1. DISEASE CHARACTERISTICS
1.1 Name of the disease (synonyms)
Multi-minicore disease (MmD); multi-minicore myopathy; minicore myopathy; multicore myopathy with external ophthalmoplegia; moderate minicore myopathy with hand involvement; antenatal onset minicore myopathy with arthrogryposis.
The large number of synonyms reflects the variability of clinical and histopathological features, as well as genetic heterogeneity. MmD, introduced following the dedicated ENMC workshops on the condition,1, 2 is the most common synonym, and is used consistently throughout this paper.
1.2 OMIM# of the disease
#255320, #117000 and #607552.
1.3 Name of the analysed genes or DNA/chromosome segments
Skeletal muscle ryanodine receptor (RYR1) gene/19q13.1; selenoprotein N (SEPN1) gene/1p35.
1.4 OMIM# of the gene(s)
*180901 (RYR1) and *606210 (SEPN1).
1.5 Mutational spectrum
RYR1 gene: More than 200 RYR1 mutations have been reported to date, some exclusively associated with MmD and other congenital myopathy phenotypes, others with the malignant hyperthermia susceptibility (MHS) trait, or both.2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 RYR1 mutations associated with MmD are mainly recessive and, less frequently, dominant.7 The RYR1 mutational spectrum associated with MmD is wide and comprises missense mutations, nonsense mutations, intronic splice mutations, deletions and duplications. Compound heterozygosity for missense and truncating RYR1 mutations is a commonly observed genotype in MmD and other recessive, RYR1-related myopathies.7, 8, 9 Monoallelic expression of heterozygous RYR1 missense mutations on the background of an imprinted maternal allele has been suggested in few families,13 but more recent data suggest that this is not a major contributory factor.
SEPN1 gene: SEPN1 mutations associated with MmD are generally recessive and predominantly truncating,14, 15 with only few missense mutations typically affecting functionally important domains of the protein such as the SECIS,16 or the selenocysteine redefinition element (SRE).17 Homozygous mutations are unexpectedly common even in families from non-consanguineous backgrounds, due to the presence of few founder mutations in different European populations. Forms of MmD due to recessive mutations in the SEPN1 gene are considerably rarer than those due to mutations in the RYR1 gene (Muntoni and Jungbluth, unpublished observation).
1.6 Analytical methods
Considering that cores on muscle biopsy are a non-specific finding, and variations of uncertain significance are particularly common in the RYR1 gene, genetic testing in MmD should only be initiated on the basis of a comprehensive assessment of clinical, histopathological and, increasingly, muscle MRI features at a specialist neuromuscular centre. Certain combinations of features are more indicative of either SEPN1 or RYR1 involvement, and should prompt mutation screening of the respective gene.
Clinical features: Patients with SEPN1-related MmD have a consistent clinical phenotype characterized by marked axial weakness with spinal rigidity, early scoliosis and severe respiratory impairment often requiring non-invasive ventilation, even in still ambulant individuals.14 Extraocular muscle involvement (ophthalmoparesis) is extremely rare, but occasionally seen in the most severe cases (Ferreiro, unpublished observation). Cardiac involvement may occur secondary to marked respiratory impairment. Clinical features of RYR1-related MmD are more variable: Extraocular muscle involvement (ophthalmoparesis) is common, often associated with axial and proximal weakness, and mild-to-moderate bulbar and respiratory involvement.6 Other patients share clinical features with dominantly inherited CCD, featuring mild-to-moderate weakness pronounced in the hip girdle, but no extraocular or significant bulbar or respiratory involvement.5 Distal involvement with marked hyperlaxity pronounced in the upper limb is a frequently associated finding. A primary cardiomyopathy is not a feature in SEPN1- or RYR1-related forms of MmD.
Histopathological features: SEPN1-related MmD typically show numerous, often poorly defined small core lesions spanning only few sarcomeres, and irregularly distributed throughout the fibre on longitudinal sections.14 RYR1-related MmD shows some overlap with CCD due to dominant mutation in the same gene, although by definition, cores are more often multiple and eccentric and do not run a significant extent along the fibre axis on longitudinal sections.6 In cases with suggestive clinical features but equivocal histopathological findings, muscle MRI may be more indicative of specific backgrounds than muscle biopsy.
Muscle MR imaging: Muscle MR imaging in MmD shows different patterns of selective involvement depending on the genetic background and may aid genetic testing. In particular, in SEPN1-related MmD, within the thigh, the sartorius is usually the first and most prominently affected muscle. In RYR1-related MmD, within the thigh, there is selective sparing of the rectus femoris compared with the vasti, of the adductor longus compared with the adductor magnus, and of the gracilis compared with the sartorius. Although still discernible, the contrast between affected and unaffected muscles is often not as prominent in recessive RYR1-related MmD as in CCD due to dominant mutations in the RYR1 gene. In addition to distinguishing these forms from each other, muscle MRI may also help to distinguish SEPN1- and RYR1-related MmD from genetically distinct congenital myopathies with or without spinal rigidity.18, 19, 20
Genomic sequencing of coding regions including functionally important domains, such as the SECIS16 or the SRE,17 is currently the strategy of choice for screening of the SEPN1 gene. Multiple ligation probe analysis will enable detection of large deletions in future.
Genomic sequencing of coding regions and flanking intronic sequence is currently the main strategy for RYR1 mutation screening. In future, array CGH, next-generation sequencing and/or multiplex ligation-dependent probe amplification are likely to enable the detection of larger deletions, duplications and genomic rearrangements, relatively common in MmD and other recessive RYR1-related myopathies.
1.7 Analytical validation
Direct sequencing of both DNA strands is performed. Any sequence variants identified on genomic DNA sequencing is confirmed on a second DNA dilution from the index case. If a gross deletion or duplication is identified using, for example, next-generation sequencing, confirmation with a second technique is advisable. The pathogenicity of variants can be assessed using commercially available mutation interpretation software or alternative approaches to interrogate online data resources.
The majority of mutations in the SEPN1 gene are truncating with few missense mutations reported affecting functionally important domains of the protein. Functional studies (ie, studies of the mutant RyR1 channel in patient myoblasts or homologous and heterologous expression systems) for the assessment of RYR1 variations of uncertain significance are currently only available in selected cases on a research basis.
1.8 Estimated frequency of the disease (incidence at birth (‘birth prevalence’) or population prevalence)
The birth prevalence or population prevalence of MmD is currently unknown. However, forms of MmD due to recessive mutations in the SEPN1 gene are significantly rarer than those due to RYR1 mutations (Muntoni and Jungbluth, unpublished observation). The carrier frequency for heterozygous RYR1 mutations in the Japanese population has been estimated at 1 in 2000.21
1.9 If applicable, prevalence in the ethnic group of investigated person
Homozygous SEPN1 mutations are unexpectedly common even in families from non-consanguineous backgrounds, due to the presence of few founder mutations in different European populations.14
The prevalence of RYR1-related MmD in specific ethnic groups is not known. However, specific malignant hyperthermia-related RYR1 mutations or other RYR1-related myopathies have been found to be more prevalent in certain ethnic populations.9, 22
1.10 Diagnostic setting
Predictive testing: Testing for RYR1 mutations does not only test for MmD and CCD, but also for the MHS trait, an allelic but not consistently associated complication of RYR1 mutations. Although the association of some CCD-related dominant RYR1 mutations and MHS has been well documented, the association is less clear with regards to more recently identified, recessive RYR1 mutations. In families where the mutation identified has been previously documented to be MHS-associated, the index case and relatives found to harbour the same change can be advised directly about their MHS risk. In families where the mutation identified has not been previously documented to be MHS-associated, the index case and relatives found to harbour the same change can be referred for appropriate testing. Identification of homozygous or compound heterozygous SEPN1 mutations in minimally symptomatic relatives of an index case predicts a high risk of developing respiratory failure, and indicates early polysomnographic studies.
Risk assessment in relatives: Families with more than one pathogenic RYR1 mutation running independently in the family have been recognised. It is therefore advisable to screen the entire RYR1 gene in affected relatives with suggestive clinical and histopathological features, even if the RYR1 mutation(s) previously identified in an affected index case has been excluded. Heterozygous carriers of SEPN1 mutations remain asymptomatic.
Prenatal diagnosis: It is expected that the greater availability of RYR1 mutation screening will also increase requests for prenatal diagnosis. Prenatal diagnosis may be difficult in MmD and other RYR1-related myopathies due to the large number of RYR1 variations of uncertain significance. We would therefore only consider prenatal diagnosis in families where pathogenicity for the RYR1 mutation(s) identified has been clearly established, and no other sequence variations of uncertain significance have been identified on complete sequencing of both parents. Prenatal SEPN1 mutation screening may be offered where two SEPN1 mutations of proven pathogenicity have been previously identified in trans in the index case in the family.
2. TEST CHARACTERISTICS
2.1 Analytical sensitivity (proportion of positive tests if the genotype is present)
No precise data regarding the analytical sensitivity of SEPN1 and RYR1 testing in MmD are currently available; however, analytical sensitivity is likely to be higher for SEPN1 than for RYR1 mutations. Analytical sensitivity for SEPN1 testing is likely to be close to 100%. Analytical sensitivity for RYR1 testing is likely to be substantially less than 100% if no diagnostic test for large scale deletions, duplications or genomic rearrangements has been performed
Criteria for determining the pathogenicity of an SEPN1 mutation are as follows:
Splice-site mutations affecting canonical splice sequence or shown to alter splicing at mRNA/cDNA level.
Out-of-frame and in-frame deletion or insertion.
De novo compound heterozygous missense mutation (with proven paternity and absence of disease in parents).
Missense mutations previously shown to segregate in MmD families.
Criteria for determining the pathogenicity of an RYR1 mutation are as follows:
Splice-site mutations affecting canonical splice sequence or shown to alter splicing at mRNA/cDNA level.
Out-of-frame and in-frame deletion or insertion.
De novo missense mutation (with proven paternity and absence of disease in parents).
Missense mutation previously shown to segregate in an MmD family.
Missense mutation involving a highly conserved amino acid. For other missense mutations, the search for segregation in the family should be performed if possible.
2.2 Analytical specificity (proportion of negative tests if the genotype is not present)
No precise data regarding the analytical specifity of SEPN1 and RYR1 testing in MmD are currently available. However, RYR1 sequence variations of uncertain significance are common; only a small proportion of those have been functionally characterized to date, with an associated risk of false positives.
2.3 Clinical sensitivity (proportion of positive tests if the disease is present)
In general terms, clinical sensitivity is dependent on variable factors such as age at testing, and a positive or negative family history. More specifically, clinical sensitivity, particularly for RYR1 mutation screening also depends on the method used for mutation screening, as for example, larger copy number variations or genomic rearrangements are relatively common in RYR1-related MmD and other recessive RYR1-related myopathies, and may be missed on routine sequencing. Most importantly, the stringent application of clinical and histopathological selection criteria as outlined in paragraph 1.6 is a major determinant of clinical sensitivity for SEPN1 and RYR1 testing in MmD.
Although recent larger series indicate recessive SEPN1 and RYR1 mutations as a common cause of MmD, there is also evidence for genetic heterogeneity accounting for the imperfect clinical sensitivity of SEPN1 and RYR1 screening in MmD:
in the original series of 62 families with suggestive features of the ‘classical’ phenotype of MmD, only 12 families were found to carry causative SEPN1 mutations.14 Although some of the remaining 50 families were subsequently found to be RYR1-related, RYR1 mutations could be excluded in others.
multi-minicores and central cores as the main feature on muscle biopsy have been reported in a number of genetically distinct myopathies, often associated with dominant inheritance or clinical features unusual in the context of SEPN1- or RYR1-related MmD, such as a primary cardiomyopathy. A primary cardiomyopathy associated with multi-minicores on muscle biopsy has also been documented in a mildly affected family harbouring dominant ACTA1 mutations,23 and severely affected siblings with homozygous truncating titin mutations.24 Missense mutations in the β-myosin heavy-chain gene, MYH7,25 may give rise to cores on muscle biopsy with a distinct associated-myopathy phenotype with or without cardiac impairment.26
central cores and multi-minicores as a secondary feature on muscle biopsy have been reported to be associated with mutations in the ACTA1,27 DNM228 and NEB29 genes; however, in most of these cases, other findings, namely nemaline rods or centralized internal nuclei, were the more prominent histopathological feature.
2.4 Clinical specificity (proportion of negative tests if the disease is not present)
No precise data regarding the clinical specifity of RYR1 or SEPN1 testing in MmD are currently available; however, clinical specificity is likely to be less than 100% for RYR1 testing, considering the large number of sequence variations of uncertain significance identified in the RYR1 gene. In most cases, a detailed clinical assessment and muscle biopsy will have been performed before genetic testing; therefore, presence of the condition is a prerequisite for the initiation of genetic testing, but also of importance for the interpretation of RYR1 variations of uncertain significance.
2.5 Positive clinical predictive value (life-time risk to develop the disease if the test is positive)
Penetrance of MmD-related SEPN1 mutations is likely to be near 100%. Inter- and intra-familial clinical variability has to be taken into account in RYR1-related MmD, where additional sequence variations running independently in the family may modifiy the phenotype.
2.6 Negative clinical predictive value (probability not to develop the disease if the test is negative)
Index case in that family had been tested:
The negative clinical predictive value is likely to be near 100% for SEPN1 testing, but less than 100% in RYR1-related MmD, as pedigrees with more than one disease-causing RYR1 mutation running independently in different branches of the family, as well as locus heterogeneity, have been recognised. In a prenatal diagnosis situation, where the possibility of additional pathogenic RYR1 mutations can be ruled out (eg, by completely sequencing DNA from both parents), the negative clinical predictive value is expected to be close to 100%.
Index case in that family had not been tested:
When the index case in that family had not been tested, predictive testing in another family member should only be proposed when the family member fulfils the clinical and pathological criteria as outlined in paragraph 1.6.
3. Clinical utility
3.1 (Differential) diagnosis: The tested person is clinically affected
(To be answered if in 1.10 ‘A’; was marked)
Genetic testing for SEPN1 and RYR1 mutations is important in the differential diagnosis of patients with clinical features of a congenital myopathy and histopathological findings suggestive of MmD.
3.1.1 Can a diagnosis be made other than through a genetic test?
Because MmD is a clinical and, most importantly, a histopathological diagnosis, a primary molecular genetic analysis is indicated only in familial cases with typical clinical features and known-associated SEPN1 or RYR1 mutations. In most other cases, a comprehensive assessment comprising detailed evaluation of clinical, histopathological and, possible, muscle MRI imaging features should be performed before genetic testing, and therefore represents a prerequisite to genetic testing rather than a diagnostic alternative.
3.1.2 Describe the burden of alternative diagnostic methods to the patient?
Detailed clinical neuromuscular assessment, a muscle biopsy with or without muscle MRI imaging, is required in the index case to inform the choice of genetic testing and to establish the diagnosis. A muscle biopsy, in particular, is an invasive procedure and will require local or general anaesthesia, but its complication rate is usually low. Muscle MR imaging may require sedation in young children less than 5 years of age. Molecular genetic analysis may replace above procedures in similarly affected relatives of index cases, where the genetic diagnosis has been unequivocally established.
3.1.3 How is the cost effectiveness of alternative diagnostic methods to be judged?
3.1.4 Will disease management be influenced by the result of a genetic test?
3.2 Predictive setting: The tested person is clinically unaffected but carries an increased risk based on family history
(To be answered if in 1.10 ‘B’ was marked)
3.2.1 Will the result of a genetic test influence lifestyle and prevention?
If the test result is positive (please describe):
Genetic confirmation of the clinic-pathological diagnosis of RYR1- or SEPN1-related MmD will help to focus on the multidisciplinary follow-up and management as outlined in Paragraph 3.1.4.
If the test result is negative (please describe):
Follow-up is dispensable if familial mutations in SEPN1 or RYR1 have been excluded, and no clinico-pathological features of MmD are present. Follow-up should be arranged as outlined in Paragraph 3.1.4 if clinico-pathological features of MmD are present, but no SEPN1 or RYR1 mutations could be identified.
3.2.2 Which options in view of lifestyle and prevention does a person at-risk have if no genetic test has been done (please describe)?
If the person has a positive family history of MmD and is clinically affected, follow-up should be arranged as outlined in Paragraph 3.1.4. If the person has a positive family history of MmD and is clinically not affected, specialist follow-up is dispensable, unless suggestive symptoms developed.
3.3 Genetic risk assessment in family members of a diseased person
(To be answered if in 1.10 ‘C’ was marked)
3.3.1 Does the result of a genetic test resolve the genetic situation in that family?
Yes, in SEPN1-related MmD, if two recessive mutations are identified in trans. Yes, in RYR1-related MmD, if two recessive mutations in trans or a heterozygous dominant mutation of proven pathogenicity are identified, provided that sequencing of the entire RYR1 gene has been performed and no additional RYR1 mutations are running independently in the family.
3.3.2 Can a genetic test in the index patient save genetic or other tests in family members?
3.3.3 Does a positive genetic test result in the index patient enable a predictive test in a family member?
3.4 Prenatal diagnosis
(To be answered if in 2.10 ‘D’ was marked)
3.4.1 Does a positive genetic test result in the index patient enable a prenatal diagnostic?
Yes (but note cautions as outlined in Paragraph 1.10).
4. IF APPLICABLE, FURTHER CONSEQUENCES OF TESTING
Please assume that the result of a genetic test has no immediate medical consequences. Is there any evidence that a genetic test is nevertheless useful for the patient or his/her relatives? (Please describe)
Yes. In many cases, the genetic diagnosis contributes substantially to a diagnostic conclusion, particularly if histopathological findings are not entirely typical. Recognising a particular congenital myopathy as RYR1- or SEPN1-related MmD will help to anticipate future course, plan interventions and prevent potential complications. It will also end a lengthy diagnostic process for affected individuals and their families.
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This work was supported by EuroGentest, an EU-FP6 supported NoE, contract number 512148 (EuroGentest Unit 3: ‘Clinical genetics, community genetics and public health’, Workpackage 3.2).
Suzanne Lillis and Stephen Abbs are employed by GSTS Pathology, a joint venture private partnership organisation, which offers clinical diagnostic testing of the RYR1 gene.
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Lillis, S., Abbs, S., Ferreiro, A. et al. Clinical utility gene card for: Multi-minicore disease. Eur J Hum Genet 20, 5 (2012). https://doi.org/10.1038/ejhg.2011.180