Whole-exome sequencing identifies <i>SGCD</i> and <i>ACVRL1</i> mutations associated with total anomalous pulmonary venous return (TAPVR) in Chinese population

Li, Jun; Yang, Shiwei; Pu, Zhening; Dai, Juncheng; Jiang, Tao; Du, Fangzhi; Zhu, Jun; Cheng, Yue; Dai, Genyin; Wang, Jun; Qi, Jirong; Cheng, Xiao; Ren, Cong; Li, Xinli; Qin, Yong

doi:10.18632/oncotarget.15434

Cited by 13 publications

(7 citation statements)

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“…1,2 Patients with scimitar syndrome and multiple congenital anomalies can be challenging to manage due to their multiple organ system pathologies.Although some forms of CHD have been linked to various genetic syndromes, the mechanisms that contribute to scimitar syndrome remains elusive. [3][4][5][6][7][8][9] Studies have demonstrated an association between scimitar syndrome and extracardiac anomalies including congenital diaphragmatic hernia, imperforate anus, and variants of VACTERL association. [10][11][12][13][14] Although pathogenic variants in specific genes can clearly cause CHDs, the genetic factors contributing to most cases of scimitar syndrome remain unidentified.…”

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The frequency and efficacy of genetic testing in individuals with scimitar syndrome

et al. 2021

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Background: Scimitar syndrome is a rare CHD composed of partial anomalous pulmonary venous connection from the right lung, via a scimitar vein, to the inferior vena cava rather than the left atrium. Genetic conditions associated with scimitar syndrome have not been well investigated at present. Methods: Our study included patients with scimitar syndrome diagnosed at Texas Children’s Hospital from January 1987 to July 2020. Medical records were evaluated to determine if genetic testing was performed, including chromosomal microarray analysis or whole-exome sequencing. Copy number variants identified as pathogenic/likely pathogenic and variants of unknown significance were collected. Analyses of cardiac and extracardiac findings were performed via chart review. Results: Ninety-eight patients were identified with scimitar syndrome, 89 of which met inclusion criteria. A chromosome analysis or chromosomal microarray analysis was performed in 18 patients (20%). Whole-exome sequencing was performed in six patients following negative chromosomal microarray analysis testing. A molecular genetic diagnosis was made in 7 of 18 cases (39% of those tested). Ninety-six per cent of the cohort had some type of extracardiac finding, with 43% having asthma and 20% having a gastrointestinal pathology. Of the seven patients with positive genetic testing, all had extracardiac anomalies with all but one having gastrointestinal findings and 30% having congenital diaphragmatic hernia. Conclusions: Genetic testing revealed an underlying diagnosis in roughly 40% of those tested. Given the relatively high prevalence of pathogenic variants, we recommend chromosomal microarray analysis and whole-exome sequencing for patients with scimitar syndrome and extracardiac defects.

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The frequency and efficacy of genetic testing in individuals with scimitar syndrome

et al. 2021

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“…ABAT , CYFIP2 , FN1 and TEK are all expressed in vascular and lung tissue, EMP2 , FN1 and TEK are expressed in tracheal tissue (UniGene cDNA sources). Four further genes intersect between cytoskeleton and blood flow: AAMP (angio-associated migratory cell protein) is associated with angiogenesis and has potential roles in endothelial tube formation and the migration of endothelial cells, KCNMA1 (potassium calcium-activated channel subfamily M α 1), RAP1GDS1 (Rap1 GTPase-GDP dissociation stimulator 1) and SGCD (sarcoglycan delta) are associated with total anomalous pulmonary venous return [33].…”

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confidence: 99%

A Mechanogenetic Model of Exercise-Induced Pulmonary Haemorrhage in the Thoroughbred Horse

Blott

Cunningham

Malkowski

et al. 2019

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Exercise-induced pulmonary haemorrhage (EIPH) occurs in horses performing high-intensity athletic activity. The application of physics principles to derive a ‘physical model’, which is coherent with existing physiology and cell biology data, shows that critical parameters for capillary rupture are cell–cell adhesion and cell stiffness (cytoskeleton organisation). Specifically, length of fracture in the capillary is a ratio between the energy involved in cell–cell adhesion and the stiffness of cells suggesting that if the adhesion diminishes and/or that the stiffness of cells increases EIPH is more likely to occur. To identify genes associated with relevant cellular or physiological phenotypes, the physical model was used in a post-genome-wide association study (GWAS) to define gene sets associated with the model parameters. The primary study was a GWAS of EIPH where the phenotype was based on weekly tracheal wash samples collected over a two-year period from 72 horses in a flat race training yard. The EIPH phenotype was determined from cytological analysis of the tracheal wash samples, by scoring for the presence of red blood cells and haemosiderophages. Genotyping was performed using the Illumina Equine SNP50 BeadChip and analysed using linear regression in PLINK. Genes within significant genome regions were selected for sets based on their GeneOntology biological process, and analysed using fastBAT. The gene set analysis showed that genes associated with cell stiffness (cytoskeleton organisation) and blood flow have the most significant impact on EIPH risk.

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“…Li et al analysed whole exome sequencing (WES) data from 6 sporadic TAPVC cases and 81 non-TAPVC counterparts, providing evidence for ACVRL1 as a known causative gene and for SGCD as a candidate TAPVC gene [9]. Nash et al used WGS analysis to identify a nonsynonymous variant in RBP5 gene that was predicted to be deleterious and overrepresented in TAPVC [10].…”

Section: Introductionmentioning

confidence: 99%

Next-generation sequencing identifies novel genes with rare variants in total anomalous pulmonary venous connection

et al. 2018

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BackgroundTotal anomalous pulmonary venous connection (TAPVC) is recognized as a rare congenital heart defect (CHD). With a high mortality rate of approximately 80%, the survival rate and outcomes of TAPVC patients are not satisfactory. However, the genetic aetiology and mechanism of TAPVC remain elusive. This study aimed to investigate the underlying genomic risks of TAPVC through next-generation sequencing (NGS).MethodsRare variants were identified through whole exome sequencing (WES) of 78 sporadic TAPVC cases and 100 healthy controls using Fisher's exact test and gene-based burden test. We then detected candidate gene expression patterns in cells, pulmonary vein tissues, and embryos. Finally, we validated these genes using target sequencing (TS) in another 100 TAPVC cases.FindingsWe identified 42 rare variants of 7 genes (CLTCL1, CST3, GXYLT1, HMGA2, SNAI1, VAV2, ZDHHC8) in TAPVC cases compared with controls. These genes were highly expressed in human umbilical vein endothelial cells (HUVECs), mouse pulmonary veins and human embryonic hearts. mRNA levels of these genes in human pulmonary vein samples were significantly different between cases and controls. Through network analysis and expression patterns in zebrafish embryos, we revealed that SNAI1, HMGA2 and VAV2 are the most important genes for TAPVC.InterpretationOur study identifies novel candidate genes potentially related to TAPVC and elucidates the possible molecular pathogenesis of this rare congenital birth defect. Furthermore, SNAI1, HMGA2 and VAV2 are novel TAPVC candidate genes that have not been reported previously in either humans or animals.FundNational Natural Science Foundation of China.

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Whole-exome sequencing identifies SGCD and ACVRL1 mutations associated with total anomalous pulmonary venous return (TAPVR) in Chinese population

Cited by 13 publications

References 25 publications

The frequency and efficacy of genetic testing in individuals with scimitar syndrome

The frequency and efficacy of genetic testing in individuals with scimitar syndrome

A Mechanogenetic Model of Exercise-Induced Pulmonary Haemorrhage in the Thoroughbred Horse

Next-generation sequencing identifies novel genes with rare variants in total anomalous pulmonary venous connection

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