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Invitae Comprehensive Muscular Dystrophy Panel
Test description
The Invitae Comprehensive Muscular Dystrophy Panel analyzes up to 56 genes that are associated with inherited muscular dystrophies. Muscular dystrophies are a heterogeneous group of neuromuscular disorders that are characterized by weakness and wasting due to muscle dysfunction. Age of onset, symptom severity, and histopathological findings are variable between different forms of muscular dystrophies. The genes in this panel were curated based on current available evidence to provide a comprehensive test for the genetic causes of inherited muscular dystrophy.
Given the clinical overlap between different types of muscular dystrophy, comprehensive testing allows for a more efficient evaluation of several conditions based on a single indication for testing. Identification of the molecular basis of disease can be useful in confirming a diagnosis, predicting disease course, and informing recurrence risk.
Genes tested
Primary panel
ANO5 B3GALNT2 B4GAT1 CAPN3 CAV3 CHKB COL12A1 COL6A1 COL6A2 COL6A3 DAG1 DES DMD DNAJB6 DPM1 DPM2 DPM3 DYSF EMD FHL1 FKRP FKTN GAA GMPPB ISPD ITGA7 LAMA2 LARGE1 LMNA MYOT PLEC PNPLA2 POMGNT1 POMGNT2 POMK POMT1 POMT2 RXYLT1 SGCA SGCB SGCD SGCG TCAP TNPO3 TOR1AIP1 TRAPPC11 TRIM32 TTN
Add-on Preliminary-evidence Genes for Muscular Dystrophy
HNRNPDL LIMS2 SUN1 SUN2 SYNE1 SYNE2 TMEM43
Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test. Some clinicians may wish to include genes which do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.
Add-on Facioscapulohumeral Muscular Dystrophy Type 2 (FSHD2) Gene
SMCHD1
Pathogenic variants in SMCHD1 account for approximately 5% of facioscapulohumeral muscular dystrophy. SMCHD1 variants should be interpreted in the context of D4Z4 hypomethylation and a permissive 4qA haplotype, which is not part of this assay. Depending on the clinical presentation of the individual and within the context of additional laboratory results, clinicians may wish to broaden analysis by including this gene, which can be added at no additional charge.
Order test
Primary panel (48 genes)
Customized gene selection (0 included, 0 excluded)
ANO5 B3GALNT2 B4GAT1 CAPN3 CAV3 CHKB COL12A1 COL6A1 COL6A2 COL6A3 DAG1 DES DMD DNAJB6 DPM1 DPM2 DPM3 DYSF EMD FHL1 FKRP FKTN GAA GMPPB ISPD ITGA7 LAMA2 LARGE1 LMNA MYOT PLEC PNPLA2 POMGNT1 POMGNT2 POMK POMT1 POMT2 RXYLT1 SGCA SGCB SGCD SGCG TCAP TNPO3 TOR1AIP1 TRAPPC11 TRIM32 TTN
Add-on Preliminary-evidence Genes for Muscular Dystrophy (7 genes)
Customized gene selection (0 included, 0 excluded)
Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test. Some clinicians may wish to include genes which do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.
HNRNPDL LIMS2 SUN1 SUN2 SYNE1 SYNE2 TMEM43
Add-on Facioscapulohumeral Muscular Dystrophy Type 2 (FSHD2) Gene (1 gene)
Customized gene selection (0 included, 0 excluded)
Pathogenic variants in SMCHD1 account for approximately 5% of facioscapulohumeral muscular dystrophy. SMCHD1 variants should be interpreted in the context of D4Z4 hypomethylation and a permissive 4qA haplotype, which is not part of this assay. Depending on the clinical presentation of the individual and within the context of additional laboratory results, clinicians may wish to broaden analysis by including this gene, which can be added at no additional charge.
SMCHD1
Alternative tests to consider
In some cases, muscular dystrophies may have overlapping features with myopathies. If a congenital myopathy is suspected, clinicians may consider the Invitae Congenital Myopathy Panel, or the Invitae Comprehensive Myopathy panel.
For a broader analysis of the genetics of hereditary neuromuscular disorders (muscular dystrophies, myopathies, and congenital myasthenic syndrome):
Clinical information
Clinical description
Muscular dystrophies are characterized by skeletal muscle dysfunction that leads to muscle weakness and wasting of varying severity. In specific forms, other muscles—including respiratory muscles, cardiac smooth muscles, and swallowing muscles—can also be affected. In rare variants, the disorder is associated with involvement of other organs or tissues, such as the brain, inner ear, eyes, or skin. Traditionally, the diagnosis of muscular dystrophies requires a comprehensive medical history and physical examination in addition to such investigations as a serum creatinine phosphokinase test, electromyography, and muscle biopsy. More recently, the majority of muscular dystrophies have been classified based on molecular genetic confirmation.
| Gene | Inheritance | Associated neuromuscular disorders and subtypes | ||
|---|---|---|---|---|
| Autosomal recessive | Autosomal dominant | X-linked | ||
| ANO5 | ✓ | LGMD2L, Miyoshi muscular dystrophy-3 | ||
| B3GALNT2 | ✓ | MDDGA11 | ||
| B4GAT1 | ✓ | MDDGA13 | ||
| CAPN3 | ✓ | LGMD2A | ||
| CAV3 | ✓ | ✓ | LGMD1C, hypertrophic cardiomyopathy, hyperCKemia, distal myopathy | |
| CHKB | ✓ | congenital muscular dystrophy, megaconial type | ||
| COL12A1 | ✓ | ✓ | Bethlem myopathy, Ullrich congenital muscular dystrophy | |
| COL6A1 | ✓ | ✓ | Bethlem myopathy, Ullrich congenital muscular dystrophy | |
| COL6A2 | ✓ | ✓ | Bethlem myopathy, Ullrich congenital muscular dystrophy | |
| COL6A3 | ✓ | ✓ | Bethlem myopathy, Ullrich congenital muscular dystrophy | |
| DAG1 | ✓ | MDDGA9, MDDGC9 (LGMD2P) | ||
| DES | ✓ | ✓ | LGMD2R, myofibrillar myopathy-1, dilated cardiomyopathy | |
| DMD | ✓ | Becker muscular dystrophy, Duchenne muscular dystrophy | ||
| DNAJB6 | ✓ | LGMD1E, distal myopathy | ||
| DPM1 | ✓ | CDG1E | ||
| DPM2 | ✓ | CDG1U | ||
| DPM3 | ✓ | CDG1O | ||
| DYSF | ✓ | LGMD2B, Miyoshi muscular dystrophy-1 | ||
| EMD | ✓ | EDMD1 | ||
| FHL1 | ✓ | EDMD6 | ||
| FKRP | ✓ | MDDGA5, MDDGB5, MDDGC5 (LGMD2I), dilated cardiomyopathy | ||
| FKTN | ✓ | MDDGA4, MDDGB4, MDDGC4 (LGMD2M), dilated cardiomyopathy | ||
| GAA | ✓ | glycogen storage disease-2 (Pompe disease) | ||
| GMPPB | ✓ | MDDGA14, MDDGB14, MDDGC14 (LGMD2T) | ||
| HNRNPDL* | ✓ | LGMD1G | ||
| ISPD | ✓ | MDDGA7, MDDGC7 (LGMD2U) | ||
| ITGA7 | ✓ | congenital muscular dystrophy due to integrin alpha-7 deficiency | ||
| LAMA2 | ✓ | laminin alpha 2-deficient congenital muscular dystrophy/merosin-deficient congenital muscular dystrophy type 1A | ||
| LARGE1 (formerly known as LARGE) | ✓ | MDDGA6, MDDGB6 | ||
| LIMS2* | ✓ | LGMD2W | ||
| LMNA | ✓ | ✓ | Emery-Dreifuss muscular dystrophy, LGMD1B, congenital muscular dystrophy, dilated cardiomyopathy | |
| MYOT | ✓ | LGMD1A, myofibrillar myopathy-3 | ||
| PLEC | ✓ | LGMD2Q | ||
| PNPLA2 | ✓ | neutral lipid storage disease with myopathy (NLSDM) | ||
| POMGNT1 | ✓ | MDDGA3, MDDGB3, MDDGC3 (LGMD2O) | ||
| POMGNT2 | ✓ | MDDGA8 | ||
| POMK | ✓ | MDDGA12, MDDGC12 | ||
| POMT1 | ✓ | MDDGA1, MDDGB1, MDDGC1 (LGMD2K) | ||
| POMT2 | ✓ | MDDGA2, MDDGB2, MDDGC2 (LGMD2N) | ||
| RXYLT1 (formerly known as TMEM5) | ✓ | MDDGA10 | ||
| SGCA | ✓ | LGMD2D | ||
| SGCB | ✓ | LGMD2E | ||
| SGCD | ✓ | ✓ | LGMD2F, dilated cardiomyopathy | |
| SGCG | ✓ | LGMD2C | ||
| SMCHD1 | FSHD2 (digenic inheritance with D4Z4 hypomethylation and 4qA allele) | |||
| SUN1* | ✓ | Emery-Dreifuss muscular dystrophy | ||
| SUN2* | ✓ | Emery-Dreifuss muscular dystrophy | ||
| SYNE1* | ✓ | EDMD4 | ||
| SYNE2* | ✓ | EDMD5 | ||
| TCAP | ✓ | ✓ | LGMD2G, dilated cardiomyopathy, hypertrophic cardiomyopathy | |
| TMEM43* | ✓ | EDMD7 | ||
| TNPO3 | ✓ | LGMD1F | ||
| TOR1AIP1 | ✓ | LGMD2Y | ||
| TRAPPC11 | ✓ | LGMD2S | ||
| TRIM32 | ✓ | LGMD2H, sarcotubular myopathy | ||
| TTN | ✓ | ✓ | LGMD2J, tibial muscular dystrophy | |
*Preliminary-evidence gene
Clinical sensitivity
The clinical sensitivity of this test is dependent on the individual’s underlying genetic condition. Please see test specific pages for Invitae Type VI Collagenopathy, Invitae Emery-Dreifuss Muscular Dystrophy, Invitae Limb-Girdle Muscular Dystrophy, Invitae Dystroglycanopathy, and Invitae Congenital Muscular Dystrophy for disease-specific clinical sensitivity information. The Invitae Comprehensive Muscular Dystrophy Panel also includes other genes that have been identified as causes of muscular dystrophy, although the exact contribution of these genes to the overall detection rate is not known and is dependent on the clinical presentation of the individual. For some forms of muscular dystrophy, the underlying genetic cause remains unknown. As a result, a genetic diagnosis may not be achieved for some affected individuals, even upon testing all currently known causative genes.
Inheritance
Muscular dystrophies can be associated with different inheritance patterns, including autosomal dominant, autosomal recessive, and X-linked. Some genes are associated with both autosomal dominant and autosomal recessive neuromuscular disorders. FSHD2 is associated with digenic inheritance.
Penetrance
For most forms of muscular dystrophy, penetrance is thought to be high. Depending on the causative gene, the age of symptom onset can be variable, ranging from childhood to late adulthood and making determination of penetrance difficult. FSHD2 has been reported to exhibit incomplete penetrance in 20% of individuals with a SMCHD1 mutation, hypomethylation of D4Z4 and a permissive 4qA allele.
Prevalence/Incidence
Approximately 1 in 3,000–5,000 newborn males will be affected with Duchenne muscular dystrophy, making it the most common inherited muscle disease of childhood. Becker muscular dystrophy is much less common (approximately 1 in 20,000 male births). Of the limb-girdle muscular dystrophies, the recessive forms are more common than the dominant variants. Limb-girdle muscular dystrophy 2A seems to be more prevalent in southern Europe, whereas limb-girdle muscular dystrophy 2I is common in northern Europe, followed by limb-girdle muscular dystrophy 2B. Similarly, the frequencies of the different forms of congenital muscular dystrophy vary by region. Fukuyama muscular dystrophy is the most common CMD subtype in Japan due to a founder mutation in the FKTN gene. Laminin alpha-2 deficiency and type VI collagenopathies are the most common CMD subtypes in many countries with populations of European origin.
Considerations for testing
The clinical spectrum of muscular dystrophies is variable. Genetic testing may confirm a suspected diagnosis or rule out other disorders with similar symptoms. A genetic diagnosis may also help predict disease progression and inform recurrence risk.
References
- Wang, CH, et al. Consensus statement on standard of care for congenital muscular dystrophies. J. Child Neurol. 2010; 25(12):1559-81. PMID: 21078917
- Mercuri, E, Muntoni, F. Muscular dystrophies. Lancet. 2013; 381(9869):845-60. PMID: 23465426
- Bönnemann, CG, et al. Diagnostic approach to the congenital muscular dystrophies. Neuromuscul. Disord. 2014; 24(4):289-311. PMID: 24581957
- Kang, PB, et al. Evidence-based guideline summary: Evaluation, diagnosis, and management of congenital muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology. 2015; 84(13):1369-78. PMID: 25825463
- Mah, JK, et al. A Systematic Review and Meta-analysis on the Epidemiology of the Muscular Dystrophies. Can J Neurol Sci. 2016; 43(1):163-77. PMID: 26786644
- Lemmers, RJ, et al. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat. Genet. 2012; 44(12):1370-4. PMID: 23143600
Management guidelines
For management guidelines please refer to:
Assay
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 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.
| Gene | Transcript reference | Sequencing analysis | Deletion/Duplication analysis |
|---|---|---|---|
| ANO5 | NM_213599.2 | ||
| B3GALNT2 | NM_152490.4 | ||
| B4GAT1 | NM_006876.2 | ||
| CAPN3 | NM_000070.2 | ||
| CAV3 | NM_033337.2 | ||
| CHKB | NM_005198.4 | ||
| COL12A1 | NM_004370.5 | ||
| COL6A1 | NM_001848.2 | ||
| COL6A2 | NM_001849.3 | ||
| COL6A3 | NM_004369.3 | ||
| DAG1 | NM_004393.5 | ||
| DES | NM_001927.3 | ||
| DMD* | NM_004006.2 | ||
| DNAJB6 | NM_058246.3 | ||
| DPM1 | NM_003859.1 | ||
| DPM2 | NM_003863.3 | ||
| DPM3 | NM_153741.1 | ||
| DYSF | NM_003494.3 | ||
| EMD | NM_000117.2 | ||
| FHL1 | NM_001449.4 | ||
| FKRP | NM_024301.4 | ||
| FKTN* | NM_001079802.1 | ||
| GAA* | NM_000152.3 | ||
| GMPPB | NM_013334.3 | ||
| HNRNPDL | NM_031372.3 | ||
| ISPD | NM_001101426.3 | ||
| ITGA7 | NM_002206.2 | ||
| LAMA2 | NM_000426.3 | ||
| LARGE1 | NM_004737.4 | ||
| LIMS2 | NM_001136037.2 | ||
| LMNA | NM_170707.3 | ||
| MYOT | NM_006790.2 | ||
| PLEC | NM_000445.4; NM_201378.3 | ||
| PNPLA2 | NM_020376.3 | ||
| POMGNT1 | NM_017739.3 | ||
| POMGNT2 | NM_032806.5 | ||
| POMK | NM_032237.4 | ||
| POMT1 | NM_007171.3 | ||
| POMT2 | NM_013382.5 | ||
| RXYLT1 | NM_014254.2 | ||
| SGCA | NM_000023.2 | ||
| SGCB | NM_000232.4 | ||
| SGCD | NM_000337.5 | ||
| SGCG | NM_000231.2 | ||
| SMCHD1 | NM_015295.2 | ||
| SUN1 | NM_001130965.2 | ||
| SUN2 | NM_015374.2 | ||
| SYNE1 | NM_033071.3 | ||
| SYNE2 | NM_182914.2 | ||
| TCAP | NM_003673.3 | ||
| TMEM43 | NM_024334.2 | ||
| TNPO3 | NM_012470.3 | ||
| TOR1AIP1 | NM_001267578.1 | ||
| TRAPPC11 | NM_021942.5 | ||
| TRIM32 | NM_012210.3 | ||
| TTN* | NM_001267550.2 |
DMD: Analysis guarantees del/dup detection at single-exon resolution.
FKTN: Analysis includes the intronic variant NM_001079802.1:c.647+2084G>T (also known as NM_001079802.1:c.648-1243G>T) and the ~3 kb retrotransposon insertion in the 3' UTR at position NM_001079802.1:c.*4392_*4393.
GAA: Analysis includes the promoter variant NM_000152.3:c.-32-13T>G as well as the common exon 18 deletion.
TTN: Deletion/duplication and sequencing analysis is not offered for exons 153-155 (NM_133378.4). Variants are named relative to the NM_001267550.2 (meta) transcript, but only variants in the coding sequence and intronic boundaries of the clinically relevant NM_133378.4 (N2A) isoform are reported (PMID: 25589632).
Resources
Patient resources
Patient guide: Genetic testing simplifiedReferences
- Bönnemann, CG, et al. Diagnostic approach to the congenital muscular dystrophies. Neuromuscul. Disord. 2014; 24(4):289-311. PMID: 24581957
- Kang, PB, et al. Evidence-based guideline summary: Evaluation, diagnosis, and management of congenital muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology. 2015; 84(13):1369-78. PMID: 25825463
- Lemmers, RJ, et al. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat. Genet. 2012; 44(12):1370-4. PMID: 23143600
- Mah, JK, et al. A Systematic Review and Meta-analysis on the Epidemiology of the Muscular Dystrophies. Can J Neurol Sci. 2016; 43(1):163-77. PMID: 26786644
- Mercuri, E, Muntoni, F. Muscular dystrophies. Lancet. 2013; 381(9869):845-60. PMID: 23465426
- Wang, CH, et al. Consensus statement on standard of care for congenital muscular dystrophies. J. Child Neurol. 2010; 25(12):1559-81. PMID: 21078917
