Invitae Congenital Muscular Dystrophy Panel
Test description
The Invitae Congenital Muscular Dystrophy Panel analyzes 27 genes that are associated with congenital muscular dystrophies, a heterogeneous group of neuromuscular disorders with widely variable symptom severity. These genes were curated based on current available evidence to provide a comprehensive test for the genetic causes of congenital muscular dystrophies.
Given that congenital muscular dystrophies are a heterogeneous group of disorders, identification of the underlying genetic cause can help predict outcome for the individual 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
B3GALNT2 B4GAT1 CHKB COL12A1 COL6A1 COL6A2 COL6A3 DAG1 DMD DPM1 DPM2 DPM3 FKRP FKTN GMPPB ISPD ITGA7 LAMA2 LARGE1 LMNA POMGNT1 POMGNT2 POMK POMT1 POMT2 RXYLT1 TCAP
Order test
Primary panel (27 genes)
Customized gene selection (0 included, 0 excluded)
B3GALNT2 B4GAT1 CHKB COL12A1 COL6A1 COL6A2 COL6A3 DAG1 DMD DPM1 DPM2 DPM3 FKRP FKTN GMPPB ISPD ITGA7 LAMA2 LARGE1 LMNA POMGNT1 POMGNT2 POMK POMT1 POMT2 RXYLT1 TCAP
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
The congenital muscular dystrophies (CMDs) are a group of genetically and clinically heterogeneous conditions that are characterized by congenital hypotonia, delayed motor development, and the early onset of progressive muscle weakness and wasting associated with a dystrophic pattern on muscle biopsy. The degree of muscular or central nervous system involvement is variable within a spectrum and ranges from severe infantile onset hypotonia with feeding and respiratory complications and structural brain and eye abnormalities to moderate motor delay and mild or moderate limb-girdle involvement during childhood. Since delay of motor skill acquisition may be a presenting symptom of CMD, onset of manifestations before age two years may be a reasonable diagnostic criterion, although the exact age at onset may be difficult to define in some cases, especially for the milder variants.
| CMD type | Gene | Subtype(s) | Inheritance | Associated phenotype | ||
|---|---|---|---|---|---|---|
| Autosomal dominant | Autosomal recessive | X-linked | ||||
| Type VI collagenopathies | COL6A1, COL6A2, COL6A3, COL12A1 | BTHLM1/BTHLM2, UCMD1/UCMD2 | ✓ | ✓ | Bethlem myopathy-1 and 2, Ullrich congenital muscular dystrophy-1 and 2 | |
| Dystroglycanopathy | B3GALNT2, B4GAT1, DAG1, FKRP, FKTN, GMPPB, ISPD, LARGE1, POMGNT1, POMGNT2, POMK, POMT1, POMT2, RXYLT1 (formerly known as TMEM5) | MDDGA1, MDDGA2, MDDGA3, MDDGA4, MDDGA5, MDDGA6, MDDGA7, MDDGA8, MDDGA9, MDDGA10, MDDGA11, MDDGA12, MDDGA13, MDDGA14, MDDGB1, MDDGB2, MDDGB3, MDDGB4, MDDGB5, MDDGB6, MDDGB14, MDDGC1, MDDGC2, MDDGC3, MDDGC4, MDDGC5, MDDGC7, MDDGC9, MDDGC12, MDDGC14 | ✓ | Walker-Warburg syndrome, Muscle-eye-brain disease, Fukuyama and Fukuyama-like muscular dystrophy, CMD with cerebellar involvement, CMD with intellectual disability, CMD without intellectual disability, LGMD with intellectual disability, LGMD without intellectual disability | ||
| Congenital disorders of glycosylation (CDG) | DPM1, DPM2, DPM3 | CDG1E, CDG1U, CDG1O | ✓ | CDG with abnormal alpha-dystroglycan glycosylation | ||
| Dystrophinopathies | DMD | N/A | ✓ | Duchenne/Becker muscular dystrophy | ||
| CHKB-related CMD | CHKB | N/A | ✓ | congenital weakness; cognitive impairment; pruritus; enlarged mitochondria found in muscle biopsy | ||
| Integrin alpha-7 deficiency | ITGA7 | N/A | ✓ | very rare; delayed motor milestones; walking within 2–3 years of life | ||
| Laminin alpha 2-deficiency | LAMA2 | MDC1A | ✓ | most common single gene to cause CMD; typically symptomatic at birth, with hypotonia and poor suck; in childhood, white matter abnormalities on brain imaging are common | ||
| LMNA-related CMD | LMNA | N/A | ✓ | dropped head syndrome; axial and scapuloperoneal involvement; absent or early loss of ambulation | ||
| Telethoninopathy | TCAP | LGMD2G | ✓ | typically has LGMD presentation, but may present in infancy with clinical features overlapping with mild forms of α-dystroglycanopathy | ||
Clinical sensitivity
Mutation detection rate for CMDs in general ranges from 20% to 46%. The clinical sensitivity can also vary depending on the CMD subtype. In individuals with collagenopathies (Ullrich CMD or Bethlem myopathy), pathogenic variants in COL6A1, COL6A2, and COL6A3 account for the majority of cases. Pathogenic variants are identified in 30% to 66% of children with dystroglycanopathy. In Fukuyama CMD, FKTN mutations are detected in as many as 100% of individuals. In muscle-eye-brain disease, POMGNT1 mutations may be detected in 100% of individuals, while in Walker–Warburg syndrome, only 40% of individuals have mutations in the known genes. This panel also includes other genes that have been identified as causes of CMD, 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.
Inheritance
CMD can be inherited in an autosomal dominant, autosomal recessive, or an X-linked pattern.
Penetrance
CMDs are thought to have penetrance approaching 100%. For some CMD genes, only a limited number of affected individuals have been described to date, making penetrance estimates difficult.
Prevalence/Incidence
Prevalence estimates range from 0.68–2.5 per 100,000, although the incidence and prevalence of CMD in various populations are still being characterized and may have been initially underestimated in early published CMD studies due to more limited diagnostic studies. The relative frequency of individual types also varies in different populations. For example, 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 subtypes in many countries with populations of European origin.
Considerations for testing
The clinical spectrum of CMD is broad. 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
- Wang, CH, et al. Consensus statement on standard of care for congenital muscular dystrophies. J. Child Neurol. 2010; 25(12):1559-81. PMID: 21078917
- 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
- Bönnemann, CG, et al. Diagnostic approach to the congenital muscular dystrophies. Neuromuscul. Disord. 2014; 24(4):289-311. PMID: 24581957
- Sparks, S, et al. Congenital Muscular Dystrophy Overview. 2001 Jan 22. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301468
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 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 |
|---|---|---|---|
| B3GALNT2 | NM_152490.4 | ||
| B4GAT1 | NM_006876.2 | ||
| CHKB | NM_005198.4 | ||
| COL12A1 | NM_004370.5 | ||
| COL6A1 | NM_001848.2 | ||
| COL6A2 | NM_001849.3 | ||
| COL6A3 | NM_004369.3 | ||
| DAG1 | NM_004393.5 | ||
| DMD | NM_004006.2 | ||
| DPM1 | NM_003859.1 | ||
| DPM2 | NM_003863.3 | ||
| DPM3 | NM_153741.1 | ||
| FKRP | NM_024301.4 | ||
| FKTN | NM_001079802.1 | ||
| GMPPB | NM_021971.2 | ||
| ISPD | NM_001101426.3 | ||
| ITGA7 | NM_002206.2 | ||
| LAMA2 | NM_000426.3 | ||
| LARGE1 | NM_004737.4 | ||
| LMNA | NM_170707.3 | ||
| POMGNT1 | NM_017739.3 | ||
| POMGNT2 | NM_032806.5 | ||
| POMK | NM_032237.4 | ||
| POMT1 | NM_007171.3 | ||
| POMT2 | NM_013382.5 | ||
| RXYLT1 | NM_014254.2 | ||
| TCAP | NM_003673.3 |
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
- Sparks, S, et al. Congenital Muscular Dystrophy Overview. 2001 Jan 22. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301468
- Wang, CH, et al. Consensus statement on standard of care for congenital muscular dystrophies. J. Child Neurol. 2010; 25(12):1559-81. PMID: 21078917
