CDCD1; CDDC; CMD1A; CMT2B1; EMD2; FPL; FPLD; FPLD2; HGPS; IDC; LDP1; LFP; LGMD1B; LMN1; LMNC; LMNL1; PRO1
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) and autosomal recessive Charcot-Marie-Tooth disease type 2B1 (CMT2B1) (MedGen UID: 343064). It is also associated with the following autosomal dominant conditions: limb-girdle muscular dystrophy type 1B (LGMD1B) (MedGen UID: 320400), congenital muscular dystrophy (MedGen UID: 413043), dilated cardiomyopathy (DCM) (MedGen UID: 258500), familial partial lipodystrophy (FPLD2) (MedGen UID: 354526) and Hutchinson-Gilford progeria syndrome (HGPS) (MedGen UID: 46123). Other conditions have also been reported (OMIM: 150330).
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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.
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).
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).
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.
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:
Ongoing evaluations and management of symptoms:
Review date: November 2017
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 in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
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