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  • Test code: 03304
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)
  • Alternate specimens:
    Saliva, assisted saliva, buccal swab and gDNA
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  1. Test Catalog
  2. Invitae Limb-Girdle Muscular Dystrophy Panel

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.

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.

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.

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Primary panel (31 genes)

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

Panel details and technical assay limitations
Add-on Preliminary-evidence Genes for Limb-Girdle Muscular Dystrophy (2 genes)

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

Panel details and technical assay limitations
Add-on Facioscapulohumeral Muscular Dystrophy Type 2 (FSHD2) Gene (1 gene)

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

Panel details and technical assay limitations

Alternative tests to consider

For a broader analysis of genes associated with muscular dystrophies, clinicians may consider the 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

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.

GeneInheritanceAssociated neuromuscular disorders and subtypesTypical age of onsetProportion of LGMD cases
Autosomal recessiveAutosomal dominantX-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

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.

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.

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.

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.

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.

  1. Hauser, MA, et al. Myotilin is mutated in limb girdle muscular dystrophy 1A. Hum. Mol. Genet. 2000; 9(14):2141-7. PMID: 10958653
  2. 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
  3. Duggan, DJ, et al. Mutations in the sarcoglycan genes in patients with myopathy. N. Engl. J. Med. 1997; 336(9):618-24. PMID: 9032047
  4. 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
  5. Urtasun, M, et al. Limb-girdle muscular dystrophy in Guipúzcoa (Basque Country, Spain). Brain. 1998; 121 ( Pt 9):1735-47. PMID: 9762961
  6. Mitsuhashi, S, Kang, PB. Update on the genetics of limb girdle muscular dystrophy. Semin Pediatr Neurol. 2012; 19(4):211-8. PMID: 23245554
  7. 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
  8. 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
  9. Nigro, V, Savarese, M. Genetic basis of limb-girdle muscular dystrophies: the 2014 update. Acta Myol. 2014; 33(1):1-12. PMID: 24843229

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 and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

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_021971.2
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

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).

Clinical resources
Invitae brochure Neurology requisition form and gene list
Patient resources
Patient guide: Genetic testing simplified
Test information
Forms page Specimen requirements page

References

  1. 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
  2. Duggan, DJ, et al. Mutations in the sarcoglycan genes in patients with myopathy. N. Engl. J. Med. 1997; 336(9):618-24. PMID: 9032047
  3. Hauser, MA, et al. Myotilin is mutated in limb girdle muscular dystrophy 1A. Hum. Mol. Genet. 2000; 9(14):2141-7. PMID: 10958653
  4. 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
  5. Mitsuhashi, S, Kang, PB. Update on the genetics of limb girdle muscular dystrophy. Semin Pediatr Neurol. 2012; 19(4):211-8. PMID: 23245554
  6. Nigro, V, Savarese, M. Genetic basis of limb-girdle muscular dystrophies: the 2014 update. Acta Myol. 2014; 33(1):1-12. PMID: 24843229
  7. 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
  8. Urtasun, M, et al. Limb-girdle muscular dystrophy in Guipúzcoa (Basque Country, Spain). Brain. 1998; 121 ( Pt 9):1735-47. PMID: 9762961
  9. 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

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