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Whole-exome sequencing and homozygosity mapping identify variants in NCOR1 and MAP2K3 associated with non-syndromic congenital heart defects

Egyptian Journal of Medical Human Genetics, 2020-10, Vol.21 (1), p.1-10 [Peer Reviewed Journal]

The Author(s) 2020 ;COPYRIGHT 2020 Springer ;The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. ;ISSN: 1110-8630 ;EISSN: 2090-2441 ;DOI: 10.1186/s43042-020-00101-4

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Title:
Whole-exome sequencing and homozygosity mapping identify variants in NCOR1 and MAP2K3 associated with non-syndromic congenital heart defects
Author: Gholipoorfeshkecheh, Rahim ; Agarwala, Swati ; G, Kavya ; Krishnappa, Santhosh ; Savitha, Mysore R. ; Ramachandra, Nallur B.
Subjects: Analysis ; Chromosome 17 ; Congenital diseases ; Congenital heart disease ; Coronary artery disease ; Gene mapping ; Genes ; Genetic disorders ; Genomes ; Haploinsufficiency ; Haplotypes ; Heart diseases ; Homozygous regions ; In silico validation ; Kinases ; MAP kinase ; Medicine ; Medicine & Public Health ; Mitogen-Activated Protein Kinase 3 ; Mitogens ; Myogenesis ; Nuclear Corepressor ; Protein kinase ; Protein kinases ; Tetralogy of Fallot ; Transcription ; Ventricle ; Ventricular septal defect ; Whole-exome sequencing
Is Part Of: Egyptian Journal of Medical Human Genetics, 2020-10, Vol.21 (1), p.1-10
Description: Background Homozygosity mapping is an efficient gene mapping method applicable to recessive disorders. It can detect homozygous segments of identical haplotype structures shared at a higher frequency among ventricular septal defect (VSD) and tetralogy of Fallot (TOF) cases. This study aims to identify the recessive genes involved in congenital heart disease (CHD) cases by homozygosity mapping . A total of 36 CHD cases of Indian origin were recruited based on inclusion and exclusion criteria, disease severity, and hole size. Of these, ten prediagnosed VSD and TOF cases were selected for homozygosity mapping. For in silico validation of variations, overlapping gene variants were analyzed from 26 cases based on pathogenecity and haploinsufficiency scores. Results Genome-wide homozygosity mapping identified 34 homozygous regions with a maximum block length of 80 bp marked for the CHD samples under study. A total of 4863 genes were identified in these 34 homozygous regions, which were present across almost all chromosomes except chromosomes 4, 8, 12, and 13. The homozygosity region found in chromosome 17 revealed genes for CHD manifestation. This homozygous region contained VSD- and TOF-related genes— Nuclear Corepressor 1 ( NCOR1 ) and Mitogen-Activated Protein Kinase Kinase 3 ( MAP2K3 ). In silico validation identified damaging variants for NCOR1 and MAP2K3 . Three variants, G207C, C241T, and G244A, were found on exon 2 in the transcript NM_001190438 for NCOR1 . Three variants were also found for MAP2K3 , namely G194T and C199T in exon 5 and C578T in exon 8 in the transcript NM_002756. All these variants were present in the protein kinase domain. Conclusion Presence of homozygous regions identifies recessive genes leading to disease severity. Defects in recessive genes NCOR1 and MAP2K3 are responsible for abnormal myogenesis, resulting in CHD manifestation.
Publisher: Berlin/Heidelberg: Springer Berlin Heidelberg
Language: English
Identifier: ISSN: 1110-8630
EISSN: 2090-2441
DOI: 10.1186/s43042-020-00101-4
Source: GFMER Free Medical Journals
Springer Nature OA/Free Journals
DOAJ Directory of Open Access Journals

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Whole-exome sequencing and homozygosity mapping identify variants in NCOR1 and MAP2K3 associated with non-syndromic congenital heart defects

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