Invitae Dystroglycanopathy Panel

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  • Test code: 03302
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Test description

The Invitae Dystroglycanopathy Panel analyzes 17 genes that are associated with muscular dystrophy-dystroglycanopathies (MDDG), a spectrum of of muscular dystrophies associated with aberrant glycosylation of alpha-dystroglycan. In addition to muscular dystrophy, these disorders may feature characteristic brain and eye malformations and intellectual disability. The genes in this panel were curated based on current available evidence to provide a comprehensive test for the genetic causes of MDDG.

Given that muscular dystrophy-dystroglycanopathies are a heterogeneous group of disorders, identification of the underlying genetic cause can help predict patient outcome and inform recurrence risk.

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Primary panel (17 genes)

B3GALNT2 B4GAT1 DAG1 DPM1 DPM2 DPM3 FKRP FKTN GMPPB ISPD LARGE1 POMGNT1 POMGNT2 POMK POMT1 POMT2 TMEM5

FKTN: Analysis includes the intronic variant NM_001079802.1:c.647+2084G>T as well as the 3 kb retrotransposon insertion in the 3' UTR at c.*4287_*4288ins3062.

Alternative tests to consider

For a broader analysis of genes associated with congenital myopathies, clinicians may consider the Invitae Congenital Muscular Dystrophy Panel or the Invitae Comprehensive Muscular Dystrophy Panel. These broader panels can be ordered at no additional charge.

  • congenital disorder of glycosylation (CDG)
  • congenital myasthenic syndrome (CMS)
  • dilated cardiomyopathy (DCM)
  • Fukuyama congenital muscular dystrophy (FCMD)
  • limb-girdle muscular dystrophy (LGMD)
  • muscular dystrophy-dystroglycanopathy (MDDG)

Muscular dystrophy-dystroglycanopathies (MDDG) are a spectrum of childhood-onset disorders. The associated phenotypes range from characteristic brain and eye malformations, profound intellectual disability and congenital muscular dystrophy (type A), to intermediate congenital muscular dystrophy with or without intellectual disability (type B), to less severe limb-girdle muscular dystrophy (type C). Onset of symptoms is typically in infancy or early childhood. While clinical severity in individuals with MDDG varies greatly, common features in all patients are the predominant involvement of the proximal muscles in the upper and lower limbs and the elevated serum creatine kinase. Type A MDDG has historically been referred to as either muscle-eye-brain disease, Walker-Warburg syndrome, or Fukuyama congenital muscular dystrophy. Clinical features of type A MDDG include cobblestone (type II) lissencephaly and cerebellar and retinal malformations. The phenotype of type B MDDG is variable but less severe than type A. Type C is the mildest form of MDDG and is characterized by a limb-girdle muscular dystrophy phenotype with later onset of muscular weakness, compared to types A and B. Type C MDDG may also have variable intellectual disability and mild brain anomalies.

Some genes associated with congenital disorders of glycosylation (CDG) can present with features similar to those observed in MDDG, including congenital muscular dystrophy.

Gene Proportion of dystroglycanopathy cases Associated disorders
B3GALNT2 5% MDDGA11
B4GAT1 Unknown MDDGA13
DAG1 Unknown MDDGA9, MDDGC9
DPM1 Unknown CDG1E
DPM2 Unknown CDG1U
DPM3 Unknown CDG1O
FKRP 3%–8% MDDGA5, MDDGB5, MDDGC5, dilated cardiomyopathy
FKTN 10% MDDGA4, MDDGB4, MDDGC4, dilated cardiomyopathy
GMPPB Unknown MDDGA14, MDDGB14, MDDGC14
ISPD 10% MDDGA7, MDDGC7
LARGE1 (formerly known as LARGE) 1% MDDGA6, MDDGB6
POMGNT1 10% MDDGA3, MDDGB3, MDDGC3
POMGNT2 Unknown MDDGA8
POMK Unknown MDDGA12, MDDGC12
POMT1 21% MDDGA1, MDDGB1, MDDGC1
POMT2 11% MDDGA2, MDDGB2, MDDGC2
TMEM5 Unknown MDDGA10

The POMT1 gene is the most common cause of MDDG and accounts for 21% of affected individuals. The FKTN, ISPD, POMGNT1, and POMT2 genes each account for approximately 10% of affected individuals overall. FKTN-associated MDDG is more common in the Japanese and Ashkenazi Jewish populations due to the presence of founder mutations. FKRP and LARGE1 are rarer causes of MDDG and account for 3%–8% and 1% of affected individuals, respectively. FKRP may account for a higher proportion of MDDG in Northern Europe.

This panel also includes other genes that have been identified as causes of MDDG or similar disorders, although the exact contribution of these genes to the overall detection rate is not known and is dependent on the clinical presentation of the patient.

Dystroglycanopathies are inherited in an autosomal recessive pattern.

Penetrance of MDDG is considered to be high. For some genes associated with MDDG, only a limited number of affected individuals have been described to date, making penetrance estimates difficult.

MDDG is a rare disorder with an unknown overall prevalence. In Japan, the incidence of FKTN-associated MDDG is estimated at 2–4 in 100,000.

The clinical spectrum of MDDG 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.

  1. Barone, R, et al. DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy. Ann. Neurol. 2012; 72(4):550-8. PMID: 23109149
  2. Brockington, M, et al. Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan. Am. J. Hum. Genet. 2001; 69(6):1198-209. PMID: 11592034
  3. Godfrey, C, et al. Dystroglycanopathies: coming into focus. Curr. Opin. Genet. Dev. 2011; 21(3):278-85. PMID: 21397493
  4. Lefeber, DJ, et al. Deficiency of Dol-P-Man synthase subunit DPM3 bridges the congenital disorders of glycosylation with the dystroglycanopathies. Am. J. Hum. Genet. 2009; 85(1):76-86. PMID: 19576565
  5. Mercuri, E, et al. Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study. Neurology. 2009; 72(21):1802-9. PMID: 19299310
  6. Muntoni, F, et al. Muscular dystrophies due to glycosylation defects: diagnosis and therapeutic strategies. Curr. Opin. Neurol. 2011; 24(5):437-42. PMID: 21825985
  7. Toda, T, et al. The Fukuyama congenital muscular dystrophy story. Neuromuscul. Disord. 2000; 10(3):153-9. PMID: 10734260
  8. Wang, CH, et al. Consensus statement on standard of care for congenital muscular dystrophies. J. Child Neurol. 2010; 25(12):1559-81. PMID: 21078917
  9. Willer, T, et al. ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome. Nat. Genet. 2012; 44(5):575-80. PMID: 22522420
  10. Yang, AC, et al. Congenital disorder of glycosylation due to DPM1 mutations presenting with dystroglycanopathy-type congenital muscular dystrophy. Mol. Genet. Metab. 2013; 110(3):345-51. PMID: 23856421

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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
B3GALNT2 NM_152490.4
B4GAT1 NM_006876.2
DAG1 NM_004393.5
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
LARGE1 NM_004737.4
POMGNT1 NM_017739.3
POMGNT2 NM_032806.5
POMK NM_032237.4
POMT1 NM_007171.3
POMT2 NM_013382.5
TMEM5 NM_014254.2

FKTN: Analysis includes the intronic variant NM_001079802.1:c.647+2084G>T as well as the 3 kb retrotransposon insertion in the 3' UTR at c.*4287_*4288ins3062.