Using exome sequencing to identify the cause of myocardial hypertrophy in a Chinese family

Pu,Tian; Guo,Qianqian; Cao,Ruixue; Xu,Rang; Sun,Kun; Chen,Sun

doi:10.3892/mmr.2015.3818

Using exome sequencing to identify the cause of myocardial hypertrophy in a Chinese family

Authors:
- Tian Pu
- Qianqian Guo
- Ruixue Cao
- Rang Xu
- Kun Sun
- Sun Chen
View Affiliations

Affiliations: Department of Pediatric Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China, Scientific Research Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China
Published online on: May 22, 2015 https://doi.org/10.3892/mmr.2015.3818
Pages: 3662-3666

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Myocardial hypertrophy is a common feature of numerous diseases. It is important to distinguish between these diseases in order to enable accurate diagnosis and the administration of appropriate therapy. Using whole‑exome sequencing, the present study aimed to identify a pathogenic mutation in a Chinese family, which may lead to cardiac hypertrophy and Wolff‑Parkinson‑White syndrome. The proband from the Chinese family exhibited left ventricular hypertrophy and pre-excitation with a short PR interval. DNA was extracted from peripheral blood obtained from the subject family, and exome sequencing was performed in the proband. Polymerase chain reaction and direct sequencing were used to confirm the presence of a mutation, and confirmed that the pathogenic mutation was 5'-AMP‑activated protein kinase subunit γ2 (PRKAG2) (p.R302Q), which has been previously reported in a family with an inherited from of WPW. A stop‑gain mutation in urotensin II receptor (UTS2R) (p.S241X), which is associated with congestive heart failure, was identified in the proband and in one other affected family member. It is important to identify the causes of myocardial hypertrophy, in order to provide a theoretical basis with which to improve clinical diagnosis and the assessment of prognosis. The results of the present study suggest that if a patient has myocardial hypertrophy with a short PR interval on electrocardiogram, a mutation in the PRKAG2 gene should be considered. In conclusion, exome sequencing methods may assist with the identification of causative genes in myocardial hypertrophy, as well as genes that are associated with an increased risk of sudden cardiac death.

View Figures

View References

1	Marin-Garcia J, Ananthakrishnan R, Goldenthal MJ, Filiano JJ and Perez-Atayde A: Cardiac mitochondrial dysfunction and DNA depletion in children with hypertrophic cardiomyopathy. J Inherit Metab Dis. 20:674–680. 1997. View Article : Google Scholar : PubMed/NCBI
2	Scaglia F, Towbin JA, Craigen WJ, et al: Clinical spectrum, morbidity, and mortality in 113 pediatric patients with mitochondrial disease. Pediatrics. 114:925–931. 2004. View Article : Google Scholar : PubMed/NCBI
3	Erdmann J, Daehmlow S, Wischke S, et al: Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy. Clin Genet. 64:339–349. 2001. View Article : Google Scholar
4	Richard P, Charron P, Carrier L, et al: Distribution of disease genes in 102 genotyped families with hypertrophic cardiomyopathy. Circulation. 104:521. 2001.
5	Sachdev B, Takenaka T, Teraguchi H, Tei C, Lee P, McKenna WJ and Elliott PM: Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy. Circulation. 105:1407–1411. 2002. View Article : Google Scholar : PubMed/NCBI
6	Patra S, Subramaniun A, Mahimaiha J, Sastry UM and Nanjappa MC: Apical hypertrophic cardiomyopathy in an infant: first presentation of pompe's disease. World J Pediatr Congenit Heart Surg. 5:491–493. 2014. View Article : Google Scholar : PubMed/NCBI
7	Moak JP and Kaski JP: Hypertrophic cardiomyopathy in children. Heart. 98:1044–1054. 2012. View Article : Google Scholar : PubMed/NCBI
8	Marian AF and Roberts R: The molecular genetic basis for hypertrophic cardiomyopathy. J Mol Cell Cardiol. 33:655–670. 2001. View Article : Google Scholar : PubMed/NCBI
9	Seidman CE, Seidman JG, InScriver CR, et al: The Metabolic and Molecular Basis of Inherited Disease. pp. 433–5418. 2001
10	Xu Q, Dewey S, Nguyen S and Gomes AV: Malignant and benign mutations in familial cardiomyopathies: Insights into mutations linked to complex cardiovascular phenotypes. J Mol Cell Cardiol. 48:899–909. 2010. View Article : Google Scholar : PubMed/NCBI
11	Howell RR, Byrne B, Darras BT, Kishnani P, Nicolino M and van der Ploeg A: Diagnostic challenges for Pompe disease: an under-recognized cause of floppy baby syndrome. Genet Med. 8:289–296. 2006. View Article : Google Scholar : PubMed/NCBI
12	Lalani SR, Thakuria JV, Cox GF, et al: 20p12.3 microdeletion predisposes to Wolff-Parkinson-White syndrome with variable neurocognitive deficits. J Med Genet. 46:168–175. 2009. View Article : Google Scholar :
13	Jay PY, Harris BS, Maguire CT, et al: Nkx2–5 mutation causes anatomic hypoplasia of the cardiac conduction system. J Clin Invest. 113:1130–1137. 2004. View Article : Google Scholar : PubMed/NCBI
14	Nishino I, Fu J, Tanji K, et al: Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature. 406:906–910. 2000. View Article : Google Scholar : PubMed/NCBI
15	Tartaglia M, Mehler EL, Goldberg R, et al: Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 29:465–468. 2001. View Article : Google Scholar : PubMed/NCBI
16	Tartaglia M, Pennacchio LA, Zhao C, et al: Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. 39:75–79. 2007. View Article : Google Scholar
17	Schubbert S, Zenker M, Rowe SL, et al: Germline KRAS mutations cause Noonan syndrome. Nat Genet. 38:331–336. 2006. View Article : Google Scholar : PubMed/NCBI
18	Metzker ML: Sequencing technologies-the next generation. Nat Rev Genet. 11:31–46. 2010. View Article : Google Scholar
19	Mamanova L, Coffey AJ, Scott CE, et al: Target-enrichment strategies for next-generation sequencing. Nat Methods. 7:111–118. 2010. View Article : Google Scholar : PubMed/NCBI
20	Liu Y, Schmidt B and Maskell DL: CUSHAW: a CUDA compatible short read aligner to large genomes based on the Burrows-Wheeler transform. Bioinformatics. 28:1830–1837. 2012. View Article : Google Scholar : PubMed/NCBI
21	Li H, Handsaker B, Wysoker A, et al: The sequence alignment/map format and SAMtools. Bioinformatics. 25:2078–2079. 2009. View Article : Google Scholar : PubMed/NCBI
22	Gollob MH, Green MS, Tang AS and Roberts R: PRKAG2 cardiac syndrome: Familial ventricular preexcitation, conduction system disease and cardiac hypertrophy. Curr Opin Cardiol. 17:229–234. 2002. View Article : Google Scholar : PubMed/NCBI
23	Fitzsimmons PJ, McWhirter PD, Peterson DW and Kruyer WB: The natural history of Wolff-Parkinson-White syndrome in 228 military aviators: A long-term follow-up of 22 years. Am Heart J. 142:530–536. 2001. View Article : Google Scholar : PubMed/NCBI
24	Gollb MH, Green MS, Tang AS, et al: Identification of a gene responsible for familial Wolff-Parkinson-White syndrome. N Engl J Med. 344:1823–1831. 2001. View Article : Google Scholar
25	Zhang BL, Ye Z, Xu RL, et al: Overexpression of G100S mutation in PRKAG2 causes Wolff-Parkinson-White syndrome in zebrafish. Clin Genet. 86:287–291. 2014. View Article : Google Scholar
26	Sidhu JS, Rajawat YS, Rami TG, et al: Transgenic mouse model of ventricular preexeitation and atrioventricular reentrant achycardia induced by an AMP-activated protein kinase loss-of-function mutation responsible for Wolff-Parkinson-White syndrome. Circulation. 111:21–29. 2005. View Article : Google Scholar
27	Tan HL, van der Wal AC, Campian ME, et al: Nodoventricular accessory pathways in PRKAG2-dependent familial preexcitation syndrome reveal a disorder in cardiac development. Circ Arrhythm Electrophysiot. 1:276–281. 2008. View Article : Google Scholar
28	Douglas SA, Tayara L, Ohlstein EH, Halawaa N and Giaid A: Congestive heart failure and expression of myocardial urotensin II. Lancet. 359:1990–1997. 2002. View Article : Google Scholar : PubMed/NCBI