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LMNA

Alias

CDCD1; CDDC; CMD1A; CMT2B1; EMD2; FPL; FPLD; FPLD2; HGPS; IDC; LDP1; LFP; LGMD1B; LMN1; LMNC; LMNL1; PRO1

Associated disorders

The LMNA gene is associated with a diverse group of disorders affecting skeletal and cardiac muscle including autosomal recessive and dominant Emery-Dreifuss muscular dystrophy type 2 (EDMD2) (MedGen UID: 98048) and type 3 (EDMD3) (MedGen UID: 413212), autosomal dominant limb-girdle muscular dystrophy type 1B (LGMD1B) (MedGen UID: 320400), congenital muscular dystrophy (MedGen UID: 413043), and dilated cardiomyopathy (DCM) (MedGen UID: 258500). It is also associated with autosomal recessive Charcot-Marie-Tooth disease type 2B1 (CMT2B1) (MedGen UID: 343064). Additional LMNA-related conditions have also been reported (OMIM: 150330).

Pathogenic variants in LMNA cause an estimated 4-5% of clinical cases of DCM, 45% of cases of autosomal dominant EDMD, 4-10% of LGMD and an unknown percentage of cases of CMT.

The LMNA gene encodes the proteins lamin A and lamin C. These lamins are structural proteins called intermediate filaments; their function is to give strength and stability to cells. Lamin A and C make up part of the scaffolding structure that gives the nucleus of the cell its shape and size.

Clinical condition

The clinical phenotypes caused by pathogenic variants in LMNA are overlapping conditions involving striated muscle (skeletal and cardiac), adipose tissue, and the peripheral nervous system (PMID: 25037088, 15773749, 17467691).

LMNA-related conditions include autosomal dominant Emery-Dreifuss muscular dystrophy (type 2 EDMD2; MedGen UID: 98048) and autosomal recessive Emery-Dreifuss muscular dystrophy (type 3 EDMD3; MedGen UID: 413212), autosomal dominant limb-girdle muscular dystrophy type 1B (LGMD1B; MedGen UID: 320400), autosomal dominant congenital muscular dystrophy (CDM; MedGen UID: 413043), autosomal dominant dilated cardiomyopathy (DCM; MedGen UID: 258500), autosomal dominant familial partial lipodystrophy (FPLD2; MedGen UID: 354526), and autosomal dominant Hutchinson-Gilford syndrome (HGPS; MedGen UID: 46123). LMNA is also associated with autosomal recessive Charcot-Marie-Tooth disease type 2B1 (CMT2B1; MedGen UID: 343064). Additional LMNA-related conditions have also been reported (OMIM: 150330).

Emery-Dreifuss muscular dystrophy: LMNA-related EDMD (types 2 and 3) is characterized by a clinical triad of joint contractures, progressive muscular weakness, and cardiomyopathy with conduction disease (PMID: 11503164, 10939567). Patients with EDMD2 typically present in childhood with weakness and difficulty running; contractures generally appear later (PMID: 10939567). Cardiac involvement initially presents as arrhythmia, and eventually progresses toward complete heart block with high risk of sudden death in adulthood (PMID: 11503164). In general, age of onset, severity, and progression of muscle and cardiac involvement demonstrate both inter- and intra-familial variability (PMID: 10939567). Autosomal recessive inheritance (EDMD3) has been reported, and is associated with a more severe presentation and earlier onset (PMID: 11503164).

Limb-Girdle muscular dystrophy: LGMD1B is the LMNA-related form of LGMD and is characterized by symmetric proximal weakness beginning in the legs. LGMD1B is associated with atrioventricular conduction disturbances, arrhythmias, and dilated cardiomyopathy (PMID: 24843229). Most patients develop proximal leg weakness first, with onset ranging from birth to the fourth decade. Cardiac arrhythmias affect nearly all patients by their 20s and are followed by cardiomyopathy and the risk for sudden death (PMID: 25037088).

Congenital muscular dystrophy: LMNA-related congenital muscular dystrophy (L-CMD) is associated with dominant de novo variants. Severe presentation occurs within the first year of life (PMID: 18551513). Patients with L-CMD either never develop muscular head and trunk support or experience progressive loss of head support after initial acquisition of sitting or walking ability (PMID: 18551513). Additional clinical features of L-CMD include weakness of the axial muscles, progressive life-threatening respiratory insufficiency, and heart rhythm disturbances (PMID: 18551513). Increased levels of creatine kinase, dystrophic changes seen on muscle biopsy, and lack of elbow contractures, along with the early age of onset are typical of L-CMD and may help differentiate it from LMNA-related EDMD and LGMD (PMID: 18551513, 25037088). To date, identified cases of L-CMD have been associated with de novo pathogenic variants; however, these same variants have also been identified as being inherited by individuals with EDMD2/3 and LGMD1B, indicating that additional factors play a role in disease severity (PMID: 18551513).

Dilated cardiomyopathy: Primarily cardiac involvement, in the form of DCM with conduction disease, may be present in individuals with pathogenic LMNA variants (PMID: 10939567, 10580070, 22224630). LMNA-related DCM causes conduction system disease, as well as heart chamber dilation and systolic dysfunction that is highly penetrant, progressive, and characterized by high rates of sudden death, thromboembolic events, and congestive heart failure (PMID: 10580070, 10939567, 22224630). The age of onset is typically early to mid-adulthood and usually begins with symptomatic conduction system disease or arrhythmia prior to ventricular dysfunction (PMID: 23582089).

Familial partial lipodystrophy: FPLD2 (also called Dunnigan type) is characterized by normal fat distribution in early childhood followed by partial lipoatrophy with progressive post-pubertal subcutaneous loss of adipose tissue in the extremities and trunk (PMID: 17711925). Affected individuals may also have excess fat deposition in the face, neck, and intra-abdominal regions (PMID: 17711925). Other features include predominant calf-muscular hypertrophy, acanthosis nigricans, insulin resistance leading to diabetes and severe hypertriglyceridemia, precocious atherosclerosis, polycystic ovarian syndrome, and liver steatosis (PMID: 17711925). Individuals with LMNA-related FPLD have also presented with lipodystrophy in combination with cardiac abnormalities, skeletal muscular abnormalities, or both (PMID: 12196663, 17711925).

Charcot-Marie-Tooth: CMT2B1 is a rare axonal (non-demyelinating) peripheral neuropathy that has been reported in a few families. In addition to the classic clinical signs of CMT (distal limb muscle weakness and atrophy, mild distal sensory disturbances, and near normal median nerve motor conduction velocity), patients present with weakness of the pelvic girdle and absent median and sural nerve sensory action potentials (PMID: 11799477, 12467734, 14607793). Consistent with the variability exhibited by LMNA-related disorders, dominant inheritance of CMT2B1 has been reported in a family with axonal neuropathy and both muscular dystrophy and cardiac disease (PMID: 14985400).

Hutchinson-Gilford progeria: HGPS is a rare disorder characterized by features reminiscent of premature ageing, including extremely short stature, low body weight, early hair loss, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, variable cardiovascular problems, and facial features that resemble aged persons (PMID: 16838330, 12714972). Cognitive development is normal, but lifespan is greatly reduced with death generally occurring by age 20 (PMID: 16838330).

Other conditions: Other LMNA-related conditions include heart-hand syndrome (Slovenian type), Malouf syndrome, mandibuloacral dysplasia, and restrictive dermopathy (OMIM: 150330, PMID: 24843229).

Gene information

The LMNA gene encodes two main protein products, lamin A and lamin C, which are generated through alternative splicing. Lamin A and lamin C are intermediate filaments that are identical up to the C-terminal domains (PMID: 22103508, 17139325). Lamin C has six unique amino acids. Lamin A is first synthesized as prelamin A, then farnesylated and cleaved, further methylated, and processed by protease to yield the mature form (PMID 22103508, 16838330). These proteins go on to dimerize and further assemble into polymers whose functions in the cellular nucleus include maintaining nuclear shape and structure, transcription regulation, nuclear positioning and function, and heterochromatin organization (PMID: 22103508, 17139325, 21173262).

The many functional roles of lamin A and lamin C coupled with different variant types (missense, nonsense, splice site, or frameshift) and locations may help explain the vast phenotypic variability associated with pathogenic variants (PMID 22103508, 17139325).

In relation to primary muscle disease, pathogenic variants of varying types throughout the gene have been found to cause disease and to exhibit well-known, extreme phenotypic variability within and among families (PMID: 10939567, 10580070, 22224630, 15773749). Pathogenic variants affecting codon 482 cause the majority of FPLD2. The introduction of cryptic splice sites at codon 608 leads to most HGPS. Specific founder variants are reported in autosomal recessive CMT2B1 (R298C; PMID: 15773749, 17139325).

Inheritance

Pathogenic variants in LMNA can cause disease in an autosomal dominant or recessive manner and may be inherited or occur de novo. EDMD2, LGMD1B, DCM, and FPLD2 exhibit autosomal dominant inheritance. This means that an affected individual with a pathogenic variant has a 50% chance of passing that variant on to their offspring. EDMD3 and CMT2B1 exhibit autosomal recessive inheritance, and affected individuals have two pathogenic variants—one in each copy of their LMNA genes. Affected individuals will pass one pathogenic LMNA variant to all of their children. L-CMD and HGPS are most often associated with dominant de novo variants. Except in the case of HGPS, which shows complete penetrance, LMNA pathogenic variants exhibit reduced but high penetrance and variable expression, meaning that the vast majority of individuals with a pathogenic variant in LMNA will go on to manifest some symptom related to these disorders in their lifetime.

Management

While no comprehensive surveillance and management guidelines currently exists across all LMNA-related conditions, the recommendations below may be appropriate for conditions within the laminopathy spectrum. HGPS is a fairly well-defined clinical and genetic subtype of laminopathy, and its specific and proper surveillance and management guidelines are outlined in the Progeria Handbook (Progeria Research Foundation. The Progeria Handbook. http://www.progeriaresearch.org/assets/files/PRFhandbook_0410.pdf. Accessed November 13, 2017).

Upon discovery of an LMNA pathogenic variant, the recommendation is for referral to a multidisciplinary clinic with expert specialists, who should screen for appropriate symptoms of LMNA-related conditions and manage accordingly (PMID: 25313375, 25825463, 19254666).

Initial evaluations after an LMNA pathogenic variant is identified include:

  • cardiac screening in the form of medical history, physical exam, electrocardiogram (EKG/ECG), and echocardiogram (PMID: 19254666, 23582089)
  • neuromuscular evaluation to establish the presence and extent of disease by clinical exam, serum creatine kinase level, nerve conduction velocity testing, needle electromyography, and/or muscle biopsy with electron microscopy (PMID: 25313375, 25037088, 26855581)
  • identification and treatment of respiratory insufficiency through pulmonary function testing, including spirometry and maximal inspiratory/expiratory force in upright and supine positions for adult patients with signs of muscular dystrophy (PMID: 25313375), and spirometry and oxygen saturation in both awake and asleep states for pediatric patients—to be performed by specialist care teams where available (PMID: 25825463)
  • laboratory evaluation of metabolic functions, including blood levels of glucose, insulin, cholesterol, and triglycerides (PMID: 12196663, 16409151)
  • genetic counseling for individuals and families to interpret genetic test results and arrange familial testing (PMID: 25825463, 26186385)
  • genetic testing for at-risk family members of an individual with a pathogenic LMNA variant (PMID: 19254666)

Ongoing evaluations and management of symptoms:

  • Cardiac screening for LMNA-related cardiac disease is recommended annually in childhood and every 1 to 3 years in adults (with suggestions favoring annual screening; PMID: 19254666, 23582089). It is recommended to treat DCM with a combination of medication, device therapy (e.g., implantable cardioverter defibrillator, pacemaker), surgical procedures (e.g., catheter ablation, cardiac resynchronization), and (potentially) heart transplantation (PMID: 23747642).
  • Patients with muscular dystrophy can have dysphagia, frequent aspiration, or weight loss, all of which further complicate the course of the disease. These patients’ growth and nutrition should be monitored, and they should be referred for swallowing or gastroenterology evaluation to assess and manage swallowing function and risk of aspiration and for consideration of a gastrostomy or jejunostomy tube (PMID: 25313375, 25825463).
  • Referrals to special education and intervention services should be made for children at risk for developmental delays due to LMNA-related disease (PMID: 25825463).
  • Management of metabolic complications includes hypoglycemic medication or insulin therapy, lipid-lowering medications, a reduced-fat and -cholesterol diet, and increased physical activity (PMID: 16409151).
  • Patients should be monitored for the development of spinal deformities (PMID: 25313375). Periodic assessments, as well as ongoing therapies, by physical and occupational therapists are recommended, as are stretching, exercise, bracing, assistive devices, and potentially surgery to preserve mobility and function (PMID: 25313375, 26855581, 25825463).
  • Discussions surrounding the disease progression, loss of mobility, need for assistance, medical complications, and end-of-life care should be had proactively with patients and family (PMID: 25313375).
  • Pulmonary function tests should be repeated at the onset of respiratory difficulty and should be managed with assisted ventilation (PMID: 25313375, 25825463).

Review date: November 2017

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
LMNA NM_170707.3; NM_005572.3