888111 Frederic.Anselme@chu-rouen.fr
Contact: Lucie Guyant-Marechal, MD +33232888037 firstname.lastname@example.org
Centre de référence maladies neuromusculaires, Institut de myologie, Hôpital Pitié-Salpêtrière
Paris, France, 75013
Contact: Tanya Stojkovic, MD email@example.com
Contact: Anthony Behin, MD +3342163774 firstname.lastname@example.org
Centre de référence pour les maladies cardiaques héréditaires
Paris, France, 75013
Contact: Philippe Charron, MD +33142162892 email@example.com
Institut National de la Santé Et de la Recherche Médicale, France