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Clinical utility gene card for: Nemaline myopathy

1. DISEASE CHARACTERISTICS

1.1 Name of the disease (synonyms)

Nemaline myopathy (NEM1 – NEM7)

Includes nemaline myopathy with excess thin filaments/actin aggregates; nemaline myopathy with cores; nemaline myopathy with intranuclear rods; and Amish nemaline myopathy.

1.2 OMIM# of the disease

NEM1 609284; NEM2 256030; NEM3 161800; NEM4 609285; NEM5 605355; NEM6 609273; NEM7 – 610687.

1.3 Name of the analysed genes or DNA/chromosome segments

Slow muscle α-tropomyosin (TPM3) – NEM1.

Nebulin (NEB) – NEM2.

Skeletal muscle α-actin (ACTA1) – NEM3.

β-tropomyosin (TPM2) – NEM4.

Slow muscle troponin-T (TNNT1) – NEM5.

Kelch-repeat and BTB (POZ) Domain containing 13 (KBTBD13) – NEM6.

Skeletal muscle cofilin (CFL2) – NEM7.

1.4 OMIM# of the gene(s)

TPM3=*191030; NEB=*161650; ACTA1=*102610; TPM2=*190990; TNNT1=*191041; KBTBD13=*613727; CFL2=*601443.

1.5 Mutational spectrum

TPM3

Mainly dominant, missense mutations,1, 2 however some recessive mutations have been described.3, 4 A 1 bp recessive deletion occurs as a founder mutation in the Turkish population.5

NEB

All the over 140 mutations identified to date are recessive and the patients usually are compound heterozygous. The majority of the mutations are either frameshift or nonsense mutations, but also missense mutations, and point mutations and deletions affecting splice sites are known.6, 7 An in-frame deletion of exon 55 is present in the Ashkenazi Jewish population at a carrier frequency of approximately 1 in 108.8

ACTA1

Over 200 different mutations identified, with the majority causing nemaline myopathy, and nemaline myopathy with other features (for example, cores, actin aggregates, intranuclear rods).9 Of these, most mutations are dominant, missense, and have arisen de novo.9 About 10% are recessive mutations, and are genetic or functional null mutations.9 Dominant inheritance is less common, and only seen in families with a milder phenotype.9

TPM2

Two heterozygous, dominant missense mutations causing nemaline myopathy are known.10 Also a homozygous null mutation in a patient with nemaline and Escobar syndrome,11 and a dominant heterozygous mutation in a mother with nemaline myopathy and her daughter with cap myopathy.12

TNNT1

A recessive nonsense founder mutation is present in the Old Order Amish population. This produces characteristic progressive nemaline myopathy with tremors and contractures.13

KBTBD13

Three dominant missense mutations have been identified; however, not all mutation carriers in the families exhibited skeletal muscle weakness.14

CFL2

A single homozygous missense mutation has been identified in one family.15

1.6 Analytical methods

The main analytical method is bi-directional Sanger sequencing of the entire coding region of the individual genes. If the family structure is amenable, linkage analysis for NEB may be useful to pre-screen, owing to the large size of the gene. Next-generation sequencing will allow for simultaneous analysis of all genes in a patient.

1.7 Analytical validation

Mutations should be confirmed by resequencing using a fresh dilution of genomic DNA.

1.8 Estimated frequency of the disease (incidence at birth (‘birth prevalence’) or population prevalence)

For the most part, the frequency of the disease is unknown. In Finland, the birth prevalence has been estimated to be 0.02 per 1000 live births.16 Dominant mutations in ACTA1 and recessive mutations in NEB are the most common causes of NEM.17, 18

1.9 If applicable, prevalence in the ethnic group of investigated person

Recessive founder mutations are known to exist in particular genes in specific populations: TNNT1 in the Amish;13 NEB in the Ashkenazi Jewish;8 ACTA1 in the Pakistani community in England; and in French and Spanish Roma;9 and TPM3 in the Turkish population.5 These specific cases aside, no clear differences exist in prevalence rates between different ethnicities.

1.10 Diagnostic setting

Comment: Requests for predictive testing are not common because of the early onset of the disease, but may be offered in families with childhood or late-onset forms of the disease.

2. TEST CHARACTERISTICS

2.1 Analytical sensitivity

(proportion of positive tests if the genotype is present)

100%

2.2 Analytical specificity

(proportion of negative tests if the genotype is not present)

100%

2.3 Clinical sensitivity

(proportion of positive tests if the disease is present)

The clinical sensitivity can be dependent on variable factors such as age or family history. In such cases a general statement should be given, even if a quantification can only be made case by case.

The clinical sensitivity is dependent on factors such as age, inheritance pattern and additional clinical features. Because of the genetic heterogeneity, and particularly the difficulty of screening NEB, full screening of all known nemaline myopathy genes is rarely carried out. If full screening were to be undertaken, it may be estimated that approximately 75% of patients would have an identifiable mutation.6, 9

2.4 Clinical specificity

(proportion of negative tests if the disease is not present)

The clinical specificity can be dependent on variable factors such as age or family history. In such cases, a general statement should be given, even if a quantification can only be made case by case.

Probably 100%.

2.5 Positive clinical predictive value

(life-time risk to develop the disease if the test is positive)

Near 100%. Potential incomplete penetrance has been suggested for certain ACTA1 variants.19

2.6 Negative clinical predictive value

(probability not to develop the disease if the test is negative)

Assume an increased risk based on family history for a non-affected person. Allelic and locus heterogeneity may need to be considered.

Index case in that family had been tested:

 Approximately 100%.

Index case in that family had not been tested:

 No predictive tests are usually performed in such cases.

3. CLINICAL UTILITY

3.1 (Differential) diagnosis: The tested person is clinically affected

(To be answered if in 1.10 ‘A’ was marked)

3.1.1 Can a diagnosis be made other than through a genetic test?

3.1.2 Describe the burden of alternative diagnostic methods to the patient

Nemaline myopathy requires both a clinical and, significantly, a histopathological/electron microscopic diagnosis. Therefore, a thorough assessment including a detailed evaluation of clinical and pathological features should be performed before genetic testing. As such, histopathology and electron microscopy are not diagnostic alternatives, rather prerequisites to genetic testing. Nevertheless, muscle biopsy is an invasive procedure, and appropriate histological and electron microscopic examination requires proximity to a specialised laboratory set up.

3.1.3 How is the cost effectiveness of alternative diagnostic methods to be judged?

Not applicable.

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)

Predictive testing is usually only applicable for the milder versions of nemaline myopathy, as most often the disease presents before, at, or shortly after birth.

3.2.1 Will the result of a genetic test influence lifestyle and prevention?

If the test result is positive (please describe):

A positive result may perhaps influence decisions in terms of lifestyle choices, for example, deciding which career to pursue (eg, an office job compared with a more physical occupation), whether to travel at a young age when mobility is not affected compared with later in life after the disease onsets, and whether to have a house on one level as opposed to over multiple stories (eg, the latter would involve climbing lots of stairs which might become problematic).

If the test result is negative (please describe):

A negative result may influence lifestyle choices in the opposite directions to those indicated above.

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)?

Not applicable.

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, if a mutation/s is identified.

3.3.2 Can a genetic test in the index patient save genetic or other tests in family members?

Yes.

3.3.3 Does a positive genetic test result in the index patient enable a predictive test in a family member?

Yes, but owing to very early disease onset in most cases, it is infrequently encountered.

3.4 Prenatal diagnosis

(To be answered if in 1.10 ‘D’ was marked)

3.4.1 Does a positive genetic test result in the index patient enable a prenatal diagnosis?

Yes. In cases where dominant de novo mutations have been identified in an affected child, genetic counselling may be difficult, as the recurrence risk is between 0 and 50%, and there is currently insufficient empirical data to indicate the risk. However, prenatal genetic testing of an at-risk pregnancy is accurate.

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, particularly if a mutation/s are identified. An accurate genetic diagnosis often ends a lengthy diagnostic odyssey for the patient and their family, removing the psychological affects of an absent disease cause, and can sometimes influence possible prognosis. An accurate genetic diagnosis can crucially indicate mode of inheritance and underpins genetic counselling, including options such as prenatal and pre-implantation testing.

References

  1. 1

    Laing NG, Wilton SD, Akkari PA et al: A mutation in the alpha tropomyosin gene TPM3 associated with autosomal dominant nemaline myopathy. Nat Genet 1995; 9: 75–79.

    CAS  Article  Google Scholar 

  2. 2

    Kiphuth IC, Krause S, Huttner HB, Dekomien G, Struffert T, Schroder R : Autosomal dominant nemaline myopathy caused by a novel alpha-tropomyosin 3 mutation. J Neurol 2010; 257: 658–660.

    CAS  Article  Google Scholar 

  3. 3

    Tan P, Briner J, Boltshauser E et al: Homozygosity for a nonsense mutation in the alpha-tropomyosin slow gene TPM3 in a patient with severe infantile nemaline myopathy. Neuromuscul Disord 1999; 9: 573–579.

    CAS  Article  Google Scholar 

  4. 4

    Wattanasirichaigoon D, Swoboda KJ, Takada F et al: Mutations of the slow muscle alpha-tropomyosin gene, TPM3, are a rare cause of nemaline myopathy. Neurology 2002; 59: 613–617.

    CAS  Article  Google Scholar 

  5. 5

    Lehtokari VL, Pelin K, Donner K et al: Identification of a founder mutation in TPM3 in nemaline myopathy patients of Turkish origin. Eur J Hum Genet 2008; 16: 1055–1061.

    CAS  Article  Google Scholar 

  6. 6

    Pelin K, Hilpela P, Donner K et al: Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Proc Natl Acad Sci USA 1999; 96: 2305–2310.

    CAS  Article  Google Scholar 

  7. 7

    Lehtokari VL, Pelin K, Sandbacka M et al: Identification of 45 novel mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Hum Mutat 2006; 27: 946–956.

    CAS  Article  Google Scholar 

  8. 8

    Anderson SL, Ekstein J, Donnelly MC et al: Nemaline myopathy in the Ashkenazi Jewish population is caused by a deletion in the nebulin gene. Hum Genet 2004; 115: 185–190.

    CAS  Article  Google Scholar 

  9. 9

    Laing NG, Dye DE, Wallgren-Pettersson C et al: Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1). Hum Mutat 2009; 30: 1267–1277.

    CAS  Article  Google Scholar 

  10. 10

    Donner K, Ollikainen M, Ridanpaa M et al: Mutations in the beta-tropomyosin (TPM2) gene-a rare cause of nemaline myopathy. Neuromuscul Disord 2002; 12: 151–158.

    Article  Google Scholar 

  11. 11

    Monnier N, Lunardi J, Marty I et al: Absence of beta-tropomyosin is a new cause of Escobar syndrome associated with nemaline myopathy. Neuromuscul Disord 2009; 19: 118–123.

    Article  Google Scholar 

  12. 12

    Tajsharghi H, Ohlsson M, Lindberg C, Oldfors A : Congenital myopathy with nemaline rods and cap structures caused by a mutation in the beta-tropomyosin gene (TPM2). Arch Neurol 2007; 64: 1334–1338.

    Article  Google Scholar 

  13. 13

    Johnston JJ, Kelley RI, Crawford TO et al: A novel nemaline myopathy in the Amish caused by a mutation in troponin T1. Am J Hum Genet 2000; 67: 814–821.

    CAS  Article  Google Scholar 

  14. 14

    Sambuughin N, Yau KS, Olive M et al: Dominant mutations in KBTBD13, a member of the BTB/Kelch family, cause nemaline myopathy with cores. Am J Hum Genet 87: 842–847.

    CAS  Article  Google Scholar 

  15. 15

    Agrawal PB, Greenleaf RS, Tomczak KK et al: Nemaline myopathy with minicores caused by mutation of the CFL2 gene encoding the skeletal muscle actin-binding protein, cofilin-2. Am J Hum Genet 2007; 80: 162–167.

    CAS  Article  Google Scholar 

  16. 16

    Wallgren-Pettersson C : Congenital nemaline myopathy: a longitudinal study. University of Helsinki, Helsinki 1990.

    Google Scholar 

  17. 17

    Wallgren-Pettersson C, Pelin K, Hilpela P et al: Clinical and genetic heterogeneity in autosomal recessive nemaline myopathy. Neuromuscul Disord 1999; 9: 564–572.

    CAS  Article  Google Scholar 

  18. 18

    Wallgren-Pettersson C, Laing NG : Report of the 83rd ENMC International Workshop: 4th Workshop on Nemaline Myopathy, 22-24 September 2000, Naarden, The Netherlands. Neuromuscul Disord 2001; 11: 589–595.

    CAS  Article  Google Scholar 

  19. 19

    Agrawal PB, Strickland CD, Midgett C et al: Heterogeneity of nemaline myopathy cases with skeletal muscle alpha-actin gene mutations. Ann Neurol 2004; 56: 86–96.

    CAS  Article  Google Scholar 

  20. 20

    Jungbluth H, Sewry CA, Brown SC et al: Mild phenotype of nemaline myopathy with sleep hypoventilation due to a mutation in the skeletal muscle alpha-actin (ACTA1) gene. Neuromuscul Disord 2001; 11: 35–40.

    CAS  Article  Google Scholar 

  21. 21

    Nowak KJ, Wattanasirichaigoon D, Goebel HH et al: Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy. Nat Genet 1999; 23: 208–212.

    CAS  Article  Google Scholar 

  22. 22

    Hutchinson DO, Charlton A, Laing NG, Ilkovski B, North KN : Autosomal dominant nemaline myopathy with intranuclear rods due to mutation of the skeletal muscle ACTA1 gene: clinical and pathological variability within a kindred. Neuromuscul Disord 2006; 16: 113–121.

    Article  Google Scholar 

  23. 23

    Laing NG, Clarke NF, Dye DE et al: Actin mutations are one cause of congenital fibre type disproportion. Ann Neurol 2004; 56: 689–694.

    CAS  Article  Google Scholar 

  24. 24

    Clarke NF, Kolski H, Dye DE et al: Mutations in TPM3 are a common cause of congenital fiber type disproportion. Ann Neurol 2008; 63: 329–337.

    CAS  Article  Google Scholar 

  25. 25

    Lawlor MW, Dechene ET, Roumm E, Geggel AS, Moghadaszadeh B, Beggs AH : Mutations of tropomyosin 3 (TPM3) are common and associated with type 1 myofiber hypotrophy in congenital fiber type disproportion. Hum Mutat 2010; 31: 176–183.

    CAS  Article  Google Scholar 

  26. 26

    Hung RM, Yoon G, Hawkins CE, Halliday W, Biggar D, Vajsar J : Cap myopathy caused by a mutation of the skeletal alpha-actin gene. ACTA1. Neuromuscul Disord 2010; 20: 238–240.

    Article  Google Scholar 

  27. 27

    Lehtokari VL, Ceuterick-de Groote C, de Jonghe P et al: Cap disease caused by heterozygous deletion of the beta-tropomyosin gene. TPM2. Neuromuscul Disord 2007; 17: 433–442.

    Article  Google Scholar 

  28. 28

    Clarke NF, Domazetovska A, Waddell L, Kornberg A, McLean C, North KN : Cap disease due to mutation of the beta-tropomyosin gene (TPM2). Neuromuscul Disord 2009; 19: 348–351.

    Article  Google Scholar 

  29. 29

    Ohlsson M, Fidzianska A, Tajsharghi H, Oldfors A : TPM3 mutation in one of the original cases of cap disease. Neurology 2009; 72: 1961–1963.

    Article  Google Scholar 

  30. 30

    De Paula AM, Franques J, Fernandez C et al: A TPM3 mutation causing cap myopathy. Neuromuscul Disord 2009; 19: 685–688.

    Article  Google Scholar 

  31. 31

    Wallgren-Pettersson C, Lehtokari VL, Kalimo H et al: Distal myopathy caused by homozygous missense mutations in the nebulin gene. Brain 2007; 130: 1465–1476.

    Article  Google Scholar 

  32. 32

    Lehtokari VL, Pelin K, Herczegfalvi A et al: Nemaline myopathy caused by mutations in the nebulin gene may present as a distal myopathy. Neuromuscul Disord 2011; 21: 556–562.

    Article  Google Scholar 

  33. 33

    Sung SS, Brassington AM, Grannatt K et al: Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes. Am J Hum Genet 2003; 72: 681–690.

    CAS  Article  Google Scholar 

  34. 34

    Scacheri PC, Hoffman EP, Fratkin JD et al: A novel ryanodine receptor gene mutation causing both cores and rods in congenital myopathy. Neurology 2000; 55: 1689–1696.

    CAS  Article  Google Scholar 

  35. 35

    Clarke NF, Waddell LB, Cooper ST et al: Recessive mutations in RYR1 are a common cause of congenital fiber type disproportion. Hum Mutat 2010; 31: E1544–E1550.

    CAS  Article  Google Scholar 

  36. 36

    Clarke NF, Kidson W, Quijano-Roy S et al: SEPN1: associated with congenital fiber-type disproportion and insulin resistance. Ann Neurol 2006; 59: 546–552.

    CAS  Article  Google Scholar 

  37. 37

    Wallgren-Pettersson C, Laing NG : Report of the 70th ENMC International Workshop: nemaline myopathy, 11-13 June 1999, Naarden, The Netherlands. Neuromuscul Disord 2000; 10: 299–306.

    CAS  Article  Google Scholar 

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Acknowledgements

This work was supported by EuroGentest2 (Unit 2: ‘Genetic testing as part of health care’), a Coordination Action under FP7 (grant agreement number 261469), the European Society of Human Genetics, an Australian National Health and Medical Research Council (NH&MRC) Fellowship APP1002147, and an Australian Research Council (ARC) Future Fellowship FT100100734.

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Correspondence to Nigel G Laing.

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Nowak, K., Davis, M., Wallgren-Pettersson, C. et al. Clinical utility gene card for: Nemaline myopathy. Eur J Hum Genet 20, 713 (2012). https://doi.org/10.1038/ejhg.2012.70

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