Clinical application of targeted next-generation sequencing in fetuses with congenital heart defect

被引:36
作者
Hu, P. [1 ]
Qiao, F. [1 ]
Wang, Y. [1 ]
Meng, L. [1 ]
Ji, X. [1 ]
Luo, C. [1 ]
Xu, T. [1 ]
Zhou, R. [1 ]
Zhang, J. [1 ]
Yu, B. [2 ]
Wang, L. [3 ]
Wang, T. [4 ]
Pan, Q. [5 ]
Ma, D. [1 ]
Liang, D. [1 ]
Xu, Z. [1 ]
机构
[1] Nanjing Med Univ, Nanjing Matern & Child Hlth Care Hosp, Affiliated Obstet & Gynecol Hosp, Dept Prenatal Diag, Nanjing, Jiangsu, Peoples R China
[2] Nanjing Med Univ, Dept Prenatal Diag, Changzhou Woman & Children Hlth Hosp, Changzhou, Jiangsu, Peoples R China
[3] Lianyungang Maternal & Child Hlth Hosp, Dept Prenatal Diag, Lianyungang, Jiangsu, Peoples R China
[4] Nanjing Med Univ, Ctr Reprod & Genet, Suzhou Hosp, Suzhou, Jiangsu, Peoples R China
[5] Huaian Maternal & Child Hlth Care Hosp, Dept Prenatal Diag, Lab Clin Genet, Huaian, Jiangsu, Peoples R China
基金
中国国家自然科学基金;
关键词
congenital heart defects; pathogenic variant; prenatal diagnosis; targeted next-generation sequencing; DIAGNOSTIC-TOOL; CHARGE-SYNDROME; KABUKI SYNDROME; DISEASE; MUTATIONS; VARIANTS; FAMILY; EXOME; INHERITANCE; SPECTRUM;
D O I
10.1002/uog.19042
中图分类号
O42 [声学];
学科分类号
070206 ; 082403 ;
摘要
Objectives To assess the value of targeted next-generation sequencing (NGS) in prenatal diagnosis of congenital heart defects (CHD) and to investigate the genetic etiology of prenatal CHD. Methods Forty-four fetuses with CHD, normalmolecular karyotype and negative chromosomal microarray results underwent targeted NGS. Fetal genomic DNA was extracted directly from amniotic fluid cells in each prenatal case. A customized targeted-NGS panel of 77 CHD-associated genes was designed to detect variants in the coding regions and the splicing sites of these genes. The detected variants were classified as pathogenic, likely pathogenic, of uncertain significance, likely benign or benign, following the guidelines recommended by the American College of Medical Genetics and Genomics. Results The detection rates of targeted NGS for pathogenic and likely pathogenic variations were 13.6% (6/44) and 2.3% (1/44), respectively. The turnaround time of the test was 3weeks. The six pathogenic variations were identified on the genes CHD7 (CHARGE syndrome), CITED2 (tetralogy of Fallot, ventricular septal defect and atrial septal defect), ZFPM2 (tetralogy of Fallot), MYH6 (atrial septal defect, familial isolated dilated cardiomyopathy) and, in two cases, KMT2D (Kabuki syndrome). The likely pathogenic variation was detected on JAG1, which is associated with tetralogy of Fallot and Alagille syndrome. Sanger sequencing in the fetuses and their parents indicated that all seven mutations were de novo. Variations of uncertain significance were detected in 79.5% of cases. Conclusions Targeted NGS in fetuses with isolated and non-isolated CHD achieved a high diagnostic yield in our cohort, with an acceptable turnaround time for the prenatal setting. Our results have important implications for clinical management and genetic counseling. Copyright (C) 2018 ISUOG. Published by John Wiley & Sons Ltd.
引用
收藏
页码:205 / 211
页数:7
相关论文
共 32 条
[1]   Exome Analysis of a Family With Pleiotropic Congenital Heart Disease [J].
Arrington, Cammon B. ;
Bleyl, Steven B. ;
Matsunami, Norisada ;
Bonnell, Gabriel D. ;
Otterud, Brith E. M. ;
Nielsen, Douglas C. ;
Stevens, Jeffrey ;
Levy, Shawn ;
Leppert, Mark F. ;
Bowles, Neil E. .
CIRCULATION-CARDIOVASCULAR GENETICS, 2012, 5 (02) :175-182
[2]   Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations [J].
Basson, CT ;
Huang, TS ;
Lin, RC ;
Bachinsky, DR ;
Weremowicz, S ;
Vaglio, A ;
Bruzzone, R ;
Quadrelli, R ;
Lerone, M ;
Romeo, G ;
Silengo, M ;
Pereira, A ;
Krieger, J ;
Mesquita, SF ;
Kamisago, M ;
Morton, CC ;
Pierpont, MEM ;
Müller, CW ;
Seidman, JG ;
Seidman, CE .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (06) :2919-2924
[3]  
Batzir NA, 2015, PEDIATR ENDOCR REV P, V13, P448
[4]   Candidate genes for congenital diaphragmatic hernia from animal models:: sequencing of FOG2 and PDGFRα reveals rare variants in diaphragmatic hernia patients [J].
Bleyl, S. B. ;
Moshrefi, A. ;
Shaw, G. M. ;
Saijoh, Y. ;
Schoenwolf, G. C. ;
Pennacchio, L. A. ;
Slavotinek, A. M. .
EUROPEAN JOURNAL OF HUMAN GENETICS, 2007, 15 (09) :950-958
[5]   Targeted Next-Generation Sequencing Identifies Pathogenic Variants in Familial Congenital Heart Disease [J].
Blue, Gillian M. ;
Kirk, Edwin P. ;
Giannoulatou, Eleni ;
Dunwoodie, Sally L. ;
Ho, Joshua W. K. ;
Hilton, Desiree C. K. ;
White, Susan M. ;
Sholler, Gary F. ;
Harvey, Richard P. ;
Winlaw, David S. .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2014, 64 (23) :2498-2506
[6]   Congenital heart disease: current knowledge about causes and inheritance [J].
Blue, Gillian M. ;
Kirk, Edwin P. ;
Sholler, Gary F. ;
Harvey, Richard P. ;
Winlaw, David S. .
MEDICAL JOURNAL OF AUSTRALIA, 2012, 197 (03) :155-159
[7]   α-Cardiac myosin heavy chain (MYH6) mutations affecting myofibril formation are associated with congenital heart defects [J].
Granados-Riveron, Javier T. ;
Ghosh, Tushar K. ;
Pope, Mark ;
Bu'Lock, Frances ;
Thornborough, Christopher ;
Eason, Jacqueline ;
Kirk, Edwin P. ;
Fatkin, Diane ;
Feneley, Michael P. ;
Harvey, Richard P. ;
Armour, John A. L. ;
Brook, J. David .
HUMAN MOLECULAR GENETICS, 2010, 19 (20) :4007-4016
[8]   Spectrum of MLL2 (ALR) Mutations in 110 Cases of Kabuki Syndrome [J].
Hannibal, Mark C. ;
Buckingham, Kati J. ;
Ng, Sarah B. ;
Ming, Jeffrey E. ;
Beck, Anita E. ;
McMillin, Margaret J. ;
Gildersleeve, Heidi I. ;
Bigham, Abigail W. ;
Tabor, Holly K. ;
Mefford, Heather C. ;
Cook, Joseph ;
Yoshiura, Koh-ichiro ;
Matsumoto, Tadashi ;
Matsumoto, Naomichi ;
Miyake, Noriko ;
Tonoki, Hidefumi ;
Naritomi, Kenji ;
Kaname, Tadashi ;
Nagai, Toshiro ;
Ohashi, Hirofumi ;
Kurosawa, Kenji ;
Hou, Jia-Woei ;
Ohta, Tohru ;
Liang, Deshung ;
Sudo, Akira ;
Morris, Colleen A. ;
Banka, Siddharth ;
Black, Graeme C. ;
Clayton-Smith, Jill ;
Nickerson, Deborah A. ;
Zackai, Elaine H. ;
Shaikh, Tamim H. ;
Donnai, Dian ;
Niikawa, Norio ;
Shendure, Jay ;
Bamshad, Michael J. .
AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2011, 155A (07) :1511-1516
[9]   The Diagnostic Value of Next Generation Sequencing in Familial Nonsyndromic Congenital Heart Defects [J].
Jia, Yaojuan ;
Louw, Jacoba J. ;
Breckpot, Jeroen ;
Callewaert, Bert ;
Barrea, Catherine ;
Sznajer, Yves ;
Gewillig, Marc ;
Souche, Erika ;
Dehaspe, Luc ;
Vermeesch, Joris Robert ;
Lambrechts, Diether ;
Devriendt, Koenraad ;
Corveleyn, Anniek .
AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2015, 167 (08) :1822-1829
[10]   A genome-wide scan in affected sibling pairs with idiopathic recurrent miscarriage suggests genetic linkage [J].
Kolte, A. M. ;
Nielsen, H. S. ;
Moltke, I. ;
Degn, B. ;
Pedersen, B. ;
Sunde, L. ;
Nielsen, F. C. ;
Christiansen, O. B. .
MOLECULAR HUMAN REPRODUCTION, 2011, 17 (06) :379-385