Clinical Utility Gene Card For: Nemaline Myopathy
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European Journal of Human Genetics (2012) 20; doi:10.1038/ejhg.2012.70 & 2012 Macmillan Publishers Limited All rights reserved 1018-4813/12 www.nature.com/ejhg CLINICAL UTILITY GENE CARD Clinical utility gene card for: Nemaline myopathy Kristen J Nowak1,2,5, Mark R Davis3,5, Carina Wallgren-Pettersson4, Phillipa J Lamont3 and Nigel G Laing*,1,2 European Journal of Human Genetics (2012) 20, doi:10.1038/ejhg.2012.70; published online 18 April 2012 1. DISEASE CHARACTERISTICS (for example, cores, actin aggregates, intranuclear rods).9 Of these, 1.1 Name of the disease (synonyms) most mutations are dominant, missense, and have arisen de novo.9 Nemaline myopathy (NEM1 – NEM7) About 10% are recessive mutations, and are genetic or functional null Includes nemaline myopathy with excess thin filaments/actin mutations.9 Dominant inheritance is less common, and only seen in aggregates; nemaline myopathy with cores; nemaline myopathy with families with a milder phenotype.9 intranuclear rods; and Amish nemaline myopathy. TPM2 1.2 OMIM# of the disease Two heterozygous, dominant missense mutations causing nemaline myopathy are known.10 Also a homozygous null mutation in a patient NEM1 – 609284; NEM2 – 256030; NEM3 – 161800; NEM4 – 609285; 11 NEM5 – 605355; NEM6 – 609273; NEM7 – 610687. with nemaline and Escobar syndrome, and a dominant heterozygous mutation in a mother with nemaline myopathy and her daughter with cap myopathy.12 1.3 Name of the analysed genes or DNA/chromosome segments Slow muscle a-tropomyosin (TPM3) – NEM1. TNNT1 Nebulin (NEB) – NEM2. A recessive nonsense founder mutation is present in the Old Order Skeletal muscle a-actin (ACTA1) – NEM3. Amish population. This produces characteristic progressive nemaline b-tropomyosin (TPM2) – NEM4. myopathy with tremors and contractures.13 Slow muscle troponin-T (TNNT1) – NEM5. Kelch-repeat and BTB (POZ) Domain containing 13 (KBTBD13) – KBTBD13 NEM6. Three dominant missense mutations have been identified; however, Skeletal muscle cofilin (CFL2) – NEM7. not all mutation carriers in the families exhibited skeletal muscle weakness.14 1.4 OMIM# of the gene(s) TPM3 ¼ *191030; NEB ¼ *161650; ACTA1 ¼ *102610; TPM2 ¼ CFL2 *190990; TNNT1 ¼ *191041; KBTBD13 ¼ *613727; CFL2 ¼ *601443. A single homozygous missense mutation has been identified in one family.15 1.5 Mutational spectrum 1.6 Analytical methods TPM3 The main analytical method is bi-directional Sanger sequencing of the Mainly dominant, missense mutations,1,2 however some recessive entire coding region of the individual genes. If the family structure is mutations have been described.3,4 A 1 bp recessive deletion occurs as a amenable, linkage analysis for NEB may be useful to pre-screen, founder mutation in the Turkish population.5 owing to the large size of the gene. Next-generation sequencing will NEB allow for simultaneous analysis of all genes in a patient. All the over 140 mutations identified to date are recessive and the patients usually are compound heterozygous. The majority of the 1.7 Analytical validation mutations are either frameshift or nonsense mutations, but also Mutations should be confirmed by resequencing using a fresh dilution missense mutations, and point mutations and deletions affecting of genomic DNA. 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 1.8 Estimated frequency of the disease approximately 1 in 108.8 (incidence at birth (‘birth prevalence’) or population prevalence) For the most part, the frequency of the disease is unknown. In ACTA1 Finland, the birth prevalence has been estimated to be 0.02 per 1000 Over 200 different mutations identified, with the majority causing live births.16 Dominant mutations in ACTA1 and recessive mutations nemaline myopathy, and nemaline myopathy with other features in NEB are the most common causes of NEM.17,18 1Centre for Medical Research, The University of Western Australia, Nedlands, Western Australia, Australia; 2The Western Australian Institute for Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia; 3Neurogenetic Laboratory, Department of Anatomical Pathology, Royal Perth Hospital, Perth, Western Australia, Australia; 4The Folkha¨lsan Institute of Genetics and Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland 5Equal first authors. *Correspondence: Professor NG Laing, The Western Australian Institute for Medical Research, Ground Floor, B Block, QEII Medical Centre, Hovea Lane, Nedlands, Western Australia 6009, Australia. Tel: +61 8 9346 4611, Fax: +61 8 9346 1818, E-mail: [email protected] Clinical Utility Gene Card 1.9 If applicable, prevalence in the ethnic group of investigated 2.5 Positive clinical predictive value person (life-time risk to develop the disease if the test is positive) Recessive founder mutations are known to exist in particular genes in Near 100%. Potential incomplete penetrance has been suggested for specific populations: TNNT1 in the Amish;13 NEB in the Ashkenazi certain ACTA1 variants.19 Jewish;8 ACTA1 in the Pakistani community in England; and in French and Spanish Roma;9 and TPM3 in the Turkish population.5 2.6 Negative clinical predictive value These specific cases aside, no clear differences exist in prevalence rates (probability not to develop the disease if the test is negative) between different ethnicities. Assume an increased risk based on family history for a non-affected person. Allelic and locus heterogeneity may need to be considered. 1.10 Diagnostic setting Index case in that family had been tested: Approximately 100%. Yes No Index case in that family had not been tested: No predictive tests are usually performed in such cases. A. (Differential) diagnostics 2 & B. Predictive testing 2 & 3. CLINICAL UTILITY C. Risk assessment in relatives 2 & 3.1 (Differential) diagnosis: The tested person is clinically affected D. Prenatal 2 & (To be answered if in 1.10 ‘A’ was marked) 3.1.1 Can a diagnosis be made other than through a genetic test? 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. No (continue with 3.1.4) Yes 2 2. TEST CHARACTERISTICS Clinically 2 Imaging 2MRI imaging of muscles may be able to direct Genotype or disease A: True positives C: False negative mutation testing, especially in uncertain/ambiguous B: False positives D: True negative cases. Present Absent Endoscopy & Biochemistry & Test Electrophysiology & 2 Positive A B Sensitivity: A/(A þ C) Other Histopathology and electron microscopy of skeletal Specificity: D/(D þ B) (please describe) muscle. Besides ‘pure’ nemaline myopathy, mutations in Negative C D Positive predictive value: A/(A þ B) the known NEM genes have also been described in Negative predictive value: D/(C þ D) association with other congenital myopathies, which clini- cally can appear similar to nemaline myopathy. Pathologi- cally, some patients have features in addition to nemaline 2.1 Analytical sensitivity bodies (eg, cores20). Patients with mutations in the NEM (proportion of positive tests if the genotype is present) genes may also have a myopathy without nemaline bodies, 100% and may be diagnosed as having actin myopathy (ACTA121), intranuclear rod myopathy (eg, ACTA122), 2.2 Analytical specificity congenital fibre type disproportion (OMIM #255310; (proportion of negative tests if the genotype is not present) ACTA1;23 TPM324,25), cap disease (ACTA1;26 TPM2;27,28 29,30 31,32 100% TPM3 ) and distal myopathy (NEB ). Mutations in TPM2 and other nemaline myopathy genes can also cause 33 2.3 Clinical sensitivity distal arthrogryposis. Mutations in other genes may also be associated with these additional phenotypes (proportion of positive tests if the disease is present) (eg, congenital fibre type disproportion and nemaline The clinical sensitivity can be dependent on variable factors such as myopathy with cores can be caused by mutations in age or family history. In such cases a general statement should be RYR134,35 and SEPN1.36 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, 3.1.2 Describe the burden of alternative diagnostic methods to the full screening of all known nemaline myopathy genes is rarely carried patient out. If full screening were to be undertaken, it may be estimated that Nemaline myopathy requires both a clinical and, significantly, a approximately 75% of patients would have an identifiable mutation.6,9 histopathological/electron microscopic diagnosis. Therefore, a thorough assessment including a detailed evaluation of clinical and 2.4 Clinical specificity pathological features should be performed before genetic testing. As (proportion of negative tests if the disease is not present) such, histopathology and electron microscopy are not diagnostic The clinical specificity can be dependent on variable factors such as alternatives, rather prerequisites to genetic testing. Nevertheless, age or family history. In such cases, a general statement should be muscle biopsy is an invasive procedure, and appropriate histological given, even if a quantification can only be made case by case. and electron microscopic examination requires proximity to a Probably 100%. specialised laboratory set up. European Journal of Human