A genetic and developmental biological approach for a family with complex congenital heart diseases—evidence of digenic inheritance
ObjectiveCongenital heart disease (CHD) is caused by cardiovascular developmental defects and has a global prevalence of ∼1%. The etiology of CHD is multifactorial and remains generally unknown, despite advances in analytical techniques based on next-generation sequencing (NGS). The aim of our study...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-04-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1135141/full |
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| author | Yu Yoshida Keiko Uchida Keiko Uchida Kazuki Kodo Reina Ishizaki-Asami Jun Maeda Yoshinori Katsumata Shinsuke Yuasa Keiichi Fukuda Kenjiro Kosaki Yusuke Watanabe Osamu Nakagawa Hiroyuki Yamagishi |
| author_facet | Yu Yoshida Keiko Uchida Keiko Uchida Kazuki Kodo Reina Ishizaki-Asami Jun Maeda Yoshinori Katsumata Shinsuke Yuasa Keiichi Fukuda Kenjiro Kosaki Yusuke Watanabe Osamu Nakagawa Hiroyuki Yamagishi |
| author_sort | Yu Yoshida |
| collection | DOAJ |
| description | ObjectiveCongenital heart disease (CHD) is caused by cardiovascular developmental defects and has a global prevalence of ∼1%. The etiology of CHD is multifactorial and remains generally unknown, despite advances in analytical techniques based on next-generation sequencing (NGS). The aim of our study was to elucidate the multi-genetic origin and pathogenesis of an intriguing familial case with complex CHD.MethodsWe performed an original trio-based gene panel analysis using NGS of the family, including two siblings with CHD of single ventricular phenotype, and their unaffected parents. The pathogenicity of the detected rare variants was investigated in silico, and the functional effects of the variants were confirmed in vitro using luciferase assays. The combinatorial effect of gene alterations of the putative responsible genes was tested in vivo using genetically engineered mutant mice.ResultsNGS-based gene panel analyses revealed two heterozygous rare variants in NODAL and in TBX20 common to the siblings and to just one of parents. Both variants were suspected pathogenic in silico, and decreased transcriptional activities of downstream signaling pathways were observed in vitro. The analyses of Nodal and Tbx20 double mutant mice demonstrated that Nodal+/−Tbx20−/− embryos showed more severe defects than Nodal+/+Tbx20−/− embryos during early heart development. The expression of Pitx2, a known downstream target of Nodal, was downregulated in Tbx20−/− mutants.ConclusionsTwo rare variants on NODAL and TBX20 genes detected in this family were considered to be loss-of-function mutations. Our results suggest that NODAL and TBX20 may be complementary for the cardiac development, and a combinatorial loss-of-function of NODAL and TBX20 could be implicated in digenic inherence as the etiology of complex CHD associated with single ventricle defects in this family. |
| first_indexed | 2024-04-09T16:06:55Z |
| format | Article |
| id | doaj.art-f83bbdf4c3474670b6f61803cc762650 |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-04-09T16:06:55Z |
| publishDate | 2023-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-f83bbdf4c3474670b6f61803cc7626502023-04-25T05:02:39ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2023-04-011010.3389/fcvm.2023.11351411135141A genetic and developmental biological approach for a family with complex congenital heart diseases—evidence of digenic inheritanceYu Yoshida0Keiko Uchida1Keiko Uchida2Kazuki Kodo3Reina Ishizaki-Asami4Jun Maeda5Yoshinori Katsumata6Shinsuke Yuasa7Keiichi Fukuda8Kenjiro Kosaki9Yusuke Watanabe10Osamu Nakagawa11Hiroyuki Yamagishi12Department of Pediatrics, Keio University School of Medicine, Tokyo, JapanDepartment of Pediatrics, Keio University School of Medicine, Tokyo, JapanHealth Center, Keio University, Kanagawa, JapanDepartment of Pediatrics, Keio University School of Medicine, Tokyo, JapanDepartment of Pediatrics, Keio University School of Medicine, Tokyo, JapanDepartment of Pediatrics, Keio University School of Medicine, Tokyo, JapanDepartment of Cardiology, Keio University School of Medicine, Tokyo, JapanDepartment of Cardiology, Keio University School of Medicine, Tokyo, JapanDepartment of Cardiology, Keio University School of Medicine, Tokyo, JapanCenter for Medical Genetics, Keio University School of Medicine, Tokyo, JapanDepartment of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, JapanDepartment of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, JapanDepartment of Pediatrics, Keio University School of Medicine, Tokyo, JapanObjectiveCongenital heart disease (CHD) is caused by cardiovascular developmental defects and has a global prevalence of ∼1%. The etiology of CHD is multifactorial and remains generally unknown, despite advances in analytical techniques based on next-generation sequencing (NGS). The aim of our study was to elucidate the multi-genetic origin and pathogenesis of an intriguing familial case with complex CHD.MethodsWe performed an original trio-based gene panel analysis using NGS of the family, including two siblings with CHD of single ventricular phenotype, and their unaffected parents. The pathogenicity of the detected rare variants was investigated in silico, and the functional effects of the variants were confirmed in vitro using luciferase assays. The combinatorial effect of gene alterations of the putative responsible genes was tested in vivo using genetically engineered mutant mice.ResultsNGS-based gene panel analyses revealed two heterozygous rare variants in NODAL and in TBX20 common to the siblings and to just one of parents. Both variants were suspected pathogenic in silico, and decreased transcriptional activities of downstream signaling pathways were observed in vitro. The analyses of Nodal and Tbx20 double mutant mice demonstrated that Nodal+/−Tbx20−/− embryos showed more severe defects than Nodal+/+Tbx20−/− embryos during early heart development. The expression of Pitx2, a known downstream target of Nodal, was downregulated in Tbx20−/− mutants.ConclusionsTwo rare variants on NODAL and TBX20 genes detected in this family were considered to be loss-of-function mutations. Our results suggest that NODAL and TBX20 may be complementary for the cardiac development, and a combinatorial loss-of-function of NODAL and TBX20 could be implicated in digenic inherence as the etiology of complex CHD associated with single ventricle defects in this family.https://www.frontiersin.org/articles/10.3389/fcvm.2023.1135141/fulltrio gene analysisnodaltbx20complex congenital heart diseaserare variants |
| spellingShingle | Yu Yoshida Keiko Uchida Keiko Uchida Kazuki Kodo Reina Ishizaki-Asami Jun Maeda Yoshinori Katsumata Shinsuke Yuasa Keiichi Fukuda Kenjiro Kosaki Yusuke Watanabe Osamu Nakagawa Hiroyuki Yamagishi A genetic and developmental biological approach for a family with complex congenital heart diseases—evidence of digenic inheritance Frontiers in Cardiovascular Medicine trio gene analysis nodal tbx20 complex congenital heart disease rare variants |
| title | A genetic and developmental biological approach for a family with complex congenital heart diseases—evidence of digenic inheritance |
| title_full | A genetic and developmental biological approach for a family with complex congenital heart diseases—evidence of digenic inheritance |
| title_fullStr | A genetic and developmental biological approach for a family with complex congenital heart diseases—evidence of digenic inheritance |
| title_full_unstemmed | A genetic and developmental biological approach for a family with complex congenital heart diseases—evidence of digenic inheritance |
| title_short | A genetic and developmental biological approach for a family with complex congenital heart diseases—evidence of digenic inheritance |
| title_sort | genetic and developmental biological approach for a family with complex congenital heart diseases evidence of digenic inheritance |
| topic | trio gene analysis nodal tbx20 complex congenital heart disease rare variants |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1135141/full |
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