Whole-exome Sequencing Identify Rare Variants in Novel Candidate Genes with Non-syndromic Patent Ductus Arteriosus

Abstract Background Patent Ductus Arteriosus (PDA) is one of the most common congenital heart defects that can cause pulmonary hypertension, heart failure, and even death. Prior studies have suggested a role for genetics in determining spontaneous ductal closure, however the clinical characteristics and genetic cause underlying PDA remain unclear. Results Therefore, to further explore genetic etiology of PDA, we applied Whole-exome Sequencing (WES) in 39unrelated isolated, non-syndromic PDApatientsand 100 healthy controls. Through a series of bio-information filtering strategies, the candidate genes are prioritized by comprehensively considering factors such as genefunctional enrichment, expression pattern and mutation burden during heart development. 18 rare damage variants of 6 total novel genes (SOX8, NES, CDH2, ANK3, EIF4G1, HIPK1)were identified for the first time and these pathogenic candidates are also highly expressed in the heart of human embryos. Conclusions WES is an efficient diagnostic tool for identifying PDA related genes. The finding of our study contributes new insights into the molecular basis of PDA and may inform further studies on genetic risk factors for this congenital birth defect.

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Integrative analyses identify potential key genes and pathways in Keshan disease using whole-exome sequencing

10.1101/2021.03.12.21253491 ◽

2021 ◽

Author(s):

Jichang Huang ◽

Chenqing Zheng ◽

Rong Luo ◽

Mingjiang Liu ◽

Qingquan Gu ◽

...

Keyword(s):

Network Analysis ◽

Exome Sequencing ◽

Candidate Genes ◽

Whole Exome Sequencing ◽

Heart Development ◽

Keshan Disease ◽

Pathway Enrichment Analysis ◽

Ppi Network ◽

Pathogenic Genes ◽

Whole Exome

AbstractKeshan disease (KD), an endemic heart disease with multifocal necrosis and replacement fibrosis of the myocardium,is still a nightmare situation for human health. However, molecular mechanism in the pathogenesis of KD remains unclear. Herein, blood samples were collected from 68 KD patients and 100 controls, and we systematically analyzed mutation profiles using whole-exome sequencing (WES). Causative genes of dilated cardiomyopathy (DCM), gene-based burden analysis, disease and pathway enrichment analysis, and protein-protein interaction (PPI) network analysis were performed. Of the 98 DCM-causative genes, 106 rare variants in 28 genes were detected in KD patients with minor allele frequency (MAF) < 0.001. Gene-based burden analysis, PPI network analysis, and automated Phenolyzer analysis were performed to prioritize 199 candidate genes, which combined with 98 DCM-causative genes, and reference genes from gene microarray or proteomics in KD. Then, 19 candidate pathogenic genes were selected, and 9 candidate genes were identified using PPI analysis, including HIF1A, GART, ALAD, VCL, DTNA, NEXN, INPPL1, NOS3, and JAK2. The 199 candidate genes were further analyzed using disease enrichment with CTD database and PPI analysis, and 21 candidate genes were identified. By combining with disease enrichment and PPI analysis, 7 Selenium (Se)-related genes were further identified, including ALAD, RBM10, GSN, GGT1, ADD1, PARP1, and NOS3. Based on the gene function and data validation, NEXN, TAF1C, FUT4, ALAD, ZNF608, and STX2 were the most likely pathogenic genes in KD. Notably, ALAD is the only candidate pathogenic gene identified by four different analyses, and its homozygous mutant mice could affect heart development and cause death.

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A Framework for AI-Assisted Detection of Patent Ductus Arteriosus from Neonatal Phonocardiogram

Healthcare ◽

10.3390/healthcare9020169 ◽

2021 ◽

Vol 9 (2) ◽

pp. 169

Author(s):

Sergi Gómez-Quintana ◽

Christoph E. Schwarz ◽

Ihor Shelevytsky ◽

Victoriya Shelevytska ◽

Oksana Semenova ◽

...

Keyword(s):

Patent Ductus Arteriosus ◽

Heart Defects ◽

Ductus Arteriosus ◽

Area Under The Curve ◽

Clinical Decision ◽

Heart Sounds ◽

Decision Tree Classifier ◽

Support Tool ◽

Tree Classifier ◽

Patent Ductus

The current diagnosis of Congenital Heart Disease (CHD) in neonates relies on echocardiography. Its limited availability requires alternative screening procedures to prioritise newborns awaiting ultrasound. The routine screening for CHD is performed using a multidimensional clinical examination including (but not limited to) auscultation and pulse oximetry. While auscultation might be subjective with some heart abnormalities not always audible it increases the ability to detect heart defects. This work aims at developing an objective clinical decision support tool based on machine learning (ML) to facilitate differentiation of sounds with signatures of Patent Ductus Arteriosus (PDA)/CHDs, in clinical settings. The heart sounds are pre-processed and segmented, followed by feature extraction. The features are fed into a boosted decision tree classifier to estimate the probability of PDA or CHDs. Several mechanisms to combine information from different auscultation points, as well as consecutive sound cycles, are presented. The system is evaluated on a large clinical dataset of heart sounds from 265 term and late-preterm newborns recorded within the first six days of life. The developed system reaches an area under the curve (AUC) of 78% at detecting CHD and 77% at detecting PDA. The obtained results for PDA detection compare favourably with the level of accuracy achieved by an experienced neonatologist when assessed on the same cohort.

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P–541 Identification of novel variants and candidate genes in women with familial idiopathic premature ovarian failure using whole-exome sequencing

Human Reproduction ◽

10.1093/humrep/deab130.540 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

R Morale. Sabater ◽

B Lledo ◽

J A Ortiz ◽

F Lozano ◽

A Bernabeu ◽

...

Keyword(s):

Exome Sequencing ◽

Candidate Genes ◽

Allele Frequency ◽

Whole Exome Sequencing ◽

Minor Allele Frequency ◽

Premature Ovarian Failure ◽

Ovarian Function ◽

Ovarian Failure ◽

Minor Allele ◽

Whole Exome

Abstract Study question Is it possible to identify a genetic cause of familial premature ovarian failure (POF) with whole-exome sequencing (WES)? Summary answer Whole-exome sequencing is the most efficient strategy to identify probably pathogenic mutations in different genes in pathologies of polygenic etiology such as premature ovarian failure. What is known already Premature ovarian failure is the loss of ovarian function before the age of 40, and it is a common cause of infertility in women. This pathology has a heterogeneous etiology. Some chromosomal and genetic alterations have been described, and could explain approximately 20% of cases. However, in most patients the origin remains unknown. Recent studies with next-generation sequencing (NGS) have identified new variants in candidate genes related with premature ovarian insufficiency (POI) or premature ovarian failure (POF). These genes are not only involved in processes such as folliculogenesis, but also with DNA damage repair, homologous recombination, and meiosis. Study design, size, duration Fourteen women, from 7 families, affected by idiopathic POF were included in the study from October 2019 to September 2020. Seven POF patients were recruited when they came to our clinic to undergo assisted reproductive treatment. In the anamnesis, it was found that they had relatives with a diagnosis of POF, who were also recruited for the study. The inclusion criteria were amenorrhea before 38 years old and analytical and ultrasound signs of ovarian failure. Participants/materials, setting, methods WES was performed using TrusightOne (Illumina®). Sequenced data were aligned through BWA tool and GATK algorithm was used for SNVs/InDel identification. VCF files were annotated using Variant Interpreter software. Only the variants shared by each family were extracted for analysis and these criteria were followed: (1) Exonic/splicing variants in genes related with POF or involved in biological ovarian functions (2) Variants with minor allele frequency (MAF) ≤0.05 and (3) having potentially moderate/strong functional effects. Main results and the role of chance Seventy-nine variants possibly related with the POF phenotype were identified in the seven families. All these variants had a minor allele frequency (MAF) ≤0.05 in the gnomAD database and 1000 genomes project. Among these candidate variants, two were nonsense, six splice region, one frameshift, two inframe deletion and 68 missense. Thirty-two of the missense variants were predicted to have deleterious effects by minimum two of the four in silico algorithms used (SIFT, PolyPhen–2, MutationTaster and PROVEAN). All variants were heterozygous, and all the families carried three or more candidate variants. Altogether, 43 probably damaging genetic variants were identified in 39 genes expressed in the ovary and related with POF/POI or linked to ovarian physiology. We have described genes that have never been associated to POF pathology, however they may be involved in key biological processes for ovarian function. Moreover, some of these genes were found in two families, for example DDX11, VWF, PIWIL3 and HSD3B1. DDX11 may function at the interface of replication-coupled DNA repair and sister chromatid cohesion. VWF gene is suggested to be associated with follicular atresia in previous studies. PIWIL3 functions in development and maintenance of germline stem cells, and HSD3B1 is implicated in ovarian steroidogenesis. Limitations, reasons for caution Whole-exome sequencing has some limitations: does not cover noncoding regions of the genome, it also cannot detect large rearrangements, copy-number variants (large deletions/duplications), mosaic mutations, mutations in repetitive or high GC rich regions and mutations in genes with corresponding pseudogenes or other highly homologous sequences. Wider implications of the findings: WES has previously shown to be an efficient tool to identify genes as cause of POF, and has demonstrated the polygenic etiology. Although some studies have focused on it, and many genes are identified, this study proposes new candidate genes and variants, having potentially moderate/strong functional effects, associated with POF. Trial registration number Not applicable

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Whole exome sequencing identifies FOXL2, FOXA2 and FOXA3 as candidate genes for monogenic congenital anomalies of the kidneys and urinary tract

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab253 ◽

2021 ◽

Author(s):

Bixia Zheng ◽

Steve Seltzsam ◽

Chunyan Wang ◽

Luca Schierbaum ◽

Sophia Schneider ◽

...

Keyword(s):

Urinary Tract ◽

Exome Sequencing ◽

Candidate Genes ◽

Whole Exome Sequencing ◽

Congenital Anomalies ◽

De Novo ◽

Horseshoe Kidney ◽

Missense Variant ◽

Whole Exome ◽

Fox Genes

Abstract Background Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the most common cause of chronic kidney disease in the first three decades of life. Variants in four Forkhead box (FOX) transcription factors have been associated with CAKUT. We hypothesized that other FOX genes, if highly expressed in developing kidney, may also represent monogenic causes of CAKUT. Methods We here performed whole exome sequencing (WES) in 541 families with CAKUT and generated 4 lists of CAKUT candidate genes: A) 36 FOX genes showing high expression during renal development, B) 4 FOX genes known to cause CAKUT to validate list A; C) 80 genes that we identified as unique potential novel CAKUT candidate genes when performing WES in 541 CAKUT families, and D) 175 genes identified from WES as multiple potential novel CAKUT candidate genes. Results To prioritize potential novel CAKUT candidates in FOX gene family, we overlapped 36 FOX genes (list A) with list C and D of WES-derived CAKUT candidates. Intersection with list C, identified a de novo FOXL2 in-frame deletion in a patient with eyelid abnormalities and ureteropelvic junction obstruction, and a homozygous FOXA2 missense variant in a patient with horseshoe kidney. Intersection with list D, identified a heterozygous FOXA3 missense variant in a CAKUT family with multiple affected individuals. Conclusion We hereby identified FOXL2, FOXA2 and FOXA3 as novel monogenic candidate genes of CAKUT, supporting the utility of a paralog-based approach to discover mutated genes associated with human disease.

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Searching for the missing genetic determinants of hereditary breast cancer risk by whole-exome sequencing of BRCA-negative patients: new candidate genes USP39, SLIT3, CREB3

Problems in oncology ◽

10.37469/0507-3758-2021-67-1-111-116 ◽

2021 ◽

Vol 67 (1) ◽

pp. 111-116

Author(s):

Kirill Zagorodnev ◽

Aleksandr Romanko ◽

Uliy Gorgul ◽

Aleksandr Ivantsov ◽

Anna Sokolenko ◽

...

Keyword(s):

Breast Cancer ◽

Exome Sequencing ◽

Candidate Genes ◽

Whole Exome Sequencing ◽

Hereditary Breast Cancer ◽

Germ Line ◽

Genetic Diagnosis ◽

Clinical Signs ◽

Causative Mutation ◽

Whole Exome

The search for the new hereditary mutations and a precise molecular genetic diagnosis that determines the causative mutation in each specific case of hereditary breast cancer (BC) is a clinically important task since it helps to define the personal therapeutic approach and increase the effectiveness of preventive measures. Using whole-exome sequencing (WES) we analyzed the full spectrum of hereditary variations in 49 Russian patients with clinical signs of a hereditary disease which allowed us to compile a list of 229 candidate probably pathogenic germ-line variants. Then, the selected candidate mutations were validated by Sanger sequencing and molecular-epidemiological studies, the predisposing roles of three oncologically relevant mutations (USP39 c.*208G>C, SLIT3 p.Arg154Cys, and CREB3 p.Lys157Glu) were confirmed. Our candidate genes are first mentioned in connection with the hereditary risk of BC. The final proofs of the causative roles of these variants could be obtained through functional tests as well as via the analysis of the mutations segregation in BC families.

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