Downloaded from jmg.bmj.com on January 12, 2013 - Published by group.bmj.com
Methods
SHORT REPORT
Rapid detection of genetic variants in hypertrophic cardiomyopathy by custom DNA resequencing array in clinical practice Siv Fokstuen,1 Analia Munoz,2 Paola Melacini,3 Sabino Iliceto,3 Andreas Perrot,4 ¨zcelik,4 Xavier Jeanrenaud,5 Claudine Rieubland,6 Martin Farr,7 Lothar Faber,7 Cemil O Ulrich Sigwart,8 Franc¸ois Mach,8 Rene´ Lerch,8 Stylianos E Antonarakis,1,2 Jean-Louis Blouin1 1
Correspondence to Dr Siv Fokstuen, Genetic Medicine, Centre Me´dical Universitaire, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland;
[email protected]
ABSTRACT Background Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease (1/500) and the most common cause of sudden cardiac death in young people. Pathogenic mutation detection of HCM is having a growing impact on the medical management of patients and their families. However, the remarkable genetic and allelic heterogeneity makes molecular analysis by conventional methods very time-consuming, expensive and difficult to realise in a routine diagnostic molecular laboratory. Method and results The authors used their custom DNA resequencing array which interrogates all possible singlenucleotide variants on both strands of all exons (n¼160), splice sites and 59 -untranslated region of 12 HCM genes (27 000 nucleotides). The results for 122 unrelated patients with HCM are presented. Thirty-three known or novel potentially pathogenic heterozygous single-nucleotide variants were identified in 38 patients (31%) in genes MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL3 and ACTC1. Conclusions Although next-generation sequencing will replace all large-scale sequencing platforms for inherited cardiac disorders in the near future, this HCM resequencing array is currently the most rapid, costeffective and reasonably efficient technology for first-tier mutation screening of HCM in clinical practice. Because of its design, the array is also an appropriate tool for initial screening of other inherited forms of cardiomyopathy.
Received 22 July 2010 Accepted 18 November 2010 Published Online First 14 January 2011
INTRODUCTION
Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland 2 Department of Genetic Medicine and Development, University of Geneva School of Medicine, Geneva, Switzerland 3 Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy 4 Cardiology and Experimental & Clinical Research Center, Charite´-Universitaetsmedizin Berlin, Germany 5 Cardiology, University Hospitals of Lausanne, Lausanne, Switzerland 6 Division of Human Genetics, Department of Paediatrics, University of Bern, Bern, Switzerland 7 Kardiologische Klinik, Herz- und Diabeteszentrum NRW, Bad-Oeynhausen, Germany 8 Cardiology, University Hospitals of Geneva, Geneva, Switzerland
The wide genetic heterogeneity of inherited cardiac disorders and the laborious, time-consuming and expensive serial molecular methods make it very difficult to unravel rapidly the causative mutation in a routine diagnostic molecular laboratory. The tremendous potential of genetic testing in clinical practice has therefore so far often been limited by the lack of efficient screening methods. Hypertrophic cardiomyopathy (HCM) represents the most common inherited cardiac disorder (prevalence of 1:500), and is also thought to be the primary cause of sudden cardiac death (SCD) in young adults and competitive athletes.1 The disease is usually familial, with an autosomal dominant mode of inheritance and a very wide inter- and intra-familial clinical variability.2 572
Over the last two decades, several hundred pathogenic mutations in at least 21 different HCM susceptibility genes have been identified.3 The most common form of HCM is caused by alterations in genes of the cardiac sarcomere. More recently, mutations in additional, non-sarcomeric genes have been identified encoding various calcium-handling (phospholamban, junctophilin-2) and Z-disc proteins (CSRP3-encoded muscle LIM protein, TCAP-encoded telethonin, LDB3-encoded LIM domain binding 3, ACTN2-encoded a-actinin 2, VCL-encoded vinculin/metavinculin, MYOZ2encoded myozenin-2).3 The majority of HCM mutations (87%) are single-nucleotide substitutions. The remaining 13% are small insertions or deletions, mainly in MYBPC3, or rare large deletions. In 3e5% of the families, double mutations have been found.4 These cases usually have a more severe clinical presentation. Interestingly, in most cases of digenic inheritance, one of the mutations usually involves MYBPC3.5 In order to overcome the laborious and expensive conventional mutation screening approach for such a heterogeneous condition, we have developed a 27 kbp custom DNA resequencing array for 12 HCM genes.6 The resequencing array is very efficient for the detection of nucleotide substitutions, but limited with regard to quantitative analysis of deletions/insertions. After the technical validation of the array in 2008,6 we analysed 122 unrelated patients with HCM from six different centres. Our results highlight that the HCM resequencing array is currently the most rapid, cost-effective and reasonably efficient method for mutation screening of HCM in clinical practice.
MATERIALS AND METHODS Patients With approval from the local ethics committee, we analysed 122 unrelated patients with HCM (64 with a positive family history and 58 with unremarkable or unknown family history) from six different centres. All patients (57 from Geneva, eight from Lausanne, one from Berne, Switzerland, 35 from Padua, Italy, 13 from Berlin, eight from Bad Oeynhausen, Germany) were selected by cardiologists according to the European diagnostic criteria for familial HCM,2 and written informed patient J Med Genet 2011;48:572e576. doi:10.1136/jmg.2010.083345
Downloaded from jmg.bmj.com on January 12, 2013 - Published by group.bmj.com
Methods consent was obtained. We included in this series of 122 patients the 38 patients previously reported on in 2008.6 For the assessment of unreported potentially pathogenic nonsynonymous variants, we used DNA samples from healthy Caucasian people as controls (96 samples from the CharitéUniversitätsmedizin Berlin, 150 samples from Padua). Cardiomyopathy was excluded by echocardiography in all of these controls, and their mean age was 70.8 years.
first evaluated by BLAST analysis in order to avoid eventual misinterpretation with the paralogous MYH6 gene. Previously unreported, non-synonymous confirmed sequence variants were further assessed for potential deleteriousness by screening a healthy control population, or more recently by consulting the 1000-Genomes browser (http://browser. 1000genomes.org/index.html).
Resequencing array
RESULTS HCM array sequence performance
DNA was isolated from lymphocytes using standard protocols. We analysed all 122 patients in Geneva by our previously described DNA resequencing array covering all coding exons (n¼160), splice-site junctions, and 59 -untranslated region (UTR) of both strands of 12 HCM genes (MYH7, MYBPC3, TNNT2, TPM1, TNNI3, MYL3, MYL2, CSRP3, PLN, ACTC1, TNNC1, PRKAG2).6 The sequence was determined on both strands. Putative functional DNA sequence variants were all confirmed by Sanger sequencing. All variants found in gene MYH7 were
After hybridisation of the 122 arrays, we had a mean nucleotide call rate of 98.4% using Affymetrix GDAS/GSEQ software pipeline (range 93.0e99.9%). We observed a constant improvement of the call rate as the number of experiments increased. We had w1.6% of unread sequence (no calls) per array, mainly observed in regions with two to six consecutive C bases, reflecting suboptimal hybridisation of CpC-rich areas. So far, no HCM mutations have been reported in such CpC-rich regions (HGMD, http://www.hgmd.org). The following exons were
Table 1
Heterozygous known or novel potentially pathogenic variants Control population studies (mutant/ normal alleles)
Gene (NCBI reference)
Exon/ area
Nucleotide change
Amino acid change
MYH7 (NM_000257.2)
39 37 36 32 30 23 22 19 14
c.5779A/T c.5326A/G c.1758c/T c.4471A>T c.4130C/T c.2770G/A c.2549C/A c.2156G/A c.1370T/C
p.lle1927Phe p.Ser1776Gly p.Thr1759Met p.Ser1491Cys p.Thr1377Met p.Glu924Lys p.Ala850Asp p.Arg719Gln p.Ile457Thr
11 5 59 -UTR 31 31
c.958G/A c.427C/G c. 1-2127A/T c.3694C/T c.3752A/G
p.Val320Met p.Arg143Gln e p.Gln1233X p.Tyr1250Cys
28 25 25 20 19 17
c.3327+2T/C c.2902+1G/T c.2825C/T c.2111C/A c.1925-2A/G c.1825G/C
p.Arg943X p.Thr704Lys
c.1484G/A c.1505G/A c.1624G/C c.1223+1G/A c.1090G/A c.646G/A c.242G/A c.170C/A c.832A/G c.557G/A c.433C/T c.1019T/A
p.Arg495Gln p.Arg502Gln p.Glu542Gln Not determined p.Ala364Thr p.Ala216Thr p.Arg81His p.Ala57Asp p.Arg278Cys p.Arg186Gln p.Arg145Trp p.Ser340Thr
0/192 0/192
ACTC1 (NM_005159.4)
15 15 15 12 11 5 3 3 15 8 7 6
TPM1 (NM_000366.5) PLN (NM_002667.3)
1 1
c.61G/C c.1-10662A/C
p.Arg21His 59 -UTR
0/192 22/170
MYBPC3 (NM_000256.3)
MYL3 (NM_000258.1) TNNT2 (NM_000364.2) TNNI3 (NM_000363.4)
0/192 0/192 2/190
0/192
0/600
0/192
0/600 0/192
p.Asp609His
Conclusion Novel mutation Known mutation Novel mutation Novel variant Known mutation Known mutation Novel mutation Known mutation Novel variant, absent in 1000 genomes (CEU)* Known mutation Known mutation Novel mutation Known mutation Novel variant, absent in 1000 genomes (CEU)* Novel mutation Novel mutation Known mutation Novel mutation Novel mutation Novel variant, absent in 1000 genomes (CEU)* Known mutation Known mutation Known mutation Novel variant Known mutation Novel mutation Novel mutation Known mutation Known mutation Known mutation Known mutation Novel variant, absent in 1000 genomes (CEU)y Novel mutation Novel variant
Reference Blair et al 20027
Richard et al 20038 Watkins et al 19929 Consevage et al 199410
Havndrup et al 200311 Kimura et al 200112 Erdmann et al 200113
Alders et al 200314
Niimura et al 199815 Niimura et al 199815 Carrier et al 199716 Melacini et al 201017
Lee et al 200118 Watkins et al 199519 Richard et al 20038 Mogensen et al 200320
Number of patients 1 1 1 1 3 1 1 1 1 1 1 1 1 1 1 1 2 1 1 1 1 2 1 1 2 1 1 1 1 1 1 1 1 4
*Probably damaging by PolyPhen (V1). yPossibly damaging by PolyPhen (V1). CEU, human population originating from Northwestern Europe; PolyPhen (V1), polymorphism phenotyping version 1.
J Med Genet 2011;48:572e576. doi:10.1136/jmg.2010.083345
573
Downloaded from jmg.bmj.com on January 12, 2013 - Published by group.bmj.com
Methods particularly rich in such unread nucleotides: MYBPC3, exon 3; TPM1, exon 4; ACTC1, exon 1; PRKAG2, exon 3.
Variants identified by the HCM array In total, we identified 34 heterozygous known or novel potentially pathogenic variants in 42/122 patients (34%) (table 1). Sixteen (two nonsense variants and 14 missense variants) were recorded in the HGMD database (table 1). Four variants were novel splice-site mutations in MYBPC3. Twelve missense variants and two 59 -UTR variants were novel changes. Eleven of the novel missense variants and the MYH7 59 -UTR change were either absent from at least 192 Caucasian control chromosomes or were not recorded in the 1000-Genomes database. Sequence alignment among different mammals and vertebrates revealed that they affect highly conserved residues. Furthermore, we identified five known non-synonymous single-nucleotide polymorphisms (SNPs) and 30 known synonymous SNPs (table 2). Four of the known non-synonymous SNPs were initially reported as disease-causing variants.20e23 Although it now seems clear that they are common variants in the general population, a modifying role in the pathogenesis of HCM cannot be ruled out. The role of the variant p.Ser175Gly in exon 33 of MYH7 (table 2) is less clear. As reported in dbSNP (rs2754155), its frequency is very low (MAF¼0.006). According to these results, at least 33 of the 69 heterozygous variants can be considered as known pathogenic mutations or as Table 2
novel very likely pathogenic variants. They were found in 38 different probands, which corresponds to a total mutation detection rate of 31% (38/122). Twenty-eight had a positive family history of SCD or HCM. Considering only the familial cases, the mutation detection rate was 45% (28/62). We did not find any patient with more than one mutation. We observed considerable clinical variability with regard to age at diagnosis and course of the disease. However, our cohort is too small to establish meaningful genotypeephenotype correlations. One patient with early-onset HCM and a positive family history of SCD had a potentially pathogenic variant in 59 -UTR of MYH7 (c.1-2127A/T, NM_000257.2). To our knowledge, no pathogenic variant has so far been reported in the 59 -UTR of a sarcomeric gene. Our variant was recorded as a SNP (rs72686233) in March 2006 assembly and in dbSNP(130). However, this 59 -UTR variant was omitted from the dbSNP(131). According to the UCSC browser, it appears to be conserved down to Opossum, and it is predicted to be at a promoter histone mark (H3K4Me3) site in HepG2 cells.
DISCUSSION Because of extensive genetic and allelic heterogeneity, molecular diagnosis of HCM by conventional serial methods is problematic. The usual experience of the patient and his/her family is that a few laboratories provide a small number of tests with a long, often unpredictable, turnaround time and very high
Variants known as synonymous or non-synonymous single-nucleotide polymorphisms
Gene
Exon/area
dbSNP ID
Amino acid change
HCM cohort carriers (n)
HCM cohort frequency
Minor allele population
ACTC CSRP3 CSRP3 CSRP3 MYBPC3 MYBPC3 MYBPC3 MYBPC3 MYBPC3 MYBPC3 MYH7 MYH7 MYH7 MYH7 MYH7 MYH7 MYH7 MYH7 MYH7 MYH7 MYH7 MYH7 MYH2 TNNC1 TNNI3 TNNI3 TNNI3 TNNI3 TNNT2 TNNT2 TNNT2 TNNT2 TNNT2 TPM1 TPM1
X5 X1 X3 X4 X23 X24 X28 X4 X6 X7 X3 X7 X8 X11 X12 X12 X12 X13 X16 X24 X33 X35 X3 59 -UTR X1 X3 X5 X7 X1 X11 X13 X7 X8 X6 X6
rs2307493 rs12222160 rs7124801 rs13451 rs3729953 rs35078470 rs1052373 rs3218719 rs3729989 rs11570058 rs2069540 rs2069541 rs2069542 rs2231124 rs735712 rs735711 rs2231126 rs3218714 rs2069543 rs7157716 rs2754155 rs3729830 rs2301610 rs1035002 rs12973773 rs3729836 rs3729711 rs3729841 rs12568262 rs11810834 rs3730238 rs3729845 rs3729547 rs1071646 rs28730801
e e e e e p.Val896Met e e p.Ser236Gly e e e e e e e e p.Arg403Trp e e p.Ser175Gly e e e e e e e e e p.Lys253Arg e e e e
2 5 1 20 9 1 57 6 6 13 82 4 32 6 15 6 18 43 1 59 1 19 15 6 3 36 5 1 6 11 6 6 48 67 19
0.017 0.042 0.008 0.167 0.075 0.008 0.475 0.050 0.050 0.108 0.683 0.033 0.267 0.050 0.125 0.050 0.150 0.358 0.008 0.492 0.008 0.158 0.125 0.050 0.025 0.300 0.042 0.008 0.050 0.092 0.050 0.050 0.400 0.558 0.158
0.064e0.080 0.017e0.150 0.000e0.133 0.000e0170 0.014e0.057 0.013 0.2e0.5 0.000e0.111 0.011e0.167 0.000e0.167 0.300e0.727 0.000-0.031 0.021e0.0620 0.000e0.040 0.000e125 0.000e0.283 0.050e0.391 unknown 0.000e0.071 0.125e0.794 0.000e0.006 0.000e0.220 0.050e0.232 0.083 Unknown 0.125e0.523 0.011e0.097 0.033e0.117 0.009e0.283 0.005e0.167 0.008e0.205 0.018e0.240 0.083e0.456 0.045e0.390 Unknown
574
Reference
Moolman et al 199921
Hayashi et al 200423
Dausse et al 199322
Mogensen et al 200320
J Med Genet 2011;48:572e576. doi:10.1136/jmg.2010.083345
Downloaded from jmg.bmj.com on January 12, 2013 - Published by group.bmj.com
Methods costs. Systematic genotyping of nine sarcomeric genes revealed that more than 80% of the disease-causing mutations are found in MYH7, MYBPC3 and TNNT2.8 Thus, genetic testing in an index case usually starts with mutation analysis of these three most commonly affected genes eventually followed, depending on the facilities of the laboratories, by the analysis of other sarcomeric genes. To overcome the great genetic heterogeneity of HCM and to improve the diagnostic possibilities, we developed a 12-gene DNA custom resequencing array for HCM.6 In the same year, Waldmüller et al published the design of a resequencing array covering the three most commonly affected HCM genes, MYH7, MYBPC3 and TNNT2.24 Shortly after our publication, a few companies (Harvard Partners, Correlagen, PGxHealth and GeneDx) offered testing for up to 17 HCM genes by array technology, and a custom resequencing array containing 19 genes for dilated cardiomyopathy has recently been published.25 To further validate our HCM array for initial mutation screening in clinical practice, we analysed 122 patients with HCM and obtained a total mutation detection rate of 31% (38/ 122), which is lower than the mean total mutation detection rate of 42.4% (range13.3e60.9%).26 One explanation of the lower detection rate is that a number of variants initially reported as disease-causing mutations are now thought to be common SNPs. We found four such variants in 13 patients. The absence of pathogenic mutations in the remaining probands may be due to phenocopies of HCM (eg, Danon disease or AndersonFabry disease), mutations in a gene or sequence not tiled on the HCM array, the involvement of additional, as yet unidentified, genes for HCM, or the inability of the resequencing arrays to detect insertions/deletions. This limitation of the resequencing array technology lowers our mutation detection rate, as insertions/deletions account for up to 13% of all HCM mutations. They occur mainly in MYBPC3 (32% of all mutations; HGMD), which actually harbour w30% of all known HCM mutations. Finally, mutations may be hidden by a region of hybridisation failure, which occurred in 1.6% of the sequences. These results show that the HCM array is highly appropriate for first-tier mutation screening in clinical practice, mostly because of the considerable gain in time, labour and cost. The complete analysis can be performed within a few weeks. Several samples can be analysed simultaneously, and the actual cost per patient (currently US$1500) is considerably lower than for Sanger sequencing of 12 HCM genes. The analysis not only identifies the causative mutation but also modifying SNPs, which may be of importance in improving the predictive value of the genotype. It is, furthermore, important to point out the small size of our cohort and to suggest that the true clinical sensitivity of the HCM array will emerge over time. In patients with no mutation identified by our HCM array, an eventual phenocopy should be considered, and MYBPC3 could be reanalysed by Sanger sequencing in order to unravel possible small insertions/deletions. Finally, targeted next-generation sequencing of HCM genes will become an affordable option.27 As mutations in the same disease gene can cause different types of primary cardiomyopathy, the HCM resequencing array may also be used for initial screening of other forms of cardiomyopathy, such as dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM) or left ventricular non-compaction cardiomyopathy (LVNC). The HCM array covers nine DCM genes (ACTC1, MYH7, MYBPC3, TNNT2, TPM1, TNNC1, TNNI3, CSRP3, PLN), three RCM genes (MYH7, TNNT2, TNNI3) and three LVNC genes (MYH7, TNNT2 and ACTC1). So far, no published study has analysed the 12 genes present on the J Med Genet 2011;48:572e576. doi:10.1136/jmg.2010.083345
HCM array for patients with DCM, RCM or LVNC. Thus, it is not possible to derive an accurate sensitivity for these disorders, but the array can be proposed as a first, rapid and cheap mutation screening method for the index patients. There is no doubt that next-generation sequencing will replace all large-scale sequencing platforms, as it already has been demonstrated in a few instances.27 28 However, these technologies are currently still expensive. For most diagnostic applications, targeted analysis of well-known pathogenic genes is at present preferred, as the interpretation of sequence variants is less complex than in whole exome sequencing, and it overcomes limitations in computational power as well as ethical concerns. The custom array sequencing technology has been validated for clinical application29 and provides a rapid, reasonably efficient and economically competitive method for molecular first-tier screening of Mendelian heterogeneous disorders such as HCM in clinical practice. It can currently be considered the method of choice until next-generation sequencing is routinely implemented in diagnostic laboratories. Acknowledgements We acknowledge P Descombes, C Barraclough, D Chollet, M Docquier from the Genomic Platform of Frontiers in Genetics, University School of Medicine, Geneva, Switzerland for technical support, and L Gwanmesia for proof reading. This study was supported by grants from the University Hospitals of Geneva, the Novartis Foundation Switzerland, the Valentine Gerbex-Bourget Foundation of Geneva, ACLON Finance Foundation Geneva and the Swiss Heart Foundation (to SF, JLB), a research grant from the Charite´-Universita¨tsmedizin Berlin (to AP) and by the Italian Ministry for Scientific and Technologic Research (PM). Competing interests None. Ethics approval This study was conducted with the approval of the University Hospitals of Geneva. Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES 1.
2.
3. 4. 5. 6.
7. 8.
9. 10.
Maron BJ, Olivotto I, Spirito P, Casey SA, Bellone P, Gohman TE, Graham KJ, Burton DA, Cecchi F. Epidemiology of hypertrophic cardiomyopathy-related death: revisited in a large non-referral-based patient population. Circulation 2000;102:858e64. Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ, Seidman CE, Shah PM, Spencer WH 3rd, Spirito P, Ten Cate FJ, Wigle ED; American College of Cardiology/European Society of Cardiology Clinical Expert Consensus Document on Hypertrophic Cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. Eur Heart J 2003;24:1965e91. Kimura A. Molecular basis of hereditary cardiomyopathy: abnormalities in calcium sensitivity, stretch response, stress response and beyond. J Hum Genet 2010;55:81e90. Ingles J, Doolan A, Chiu C, Seidman J, Seidman C, Semsarian C. Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling. J Med Genet 2005;42:e59. Van Driest SL, Vasile VC, Ommen SR, Will ML, Tajik AJ, Gersh BJ, Ackerman MJ. Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol 2004;44:1903e10. Fokstuen S, Lyle R, Munoz A, Gehrig C, Lerch R, Perrot A, Osterziel KJ, Geier C, Beghetti M, Mach F, Sztajzel J, Sigwart U, Antonarakis SE, Blouin JL. A DNA resequencing array for pathogenic mutation detection in hypertrophic cardiomyopathy. Hum Mutat 2008;29:879e85. Blair E, Redwood C, de Jesus Oliveira M, Moolman-Smook JC, Brink P, Corfield VA, Ostman-Smith I, Watkins H. Mutations of the light meromyosin domain of the betamyosin heavy chain rod in hypertrophic cardiomyopathy. Circ Res 2002;90:263e9. Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A, Isnard R, Dubourg O, Burban M, Gueffet JP, Millaire A, Desnos M, Schwartz K, Hainque B, Komajda M. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 2003;107:2227e32. Watkins H, Rosenzweig A, Hwang DS, Levi T, McKenna W, Seidman CE, Seidman JG. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med 1992;326:1108e14. Consevage MW, Salada GC, Baylen BG, Ladda RL, Rogan PK. A new missense mutation, Arg719Gln, in the beta-cardiac heavy chain myosin gene of patients with familial hypertrophic cardiomyopathy. Hum Mol Genet 1994;3:1025e6.
575
Downloaded from jmg.bmj.com on January 12, 2013 - Published by group.bmj.com
Methods 11.
12. 13.
14.
15.
16.
17. 18.
19.
Havndrup O, Bundgaard H, Andersen PS, Allan Larsen L, Vuust J, Kjeldsen K, Christiansen M. Outcome of clinical versus genetic family screening in hypertrophic cardiomyopathy with focus on cardiac beta-myosin gene mutations. Cardiovasc Res 2003;57:347e57. Kimura A, Ito-Satoh M, Hayashi T, Takahashi M, Arimura T. Molecular etiology of idiopathic cardiomyopathy in Asian populations. J Cardiol 2001;37(Suppl 1):139e46. Erdmann J, Raible J, Maki-Abadi J, Hummel M, Hammann J, Wollnik B, Frantz E, Fleck E, Hetzer R, Regitz-Zagrosek V. Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy. J Am Coll Cardiol 2001;38:322e30. Alders M, Jongbloed R, Deelen W, van den Wijngaard A, Doevendans P, Ten Cate F, Regitz-Zagrosek V, Vosberg HP, van Langen I, Wilde A, Dooijes D, Mannens M. The 2373insG mutation in the MYBPC3 gene is a founder mutation, which accounts for nearly one-fourth of the HCM cases in the Netherlands. Eur Heart J 2003;24:1848e53. Niimura H, Bachinski LL, Sangwatanaroj S, Watkins H, Chudley AE, McKenna W, Kristinsson A, Roberts R, Sole M, Maron BJ, Seidman JG, Seidman CE. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med 1998;338:1248e57. Carrier L, Bonne G, Bahrend E, Yu B, Richard P, Niel F, Hainque B, Cruaud C, Gary F, Labeit S, Bouhour JB, Dubourg O, Desnos M, Hagege AA, Trent RJ, Komajda M, Fiszman M, Schwartz K. Organization and sequence of human cardiac myosin binding protein C gene (MYBPC3) and identification of mutations predicted to produce truncated proteins in familial hypertrophic cardiomyopathy. Circ Res 1997;80:427e34. Melacini P, Basso C, Angelini A, Calore C, Bobbo F, Tokajuk B, Bellini N, Smaniotto G, Zucchetto M, Iliceto S, Thiene G, Maron BJ. Clinicopathological profiles of progressive heart failure in hypertrophic cardiomyopathy. Eur Heart J 2010;31:2111e23. Lee W, Hwang TH, Kimura A, Park SW, Satoh M, Nishi H, Harada H, Toyama J, Park JE. Different expressivity of a ventricular essential myosin light chain gene Ala57Gly mutation in familial hypertrophic cardiomyopathy. Am Heart J 2001;141:184e9. Watkins H, McKenna WJ, Thierfelder L, Suk HJ, Anan R, O’Donoghue A, Spirito P, Matsumori A, Moravec CS, Seidman JG, Seidman CE. Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. N Engl J Med 1995;332:1058e64.
20. 21.
22.
23.
24. 25.
26. 27.
28. 29.
Mogensen J, Kubo T, Duque M, Uribe W, Shaw A, Murphy R, Gimeno JR, Elliott P, McKenna WJ. Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J Clin Invest 2003;111:209e16. Moolman-Smook JC, De Lange WJ, Bruwer EC, Brink PA, Corfield VA. The origins of hypertrophic cardiomyopathy-causing mutations in two South African subpopulations: a unique profile of both independent and founder events. Am J Hum Genet 1999;65:1308e20. Dausse E, Komajda M, Fetler L, Dubourg O, Dufour C, Carrier L, Wisnewsky C, Bercovici J, Hengstenberg C, al-Mahdawi S, Isnard R, Hagege A, Bouhour JB, Desnos M, Beckmann J, Weissenbach J, Schwartz K, Guicheney P. Familial hypertrophic cardiomyopathy. Microsatellite haplotyping and identification of a hot spot for mutations in the beta-myosin heavy chain gene. J Clin Invest 1993;92:2807e13. Hayashi T, Arimura T, Itoh-Satoh M, Ueda K, Hohda S, Inagaki N, Takahashi M, Hori H, Yasunami M, Nishi H, Koga Y, Nakamura H, Matsuzaki M, Choi BY, Bae SW, You CW, Han KH, Park JE, Knoll R, Hoshijima M, Chien KR, Kimura A. Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. J Am Coll Cardiol 2004;44:2192e201. Waldmuller S, Muller M, Rackebrandt K, Binner P, Poths S, Bonin M, Scheffold T. Array-based resequencing assay for mutations causing hypertrophic cardiomyopathy. Clin Chem 2008;54:682e7. Zimmerman RS, Cox S, Lakdawala NK, Cirino A, Mancini-DiNardo D, Clark E, Leon A, Duffy E, White E, Baxter S, Alaamery M, Farwell L, Weiss S, Seidman CE, Seidman JG, Ho CY, Rehm HL, Funke BH. A novel custom resequencing array for dilated cardiomyopathy. Genet Med 2010;12:268e78. Van Driest SL, Ommen SR, Tajik AJ, Gersh BJ, Ackerman MJ. Yield of genetic testing in hypertrophic cardiomyopathy. Mayo Clin Proc 2005;80:739e44. Blouin JL, Iseli C, Robyr D, Munoz A, Antonarakis SE, Fokstuen S. Next-GenerationSequencing as a promising diagnostic tool in heterogeneous genetic conditions: the example of Hypertrophic Cardiomyopathy. In: ESoH Genetics, ed. European Human Genetics Conference. Vienna, Austria: Nature publishing group, 2009:16. Morgan JE, Carr IM, Sheridan E, Chu CE, Hayward B, Camm N, Lindsay HA, Mattocks CJ, Markham AF, Bonthron DT, Taylor GR. Genetic diagnosis of familial breast cancer using clonal sequencing. Hum Mutat 2010;31:484e91. Kothiyal P, Cox S, Ebert J, Aronow BJ, Greinwald JH, Rehm HL. An overview of custom array sequencing. Curr Protoc Hum Genet 2009;Chapter 7:Unit 7 17.
Correction
576
J Med Genet August 2011 Vol 48 No 8
Downloaded from jmg.bmj.com on January 12, 2013 - Published by group.bmj.com
Rapid detection of genetic variants in hypertrophic cardiomyopathy by custom DNA resequencing array in clinical practice Siv Fokstuen, Analia Munoz, Paola Melacini, et al. J Med Genet 2011 48: 572-576 originally published online January 14, 2011
doi: 10.1136/jmg.2010.083345
Updated information and services can be found at: http://jmg.bmj.com/content/48/8/572.full.html
These include:
References
This article cites 27 articles, 10 of which can be accessed free at: http://jmg.bmj.com/content/48/8/572.full.html#ref-list-1
Email alerting service
Topic Collections
Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Articles on similar topics can be found in the following collections Cardiomyopathy (73 articles) Epidemiology (541 articles) Genetic screening / counselling (740 articles)
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions
To order reprints go to: http://journals.bmj.com/cgi/reprintform
To subscribe to BMJ go to: http://group.bmj.com/subscribe/
