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Invitae Limb-Girdle Muscular Dystrophy Panel
Test description
The Invitae Limb-Girdle Muscular Dystrophy Panel analyzes up to 34 genes that are associated with limb-girdle muscular dystrophy (LGMD) — a heterogeneous group of disorders characterized by muscle weakness and wasting primarily affecting the limb-girdle musculature. These genes were curated based on current available evidence to provide a comprehensive test for the genetic causes of limb-girdle muscular dystrophy.
Given that limb-girdle muscular dystrophy is a heterogeneous group of disorders, identification of the underlying genetic cause can help predict outcome and inform recurrence risk.
Genes tested
Primary panel
ANO5 CAPN3 CAV3 DAG1 DES DMD DNAJB6 DYSF FKRP FKTN GAA GMPPB ISPD LMNA MYOT PLEC PNPLA2 POMGNT1 POMK POMT1 POMT2 SGCA SGCB SGCD SGCG TCAP TNPO3 TOR1AIP1 TRAPPC11 TRIM32 TTN
Add-on Preliminary-evidence Genes for Limb-Girdle Muscular Dystrophy
HNRNPDL LIMS2
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 (31 genes)
Customized gene selection (0 included, 0 excluded)
ANO5 CAPN3 CAV3 DAG1 DES DMD DNAJB6 DYSF FKRP FKTN GAA GMPPB ISPD LMNA MYOT PLEC PNPLA2 POMGNT1 POMK POMT1 POMT2 SGCA SGCB SGCD SGCG TCAP TNPO3 TOR1AIP1 TRAPPC11 TRIM32 TTN
Add-on Preliminary-evidence Genes for Limb-Girdle Muscular Dystrophy (2 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
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
For a broader analysis of genes associated with muscular dystrophies, clinicians may consider the Invitae Comprehensive Muscular Dystrophy Panel.
Invitae Comprehensive Muscular Dystrophy Panel
For a broader analysis of the genetics of hereditary neuromuscular disorders (muscular dystrophies, myopathies, and congenital myasthenic syndrome):
Clinical information
Clinical description
Limb-girdle muscular dystrophies (LGMD) are a highly heterogeneous group of disorders that are characterized by progressive weakness and wasting of the limbs and pelvic and scapular muscles. Facial and distal muscles are typically spared, although distal muscle weakness can occur in the later stages of disease. Muscle biopsy typically shows signs of muscle necrosis and regeneration, with fibrosis and adipose tissue infiltration. Onset of symptoms is variable and typically ranges from childhood to adulthood. Some genes associated with the LGMD phenotype also have additional cardiopulmonary and extra-skeletal findings.
The spectrum of phenotypes that can occur in LGMD overlaps with a number of different neuromuscular conditions, including, in severe cases, Duchenne muscular dystrophy. Muscular dystrophy-dystroglycanopathies (MDDG) are a group of variable childhood onset disorders, the mildest form of which (MDDG type C) can present as a limb-girdle muscular dystrophy phenotype with or without intellectual disability.
| Gene | Inheritance | Associated neuromuscular disorders and subtypes | Typical age of onset | Proportion of LGMD cases | ||
|---|---|---|---|---|---|---|
| Autosomal recessive | Autosomal dominant | X-linked | ||||
| ANO5 | ✓ | LGMD2L, Miyoshi muscular dystrophy-3 | adulthood | 11%–25% of recessive forms of LGMD | ||
| CAPN3 | ✓ | LGMD2A | childhood or adulthood | 10% | ||
| CAV3 | ✓ | ✓ | LGMD1C, hypertrophic cardiomyopathy, hyperCKemia, distal myopathy | childhood | 1%–2% | |
| DAG1 | ✓ | MDDGA9, MDDGC9 (LGMD2P) | childhood | unknown | ||
| DES | ✓ | ✓ | LGMD2R, myofibrillar myopathy-1, dilated cardiomyopathy | adolescence or early adulthood | unknown | |
| DMD | ✓ | Becker muscular dystrophy, Duchenne muscular dystrophy | childhood or adolescence | n/a | ||
| DNAJB6 | ✓ | LGMD1E, distal myopathy | mid-adulthood | unknown | ||
| DYSF | ✓ | LGMD2B, Miyoshi muscular dystrophy-1 | adolescence to early adulthood | 5% of recessive LGMD | ||
| FKRP | ✓ | MDDGA5, MDDGB5, MDDGC5 (LGMD2I), dilated cardiomyopathy | childhood to early adulthood | unknown | ||
| FKTN | ✓ | MDDGA4, MDDGB4, MDDGC4 (LGMD2M), dilated cardiomyopathy | childhood | unknown | ||
| GAA | ✓ | Glycogen storage disease-2 (Pompe disease) | variable | n/a | ||
| GMPPB | ✓ | MDDGA14, MDDGB14, MDDGC14 (LGMD2T) | infancy or childhood | unknown | ||
| HNRNPDL* | ✓ | LGMD1G | unknown | unknown | ||
| ISPD | ✓ | MDDGA7, MDDGC7 (LGMD2U) | infancy or childhood | unknown | ||
| LIMS2* | ✓ | LGMD2W | unknown | unknown | ||
| LMNA | ✓ | ✓ | Emery Dreifuss muscular dystrophy, LGMD1B, congenital muscular dystrophy, dilated cardiomyopathy | variable | unknown | |
| MYOT | ✓ | LGMD1A, myofibrillar myopathy-3 | childhood to adulthood | unknown | ||
| PLEC | ✓ | LGMD2Q | childhood | unknown | ||
| PNPLA2 | ✓ | neutral lipid storage disease with myopathy | early to late adulthood | unknown | ||
| POMGNT1 | ✓ | MDDGA3, MDDGB3, MDDGC3 (LGMD2O) | infancy to childhood | unknown | ||
| POMK | ✓ | MDDGA12, MDDGC12 | infancy to childhood | unknown | ||
| POMT1 | ✓ | MDDGA1, MDDGB1, MDDGC1 (LGMD2K) | infancy to childhood | unknown | ||
| POMT2 | ✓ | MDDGA2, MDDGB2, MDDGC2 (LGMD2N) | infancy to childhood | unknown | ||
| SGCA | ✓ | LGMD2D | childhood | up to 38% of severe recessive forms of LGMD | ||
| SGCB | ✓ | LGMD2E | childhood | up to 12% of severe recessive forms of LGMD | ||
| SGCD | ✓ | ✓ | LGMD2F, dilated cardiomyopathy | childhood | rare | |
| SGCG | ✓ | LGMD2C | childhood | up to 17% of severe recessive forms of LGMD | ||
| SMCHD1 | FSHD2 (digenic inheritance with D4Z4 hypomethylation and 4qA allele) | childhood | 5% of FSHD (PMID: 20301616) | |||
| TCAP | ✓ | ✓ | LGMD2G, dilated cardiomyopathy, hypertrophic cardiomyopathy | childhood to adolescence | 3% | |
| TNPO3 | ✓ | LGMD1F | variable | unknown | ||
| TOR1AIP1 | ✓ | LGMD2Y | unknown | unknown | ||
| TRAPPC11 | ✓ | LGMD2S | childhood | unknown | ||
| TRIM32 | ✓ | LGMD2H, sarcotubular myopathy | variable | 3% of recessive forms of LGMD | ||
| TTN | ✓ | ✓ | LGMD2J, tibial muscular dystrophy | variable | unknown | |
*Preliminary-evidence gene
Clinical sensitivity
Pathogenic variants in the sarcoglycan genes (SGCA, SGCB, SGCD, and SGCG) account for up to 68% of severe autosomal recessive forms of LGMD. ANO5 accounts for an additional 11%–25% of autosomal recessive LGMD while the CAPN3, DYSF, and TRIM32 genes each account for 10% or less. CAPN3-associated LGMD may be more common in populations with founder mutations, such as the Basque region in Spain. TTN-associated LGMD is only prevalent in the Finnish population due to a founder mutation. A TRIM32 founder mutation in the Hutterite population also exists. The CAV3, LMNA, and TCAP gene each account for 10% or less of LGMD overall.
Inheritance
The majority of LGMD subtypes are inherited in an autosomal recessive pattern. DNAJB6-, LMNA-, MYOT-, and TNPO3-associated disorders are autosomal dominant. DMD-associated disorders are X-linked. CAV3-associated LGMD can be inherited in either an autosomal dominant or recessive pattern. The DES, SGCD, TCAP, and TTN genes are all associated with autosomal recessive LGMD; however, these genes are also associated with other neuromuscular disorders with autosomal dominant inheritance. FSHD2 is associated with digenic inheritance.
Penetrance
For most forms of LGMD, penetrance is thought to be high. Depending on the causative gene, the age of onset of symptoms can be variable, ranging from childhood to late adulthood, which can make 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
The prevalence of LGMD is estimated at 1 in 14,500–123,000. In Finland, the prevalence of ANO5-associated LGMD is estimated at 1 in 50,000.
Considerations for testing
The clinical presentation of limb-girdle muscular dystrophies can be variable. Genetic testing may confirm a suspected diagnosis or rule out disorders with similar symptoms. A genetic diagnosis may also help predict disease progression and inform recurrence risk.
References
- van, der, Kooi, AJ, et al. The clinical spectrum of limb girdle muscular dystrophy. A survey in The Netherlands. Brain. 1996; 119 ( Pt 5):1471-80. PMID: 8931572
- Duggan, DJ, et al. Mutations in the sarcoglycan genes in patients with myopathy. N. Engl. J. Med. 1997; 336(9):618-24. PMID: 9032047
- Urtasun, M, et al. Limb-girdle muscular dystrophy in Guipúzcoa (Basque Country, Spain). Brain. 1998; 121 ( Pt 9):1735-47. PMID: 9762961
- Hauser, MA, et al. Myotilin is mutated in limb girdle muscular dystrophy 1A. Hum. Mol. Genet. 2000; 9(14):2141-7. PMID: 10958653
- Pegoraro, E, Hoffman, EP. Limb-Girdle Muscular Dystrophy Overview. 2000 Jun 08. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1408/ PMID: 20301582
- Mitsuhashi, S, Kang, PB. Update on the genetics of limb girdle muscular dystrophy. Semin Pediatr Neurol. 2012; 19(4):211-8. PMID: 23245554
- Nigro, V, Savarese, M. Genetic basis of limb-girdle muscular dystrophies: the 2014 update. Acta Myol. 2014; 33(1):1-12. PMID: 24843229
- Di, Costanzo, S, et al. POMK mutations disrupt muscle development leading to a spectrum of neuromuscular presentations. Hum. Mol. Genet. 2014; 23(21):5781-92. PMID: 24925318
- 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
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 | ||
| CAPN3 | NM_000070.2 | ||
| CAV3 | NM_033337.2 | ||
| DAG1 | NM_004393.5 | ||
| DES | NM_001927.3 | ||
| DMD* | NM_004006.2 | ||
| DNAJB6 | NM_058246.3 | ||
| DYSF | NM_003494.3 | ||
| FKRP | NM_024301.4 | ||
| FKTN* | NM_001079802.1 | ||
| GAA* | NM_000152.3 | ||
| GMPPB | NM_013334.3 | ||
| HNRNPDL | NM_031372.3 | ||
| ISPD | NM_001101426.3 | ||
| 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 | ||
| POMK | NM_032237.4 | ||
| POMT1 | NM_007171.3 | ||
| POMT2 | NM_013382.5 | ||
| SGCA | NM_000023.2 | ||
| SGCB | NM_000232.4 | ||
| SGCD | NM_000337.5 | ||
| SGCG | NM_000231.2 | ||
| SMCHD1 | NM_015295.2 | ||
| TCAP | NM_003673.3 | ||
| 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
- Di, Costanzo, S, et al. POMK mutations disrupt muscle development leading to a spectrum of neuromuscular presentations. Hum. Mol. Genet. 2014; 23(21):5781-92. PMID: 24925318
- Duggan, DJ, et al. Mutations in the sarcoglycan genes in patients with myopathy. N. Engl. J. Med. 1997; 336(9):618-24. PMID: 9032047
- Hauser, MA, et al. Myotilin is mutated in limb girdle muscular dystrophy 1A. Hum. Mol. Genet. 2000; 9(14):2141-7. PMID: 10958653
- 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
- Mitsuhashi, S, Kang, PB. Update on the genetics of limb girdle muscular dystrophy. Semin Pediatr Neurol. 2012; 19(4):211-8. PMID: 23245554
- Nigro, V, Savarese, M. Genetic basis of limb-girdle muscular dystrophies: the 2014 update. Acta Myol. 2014; 33(1):1-12. PMID: 24843229
- Pegoraro, E, Hoffman, EP. Limb-Girdle Muscular Dystrophy Overview. 2000 Jun 08. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1408/ PMID: 20301582
- Urtasun, M, et al. Limb-girdle muscular dystrophy in Guipúzcoa (Basque Country, Spain). Brain. 1998; 121 ( Pt 9):1735-47. PMID: 9762961
- van, der, Kooi, AJ, et al. The clinical spectrum of limb girdle muscular dystrophy. A survey in The Netherlands. Brain. 1996; 119 ( Pt 5):1471-80. PMID: 8931572
