Whole exome sequencing identified a novel myopalladin gene mutation in a cardiomyopathy patient
Keywords:Cardiomyopathy, Gene variant, Next generation sequencing (NGS), Mutation, Whole exome sequencing (WES)
Cardiomyopathies (CMs) are a heterogenous group of disorders that affects the heart muscle. In
cardiomyopathies, phenotypic overlapping among the inherited cardiovascular diseases (CVDs) limits the
ability to establish a diagnosis based solely on clinical features. Here, we developed a next generation
sequencing (NGS) assay to analyze a panel of 142 known cardiomyopathy genes in 9 Vietnamese patients
from Children Hospital 2, Hochiminh City and Medical University Hospital, Hochiminh City, Vietnam.
Whole exome sequencing (WES) - a technique which determines the variations of all coding regions (exons)
of the known genes - validated a total of 65 rare variants in 18 cardiomyopathy genes among the studied
Vietnamese unrelated patients. Of 65 variants identified, 28 variants were homozygous and the other 37 ones
were heterozygous. Among the 65 variants, TTN gene variants accounted the most for 13 mutations, which are
known to be benign. Other groups of 9 and 8 mutations belong to SYNE1 and MYPN genes, respectively. Ten
out of 65 mutations distributed equally to NDUFV2 and SCN5A gene variants. We detected 6 and 4 variants
for SYNE2 and COX15 genes, respectively. Each gene of DMD, KCNE1, NEBL and RBM20 has 2 variants. A
single variant was detected for AKAP9, CAV3, DSC2, DSG2, DSP, MYBPC3 and MYH6 genes. Especially,
among them, we found a novel heterozygous nonsynonymous mutation c.1527C>G on the MYPN gene. These
genetic results support the “pan-cardiomyopathy panel” approach, by which the molecular diagnosis of
cardiomyopathies, early identification of arrhythmia development and better clinical management of
cardiomyopathic patients are applied.
Alcalai R, Metzger S, Rosenheck S, Meiner V, Chajek-Shaul T (2003) A recessive mutation in desmoplakin causes arrhythmogenic right ventricular dysplasia, skin disorder and woolly hair. J Am Coll Cardiol 42: 319-327.
Boemer F, Fasquelle C, d'Otreppe S, Josse C, Dideberg V, Segers K, Guissard V, Capraro V, Debray FG, Bours V (2017) A next-generation newborn screening pilot study: NGS on dried blood spots detects causal mutations in patients with inherited metabolic diseases. Sci Rep 7: 17641.
Chen L, Cai Y, Zhou G, Shi X, Su J, Chen G, Lin K (2014) Rapid Sanger sequencing of the 16S rRNA gene for identification of some common pathogens. PLoS One 9: e88886.
Di Resta C, Galbiati S, Carrera P, Ferrari M (2018) Next-generation sequencing approach for the diagnosis of human diseases: open challenges and new opportunities. EJIFCC 29: 4-14.
Faita F, Vecoli C, Foffa I, Andreassi MG (2012) Next generation sequencing in cardiovascular diseases. World J Cardiol 4: 288-295.
Florescu C, Rogoveanu I, Vere CC, Târtea GC, Târtea EA, Mogoantă L (2016) From molecular mechanism to morphological changes in cardiomyopathy. Rom J Morphol Embryol 57: 1207-1214.
Goh G, Choi M (2012) Application of whole exome sequencing to identify disease-causing variants in inherited human diseases. Genomics Inform 10: 214-219.
Golbus JR, Puckelwartz MJ, Dellefave-Castillo L, Fahrenbach JP, Nelakuditi V, Pesce LL, Pytel P, McNally EM (2014) Targeted analysis of whole genome sequence data to diagnose genetic cardiomyopathy. Circ Cardiovasc Genet 7: 751-759.
Haskell GT, Adams MC, Fan Z, Amin K, Guzman Badillo RJ, Zhou L, Bizon C, Chahin N, Greenwood RS, Milko LV, Shiloh-Malawsky Y, Crooks KR, Strande N, Tennison M, Tilley CR, Brandt A, Wilhelmsen KC, Weck K, Evans JP, Berg JS (2018) Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders. Neurol Genet 4: e212.
McKoy G, Protonotarios N, Crosby A, Tsatsopoulou A, Anastasakis A, Coonar A, Norman M, Baboonian C, Jeffery S, McKenna WJ (2000) Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet 355: 2119-2124.
Morini E, Sangiuolo F, Caporossi D, Novelli G, Amati F (2015) Application of next generation sequencing for personalized medicine for sudden cardiac death. Front Genet 6: 55.
Norgett EE, Hatsell SJ, Carvajal-Huerta L, Cabezas JC, Common J, Purkis PE, Whittock N, Leigh IM, Stevens HP, Kelsell DP (2000) Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum Mol Genet 9: 2761-2766.
Qiao D, Ameli A, Prokopenko D, Chen H, Kho AT, Parker MM, Morrow J, Hobbs BD, Liu Y, Beaty TH, Crapo JD, Barnes KC, Nickerson DA, Bamshad M, Hersh CP, Lomas DA, Agusti A, Make BJ, Calverley PMA, Donner CF, Wouters EF, Vestbo J, Paré PD, Levy RD, Rennard SI, Tal-Singer R, Spitz MR, Sharma A, Ruczinski I, Lange C, Silverman EK, Cho MH (2018) Whole exome sequencing analysis in severe chronic obstructive pulmonary disease. Hum Mol Genet 27: 3801-3812.
Simpson S, Rutland P, Rutland CS (2017) Genomic insights into cardiomyopathies: a comparative cross-species review. Vet Sci 4: 19.
Sisakian H (2014) Cardiomyopathies: Evolution of pathogenesis concepts and potential for new therapies. World J Cardiol 6: 478-494.