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Genetic Mutation Analysis in Japanese Patients with Non-Syndromic Congenital Heart Disease

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Genetic Mutation Analysis in Japanese Patients with Non-Syndromic Congenital Heart Disease Journal of Human Genetics (2016) 61, 157–162 & 2016 The Japan Society of Human Genetics All rights reserved 1434-5161/16 www.nature.com/jhg ORIGINAL ARTICLE Genetic mutation analysis in Japanese patients with non-syndromic congenital heart disease Akiko Yoshida1,2, Hiroko Morisaki1,2,3, Mai Nakaji1,3, Masataka Kitano4, Ki-sung Kim5, Koichi Sagawa6, Shiro Ishikawa6, Ichiro Satokata7, Yoshihide Mitani8, Hitoshi Kato5, Kenji Hamaoka9, Shigeyuki Echigo4, Isao Shiraishi4 and Takayuki Morisaki1,2,3 Congenital heart disease (CHD) is the most common birth defect occurring in humans and some transcriptional factors have been identified as causative. However, additional mutation analysis of these genes is necessary to develop effective diagnostic and medical treatment methods. We conducted sequence analysis of the coding regions of NKX2.5, GATA4, TBX1, TBX5, TBX20, CFC1 and ZIC3 in 111 Japanese patients with non-syndromic CHD and 9 of their relatives. All patient samples were also analyzed by multiplex ligation-dependent probe amplification using probes involved in chromosome deletion related to CHD. Five novel variations of TBX5, GATA4 and TBX20 were detected in 6 of the patients, whereas none were found in 200 controls. The TBX5 variation p.Pro108Thr, located in the T-box domain, was identified in a patient with tricuspid atresia, an exon–intron boundary variation of GATA4 (IVS4+5G4A) was detected in a Tetralogy of Fallot patient and an 8p23 microdeletion was detected in one patient with atrioventricular septal defect and psychomotor delay. A total of seven non-synonymous polymorphisms were found in the patients and controls. Accumulation of novel variations of genes involving the cardiac development may be required for better understanding of CHD. Journal of Human Genetics (2016) 61, 157–162; doi:10.1038/jhg.2015.126; published online 22 October 2015 INTRODUCTION medical treatment. In the present study, we assessed the contributions Congenital heart disease (CHD) is the most common birth defect of those gene mutations in Japanese patients with non- occurring in humans and observed in 4–50 per 1000 live births.1 CHD syndromic CHD. may result in part from a birth malformation with a related syndrome, although most cases are identified as an isolated defect without MATERIALS AND METHODS syndromic features.2 Although the etiology of non-syndromic CHD Patients remains largely unknown, some transcriptional factors, including We recruited 111 patients diagnosed with non-syndromic CHDs who were NKX2.5,3 GATA4,4 TBX1,5 TBX5,6,7 TBX20,8 CFC19 and ZIC3,10 treated at six hospitals in Japan, including National Cerebral and Cardio- have been identified as major contributors to CHD in some cases.11 vascular Center, Kyoto Prefectural University of Medicine University Hospital, The TBX1 and TBX5 were also identified as responsible gene for National Center for Child Health and Development, Niigata University Medical ’ syndromic disorders, TBX1 mutations are detected with DiGeorge and Dental Hospital, Fukuoka Children s Hospital and Mie University Hospital, syndrome/velocardiofacial syndrome phenotype without 22q11.2 from May 2008 to September 2011. Among them, 14 patients were familial cases with CHD including 1 who had a twin, whereas the others were sporadic microdeletion5 and TBX5 mutations were detected as causative cases. Nine relatives of four CHD patients also participated in this study. gene of Holt–Oram syndrome (HOS).6,7 However, in a few cases, In addition, 200 healthy individuals were studied as controls in our search for TBX112 TBX513,14 and mutations are found in patient with mutations or variations found in CHD patients. isolated CHD. The diagnosis of CHD was confirmed by pediatric cardiologists at each According to previous reports, the prevalence of CHD caused by a hospital. The patient clinical characteristics are shown in Supplementary genetic mutation of such cardiac transcription factors is relatively rare. Table 1. The most frequent clinical feature was ventricular septal defect However, further accumulation of mutation analysis findings is (VSD), followed by pulmonary stenosis. We excluded patients with syndromic needed for developing more effective methods for diagnosis and features such as Down syndrome, Williams syndrome and DiGeorge syndrome, 1Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan; 2Department of Medical Genetics, National Cerebral and Cardiovascular Center, Suita, Japan; 3Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Japan; 4Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Suita, Japan; 5Division of Cardiology, National Center for Child Health and Development, Tokyo, Japan; 6Department of Pediatric Cardiology, Fukuoka Children’s Hospital Medical Center, Fukuoka, Japan; 7Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; 8Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan and 9Department of Pediatric Cardiology and Nephrology, Kyoto Prefectural University of Medicine Graduate School of Medical Sciences, Kyoto, Japan Correspondence: Dr T Morisaki, Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita 565-8565, Japan. E-mail:[email protected] Received 27 April 2015; revised 1 September 2015; accepted 23 September 2015; published online 22 October 2015 Genetic mutation analysis in patients with CHD A Yoshida et al 158 Table 1 Summary of variations detected in 111 patients and phenotype of cardiac defect Nucleotide Amino-acid Familial or Congenital Normal Allele Gene Position change change Location sporadic heart defect Reference control rate frequencya Prediction Programb TBX5 Exon 4 c.322C4A p.Pro108Thr T-BOX domain Sporadic TA Novel 0/200 — S: Affect protein function (P = 0.03) Po: Probably damaging Pm: Neutral Exon 8 c.791G4A p.Arg264Lys — Sporadic VSD Novel 0/200 0.75% S: Tolerated (P = 0.86) Po: Probably damaging Pm: Neutral Exon 8 c.791G4A p.Arg264Lys — Sporadic VSD and PA TBX20 Exon 7 c.991A4Gp.Thr331Ala— Sporadic VSD Novel 0/200 0.37% S: Tolerated (P = 1.00) Po: Benign Pm: Neutral GATA4 IVS4+5 G4A —— Exon–intron Sporadic TOF Novel 0/200 0.12% MaxEntScan: 1.77 boundary Exon 2 c.431C4T p.Ala144Val — Familial PA and ASD Novel 0/200 — S: Tolerated (P = 0.13) Po: Possibly damaging Pm: Pathological Abbreviations: ASD, atrial septal defect; PA, pulmonary atresia; TA, tricuspid atresia; TOF, tetralogy of fallot; VSD, ventricular septal defect. aAllele frequency Human Genetic Variation Browser. bPrediction Program: S, SIFT program; Po, Polyphen-2; Pm, PMut. as well as patients with a structural chromosomal abnormality. This study was chromosome regions reported as CHD-related regions, which were 4q34-qter, approved by the ethics committee of each institution, and written informed 9q34.3, 17p13.3, 10p15, 8p23, 22q11 and 22q13. Genes in these chromosomal consent was obtained from the subjects or their parents, as appropriate, regions are shown in Supplementary Table 9. Samples shown to have a 22q11 beforehand. deletion (DiGeorge syndrome) were excluded from analysis. MLPA was performed according to the manufacturer’s protocol using 50 ng of DNA. Sequence analysis Amplified fragments were separated with a 3130 DNA analyzer (Applied Genomic DNA was prepared from blood leukocytes or Epstein-Barr virus Biosystems) and results were quantitatively analyzed using Gene Mapper immortalized lymphocytes. We performed sequence analysis for the following software (Applied Biosystems). Data analysis was performed using Coffalyser seven genes related to CHD: NKX2.5 (NM_004387), GATA4 (NM_002052), MLPA software (MRC Holland). TBX1 (NM_080647), TBX5 (NM_000192), TBX20 (NM_001077653), CFC1 (NM_032545) and ZIC3 (NM_003413). First, we analyzed all obtained samples Allele frequency for NKX2.5, GATA4, TBX1, TBX5 and TBX20,thenCFC1 and ZIC3 were We investigated the allele frequency of genetic variations causing non- analyzed in 28 patients diagnosed with heterotaxic abnormalities, such as synonymous amino-acid change in Japanese individuals identified in this transposition of great arteries (TGA), double-outlet right ventricle (DORV), study using the Human Genetic Variation Browser (http://www.genome.med. single ventricle (SV) or asplenia. Primers were designed to contain all coding kyoto-u.ac.jp/SnpDB), accessed on 18 November 2014. exons of these genes using Primer express (Applied Biosystems, Foster City, CA, USA) or based on previous reports (Supplementary Tables 2–8). Mutation prediction PCR assays were performed using genomic DNA at 20 or 40 ng. Depending When we found new genetic variations causing a non-synonymous amino-acid on the PCR fragment length, the Taq polymerase was either AmpliTaq Gold change, we determined whether those variations could be a pathogenic (Applied Biosystems), Platinum Taq DNA Polymerase (Invitrogen, Carlsbad, mutation using the SIFT (http://sift.bii.a-star.edu.sg/index.html), PolyPhen-2 CA, USA) or LA Taq HS (TAKARA, Kusatsu, Japan). PCR was performed with (http://genetics.bwh.harvard.edu/pph2/index.shtml), PMut (http://mmb.pcb. a total volume of 20 μl containing standard PCR buffer mix, according to the ub.es/PMut/) and MaxEntScan (http://genes.mit.edu/burgelab/maxent/Xmax- protocol of the manufacturer, and the polymerase. When a GC-rich fragment entscan_scoreseq.html) programs, each accessed on 5 December 2014.
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