Molecular Genetic Testing

Genes. COL6A1, COL6A2, and COL6A3 are the three genes in which mutations are known to cause collagen type VI-related disorders.

Clinical testing

Interpretation of sequence analysis results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

• Clinical evaluation
• Measurement of serum creatine kinase concentration
• Muscle MRI for Bethlem myopathy
  Note: Muscle MRI is not always done in Ullrich CMD because of the difficulty associated with sedating babies and small children.
• Tissue evaluation
  • For suspected Ullrich CMD: muscle biopsy with collagen VI immunolabeling
  • For suspected Bethlem myopathy: skin biopsy and dermal fibroblast culture with collagen VI immunolabeling
• Molecular genetic testing of COL6A1, COL6A2, COL6A3
  
  Using genomic DNA derived from peripheral blood samples, sequence analysis of the three genes encoding collagen VI detected putative mutations in [Lampe et al 2005] (see Note):
  • 66% of individuals clinically classified as having Bethlem myopathy
  • 56% of individuals with Bethlem myopathy with an unusually severe phenotype
  • 79% of individuals with Ullrich CMD

Note: (1) The low mutation detection rate is largely attributable to the high degree of genetic heterogeneity in Bethlem myopathy and Ullrich CMD, rather than failure to detect COL6A mutations; however, deep intronic and cryptic mutations are not detectable by sequence analysis. Deletion/duplication analysis does not increase the mutation detection frequency greatly, if at all. (2) The recent finding of compound heterozygous mutations for autosomal recessive forms of collagen type VI-related disorders emphasizes the importance of sequencing the entire coding region of the three genes (COL6A1, COL6A2, COL6A3) to ensure detection of two mutant alleles, when present [Gualandi et al 2009].

Carrier testing for relatives at risk for autosomal recessive forms of collagen VI-related disorders requires prior identification of the disease-causing mutations in the family.

Note: Carriers (heterozygotes) for autosomal recessive forms of collagen type VI-related disorders are not at risk of developing the disorder.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview have been associated with mutations in COL6A1, COL6A2, and COL6A3.

Natural History

The phenotypes associated with collagen type VI-related disorders, once thought to be distinct entities, were clinically defined long before their molecular basis was discovered. The collagen type VI-related disorders are now recognized to comprise a continuum of overlapping phenotypes with Bethlem myopathy at the mild end, Ullrich congenital muscular dystrophy (CMD) at the severe end, and two less well-defined disorders – autosomal dominant limb-girdle muscular dystrophy and autosomal recessive myosclerosis myopathy – in between. Although these phenotypes are now recognized to overlap and fall on a continuum, these clinical designations are useful for clarification of prognosis and management.

Genotype-Phenotype Correlations

In 42 individuals with collagen VI-related myopathy with onset before age two years, biallelic mutations that caused premature termination codons (associated with autosomal recessive inheritance) were associated with the most severe phenotypes (ambulation never achieved), whereas heterozygous de novo in-frame exon skipping and glycine missense mutations (associated with autosomal dominant inheritance) were associated with the moderate-progressive phenotypes (loss of ambulation) [Briñas et al 2010].

In autosomal recessive Ullrich congenital muscular dystrophy (CMD), a large number of mutations appear to result in premature termination codons with consequent nonsense-mediated mRNA decay. Premature termination codons occur by nonsense mutations [Demir et al 2002, Giusti et al 2005, Lampe et al 2005] or frameshift-inducing deletions [Higuchi et al 2001, Giusti et al 2005, Lampe et al 2005], insertions [Camacho Vanegas et al 2001], duplications [Lampe et al 2005], and splice changes [Camacho Vanegas et al 2001, Ishikawa et al 2002]. Splice mutations leading to in-frame exonic deletions as well as in-frame deletions are other common mutation types in Ullrich CMD [Demir et al 2002, Ishikawa et al 2004, Baker et al 2005, Lampe et al 2005].

Bethlem myopathy and Ullrich CMD represent a clinical continuum in which individuals presenting with intermediate phenotypes could be considered to have either "mild Ullrich CMD" or "severe Bethlem myopathy." In this context, heterozygous single amino-acid substitutions disrupting the Gly-Xaa-Yaa motif of the highly conserved triple helical domain have been described in a milder form of Ullrich CMD [Giusti et al 2005, Lampe et al 2005]. As for Bethlem myopathy, given the high number of mutations resulting in benign amino acid changes described for the genes encoding collagen VI subunits, it is difficult to be certain about the pathogenicity of missense mutations other than glycine substitutions within the triple helical domain.

In autosomal dominant Ullrich CMD, heterozygous splice site mutations leading to in-frame exonic deletions and heterozygous in-frame deletions in the coding region share a common motif: they preserve a unique cysteine important for dimer formation, allowing secretion of abnormal tetramers with a consequent dominant-negative effect on microfibrillar assembly [Pan et al 2003, Baker et al 2005].

Penetrance

Parents of individuals with recessively inherited collagen VI-related disorders are usually heterozygous for a COL6A1, COL6A2, or COL6A3 mutation, but do not appear to manifest any related symptoms.

Individuals with dominantly inherited collagen VI-related disorders are heterozygous for a COL6A1, COL6A2, or COL6A3 mutation and are symptomatic. However, careful clinical examination may be necessary to identify findings diagnostic of a collagen type VI-related disorder in their minimally symptomatic parents [Peat et al 2007].

Anticipation

Anticipation is not observed.

Nomenclature

Bethlem myopathy was first described as "benign myopathy with autosomal dominant inheritance" [Bethlem & Wijngaarden 1976]. Other terms in use:

• Benign congenital myopathy
• Benign congenital muscular dystrophy
• Benign congenital myopathy with contractures

Ullrich CMD was first described as "congenital atonic sclerotic muscular dystrophy" [Ullrich 1930]. Other terms used in the past:

• Congenital hypotonic sclerotic muscular dystrophy
• Congenital muscular dystrophy with distal laxity

Prevalence

Prevalence is estimated at 0.77:100,000 in Bethlem myopathy and 0.13:100,000 in Ullrich CMD [Norwood et al 2009]; the disorders are probably currently underdiagnosed.

Both conditions have been described in individuals from a variety of ethnic backgrounds.

Evaluations Following Initial Diagnosis

Bethlem myopathy. To establish the extent of disease and needs of an individual diagnosed with Bethlem myopathy, the following evaluations are recommended:

• Evaluation of degree of muscle weakness and mobility
• Joint examination for contractures
• Physiotherapy assessment and advice regarding stretches/splints for contractures and mobility aids
• Possibly orthopedic evaluation if surgery is to be considered for tendon Achilles contractures
• Assessment of respiratory status
  • Seek history of clinical symptoms of nocturnal hypoventilation such as early morning nausea and headaches, daytime somnolence.
  • Inquire about frequency and severity of chest infections; if any concerns, perform spirometry and nocturnal pulse oximetry.

Ullrich congenital muscular dystrophy (CMD). To establish the extent of disease and needs of an individual diagnosed with Ullrich CMD, the following evaluations are recommended:

• Evaluation of degree of muscle weakness and mobility
• Examination of back for scoliosis
• Joint examination for contractures and hyperlaxity
• Physiotherapy assessment and advice regarding stretches/splints for contractures and mobility aids such as swivel walkers and standing frames to achieve upright posture and protect against the development of scoliosis and other contractures
• Possibly x-rays of thoracolumbar spine and orthopedic evaluation if scoliosis is clinically suspected
• Possibly orthopedic evaluation if hip dislocation is suspected or surgery is to be considered for tendon Achilles contractures
• Assessment of respiratory status
  • Seek history of clinical symptoms of nocturnal hypoventilation such as early morning nausea and headaches, daytime somnolence.
  • Inquire about frequency and severity of chest infections; if any concerns, perform spirometry and nocturnal pulse oximetry.
• Assessment of growth and feeding. Feeding difficulties may manifest as failure to thrive or excessive time taken to finish eating a meal.

Treatment of Manifestations

Bethlem myopathy

• Physiotherapy and possibly orthopedic management of contractures are useful to maintain mobility. Contractures may be dynamic and may require stretching and splinting.
• Symptoms of nocturnal hypoventilation respond well to noninvasive respiratory support such as mask ventilation [Wallgren-Pettersson et al 2004].
• Approximately two thirds of individuals over age 50 years need supportive aids for outdoor mobility [Jöbsis et al 1999].

Ullrich CMD

• Children require active physiotherapy management as soon as the diagnosis is established to promote mobility and independence. Early mobilization in standing frames is important to achieve upright posture and protect against the development of scoliosis and other contractures.
• Contractures tend to be aggressive and may require surgery.
• Feeding difficulties may manifest as failure to thrive or excessive time taken to finish eating a meal. Consultation with a nutrition specialist may be required to boost calorie intake; for serious problems, feeding by gastrostomy may be the best solution to promote a normal weight gain.
• Respiratory support with nocturnal ventilation usually becomes necessary in the first or second decade and can be effective in reducing symptoms, promoting quality of life, and allowing normal schooling [Wallgren-Pettersson et al 2004].
• Scoliosis frequently develops in the first or second decade and requires active management including surgery.

Prevention of Secondary Complications

Prophylaxis of chest infections with vaccination and physiotherapy as well as early and aggressive use of antibiotics may prevent further respiratory problems in both disorders.

Surveillance

Bethlem myopathy

• Clinical assessment of muscle weakness, joint contractures, and mobility to inform physiotherapeutic advice regarding stretches/splints and mobility aids
• Assessments of respiratory function to detect asymptomatic decline. (Assess clinically by seeking history of clinical symptoms of nocturnal hypoventilation such as early-morning nausea and headaches, daytime somnolence; inquire about frequency and severity of chest infections; if any concerns, perform spirometry and nocturnal pulse oximetry)

Assessments should be repeated regularly, possibly annually, depending on the clinical status of the individual.

Ullrich CMD

• Clinical assessment of muscle weakness, scoliosis, joint contractures, and mobility to inform physiotherapeutic advice regarding stretches/splints and mobility aids
• Once scoliosis is evident, regular orthopedic follow up
• Assessments of respiratory function to detect asymptomatic decline. (Assess clinically by seeking history of clinical symptoms of nocturnal hypoventilation such as early-morning nausea and headaches, daytime somnolence; inquire about frequency and severity of chest infections; if any concerns perform spirometry and nocturnal pulse oximetry);
• Clinical assessment of nutritional status

Assessments should be repeated regularly, possibly biannually, depending on the clinical status of the individual.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

For a pregnant woman with a collagen VI-related disorder, no specific pregnancy management issues exist; however, prenatal physiotherapy may be indicated.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

The collagen type VI- related disorders are inherited in an autosomal dominant or autosomal recessive manner.

• The Bethlem myopathy phenotype is usually inherited in an autosomal dominant manner, although autosomal recessive inheritance has been reported [Foley et al 2009, Gualandi et al 2009].
• The Ullrich congenital muscular dystrophy (CMD) phenotype is usually inherited in an autosomal recessive manner, although autosomal dominant inheritance has been reported in four individuals with de novo mutations [Pan et al 2003, Baker et al 2005], and suspected in three others [Lampe et al 2005].
• The autosomal dominant limb-girdle muscular dystrophy and myosclerosis myopathy phenotypes are inherited in an autosomal dominant and autosomal recessive manner, respectively.
• Most individuals with an autosomal dominant collagen type VI disorder (i.e., who are heterozygous for a COL6A1, COL6A2, or COL6A3 mutation) are symptomatic.
• Parents of individuals with an autosomal recessive collagen type VI disorder (i.e., who are usually heterozygous for a COL6A1, COL6A2, or COL6A3 mutation) do not appear to manifest any related symptoms.
• Individuals with an autosomal dominant collagen type VI disorder caused by a de novo mutation cannot be distinguished clinically from those with an autosomal recessive collagen type VI disorder.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

• Individuals diagnosed with an autosomal dominant collagen type VI-related disorder may have an affected parent.
• A proband with an autosomal dominant collagen type VI-related disorder may have the disorder as the result of a new mutation [Pan et al 2003]. The proportion of cases caused by a de novo mutation is thought to be greater than 50% [Allamand et al 2011].
• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include clinical assessment by a clinician specializing in muscle disorders and molecular genetic testing, if the mutation has been identified in the proband.

Sibs of a proband

• The risk to the sibs of a proband depends on the genetic status of the proband's parents.
• If a parent of the proband has the disease-causing mutation identified in the proband and/or is affected, the chance that a sib will inherit the mutation is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low, but greater than that of the general population because of possible reduced penetrance in the parent and/or germline mosaicism. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of an individual with an autosomal dominant collagen VI-related disorder has a 50% chance of inheriting the mutation.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent has the disease-causing mutation identified in the proband and/or is affected, his or her family members may be at risk.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

• The parents of a child with an autosomal recessive collagen type VI-related disorder are usually heterozygotes and, therefore, carry one mutant allele.
• Heterozygotes (carriers) are usually asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being neither affected nor a carrier.
• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.

Offspring of a proband. The offspring of an individual with an autosomal recessive collagen type VI-related disorder are obligate heterozygotes for a disease-causing mutation but are themselves unaffected unless they inherit a second mutation from their other parent.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for family members at risk of being carriers of an autosomal recessive collagen type VI-related disorder is possible if the disease-causing mutations have been identified in an affected family member.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Molecular Genetic Pathogenesis

Collagen VI comprises the three peptide chains α1(VI), α2(VI) (both 140 kd in size), and α3(VI) (260-300 kd in size) [Engvall et al 1986]. The α1(VI) and α2(VI) chains are encoded by the genes COL6A1 and COL6A2, respectively, which are situated head-to-tail on chromosome 21q22.3 [Heiskanen et al 1995] and separated by 150 kb of genomic DNA. COL6A3, the gene encoding the α3(VI) chain, is on chromosome 2q37 [Weil et al 1988].

All three chains contain a central short triple helical domain of 335-336 amino acids with repeating Gly-Xaa-Yaa sequences flanked by large N- and C- terminal globular domains consisting of motifs of approximately 200 amino acids each homologous to von Willebrand factor (vWF) type A domains [Chu et al 1990].

Normal allelic variants

• COL6A1 comprises 37 exons (35 of which are coding) and produces a single transcript encoding a protein of 1021 amino acids with two C-terminal and one N-terminal vWF type A-like domains.
• COL6A2 comprises 30 exons (29 of which are coding) and has been shown to produce multiple alternatively spliced mRNAs that differ in the 5'-untranslated region as well as in the 3'-coding and noncoding sequences. It produces at least three α2(VI) protein variants (828-1019 amino acids) with distinct carboxyl termini, which similarly contain two C-terminal and one N-terminal vWF type A-like domain [Saitta et al 1990].
• COL6A3 comprises 44 exons (43 of which are coding) and encodes the α3(VI) chain, which can vary in size between 2970 and 3176 amino acids. The α3(VI) chain contains two C-terminal vWF type A-like domains, subdomains similar to type III fibronectin repeats and Kunitz protease inhibitors as well as six to ten N-terminal vWF type A-like domains, thus contributing most of the amino-terminal globular domain of the collagen VI heterotrimer. Various N-terminal exons of COL6A3 are subject to alternative splicing and four variant transcripts encoding proteins with variably sized N-terminal globular domains have been characterized [Stokes et al 1991, Dziadek et al 2002].

Pathologic allelic variants

• Single amino acid substitutions disrupting the Gly-Xaa-Yaa motif of the highly conserved triple helical domain of any of the three COL6A genes [Jöbsis et al 1996, Pepe et al 1999a, Scacheri et al 2002, Lampe et al 2005, Lucioli et al 2005] constitute the most frequent pathogenic mechanism at 28% of the total pathogenic variants in COL6A1, COL6A2, and COL6A3.
• Mutations that introduce premature termination codons (splice sites and out of frame deletions/insertions) form the second most frequent group at 28%.
• Splice-site mutations that cause exon skipping occur at around the frequency [Lamande et al 1999, Pepe et al 1999b, Pan et al 2003, Lampe et al 2005, Lucioli et al 2005], with 27% of the total.
• Other splice-site mutations causing small in-frame deletions or insertions in regions that encode domains flanking the triple helical domain make up 8% of the total of pathogenic variants in COL6A1, COL6A2 and COL6A, with large genomic deletions appearing to be rare and occurring at a frequency of around 2% [Vanegas et al 2002, Lampe et al 2005, Lucioli et al 2005].

Given the high number of mutations that result in benign amino acid changes described for the three genes encoding the three collagen VI peptide chains, it is difficult to be sure about the pathogenicity of missense mutations other than glycine substitutions within the triple helical domain.

Normal gene product. Extracellular matrix molecules are critical for skeletal muscle stability, regeneration, and muscle cell matrix adhesion [Helbling-Leclerc et al 1995, Sewry & Muntoni 1999, Emery 2002]. Collagen VI is a ubiquitous extracellular matrix protein [von der Mark et al 1984] that forms a microfibrillar network in close association with the basement membrane around muscle cells and interacts with several other matrix constituents [Burg et al 1996, Kuo et al 1997, Wiberg et al 2003].

The assembly of collagen VI is a complex multistep process. Association of the three genetically distinct subunits α1(VI), α2(VI), and α3(VI) to form a triple helical monomer is followed by staggered assembly into disulfide-bonded antiparallel dimers, which then align to form tetramers, also stabilized by disulfide bonds. Outside of the cell, tetramers, the secreted form of collagen VI, associate end to end to form the characteristic beaded microfibrils [Furthmayr et al 1983, Engvall et al 1986, Lamande et al 1998].

Abnormal gene product

• Autosomal dominant collagen type VI-related disorders. Heterozygous single amino acid substitutions disrupting the Gly-Xaa-Yaa motif of the highly conserved triple helical domain of any of the three COL6A genes [Jöbsis et al 1996, Pepe et al 1999a, Scacheri et al 2002, Lampe et al 2005, Lucioli et al 2005], depending on their location, appear to either interfere with intracellular chain assembly or, following successful secretion, cause kinking of the tetramers, thus affecting extracellular microfibril formation [Lamande et al 2002]. Functional haploinsufficiency via a dominant-negative effect has also been reported as the pathogenic mechanism for some missense and splice-site mutations [Lamande et al 1999]. Heterozygous splice mutations (associated with autosomal dominant disease) leading to in-frame exonic deletions as well as in-frame genomic deletions preserve a unique cysteine important for dimer formation, allowing secretion of abnormal tetramers with a consequent dominant-negative effect on microfibrillar assembly [Pan et al 2003, Baker et al 2005].
• Autosomal recessive collagen type VI-related disorders. Most mutations associated with autosomal recessive disease reported to date are protein-truncating nonsense mutations. Some have been shown to result in absence of collagen VI because of nonsense-mediated mRNA decay [Zhang et al 2002].

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Suggested Reading

1. Bushby K, Norwood F, Straub V. The limb-girdle muscular dystrophies--diagnostic strategies. Biochim Biophys Acta. 2007;1772:238–42. [PubMed: 17123791]
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3. Chu ML, Prockop DJ. Collagen: gene structure. In: Steinmann B, Royce PM, eds. Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects. 2 ed. New York, NY: Wiley-Liss; 2002:223-48.
4. Chu ML, Pan TC, Conway D, Saitta B, Stokes D, Kuo HJ, Glanville RW, Timpl R, Mann K, Deutzmann R. The structure of type VI collagen. Ann N Y Acad Sci. 1990;580:55–63. [PubMed: 2337306]
5. De Visser M, van der Kooi AJ, Jöbsis GJ. Bethlem myopathy. In: Engel AG, Franzini-Armstrong C, eds. Myology. 3 ed. McGraw-Hill; 2004:1135-46.
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10. Kielty CM, Grant ME (2002) The collagen family: structure, assembly, and organization in the extracellular matrix. In: Steinmann B, Royce PM, eds. Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects. 2 ed. New York, NY: Wiley-Liss; 2002:159-221.
11. Lamande SR, Bateman JF, Hutchison W, McKinlay Gardner RJ, Bower SP, Byrne E, Dahl HH. Reduced collagen VI causes Bethlem myopathy: a heterozygous COL6A1 nonsense mutation results in mRNA decay and functional haploinsufficiency. Hum Mol Genet. 1998a;7:981–9. [PubMed: 9580662]
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Author Notes

Newcastle Upon Tyne Hospitals: Patient Information

Revision History

• 9 August 2012 (me) Comprehensive update posted live
• 6 April 2007 (me) Comprehensive update posted to live Web site
• 25 June 2004 (me) Review posted to live Web site
• 18 February 2004 (kf) Original submission