Haploinsufficiency of vascular endothelial growth factor related signaling genes is associated with tetralogy of Fallot

Reuter, Miriam S.; Jobling, Rebekah; Chaturvedi, Rajiv; Manshaei, Roozbeh; Costain, Gregory; Heung, Tracy; Curtis, Meredith; Hosseini, S. Mohsen; Liston, Eriskay; Lowther, Chelsea; Oechslin, Erwin; Sticht, Heinrich; Thiruvahindrapuram, Bhooma; Mil, Spencer van; Wald, Rachel M.; Walker, Susan; Marshall, Christian R.; Silversides, Candice K.; Scherer, Stephen W.; Kim, Raymond H.; Bassett, Anne S.

doi:10.1038/s41436-018-0260-9

Cited by 59 publications

(105 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We performed multiple test correction on all genes with a defined probability, and also on a more constrained subset: for truncating variants, gnomAD LOF o/e < 0.35; for missense variants, gnomAD missense o/e < 0.75 (where o/e indicates observed/expected; see Supplementary Figure S1 for the relation to the pLI and missense z-score constraint indexes). Constrained genes are presumed to be more likely to contribute to disease, since they are under negative selection; these thresholds were specifically set to include moderately constrained genes, considering the incomplete penetrance observed for TOF (5,6,8). There were 603 genes with at least one truncating singleton variant, of which 163 passed the constraint threshold; there were 2801 genes with at least one singleton missense variant, of which 739 passed the constraint threshold (see Supplementary Table S2 and Supplementary Table S3 for details).…”

Section: Resultsmentioning

confidence: 99%

“…In an independent case-only study using whole genome sequencing (WGS), we investigated 175 adults with TOF for rare loss-of-function variants (including structural variants) disrupting FLT4 and other vascular endothelial growth factor (VEGF) pathway genes predicted to be haploinsufficient based on the ExAC pLI index (6,7). We identified seven truncating variants in FLT4 , two in KDR , and one each in BCAR1 , FGD5 , FOXO1 , IQGAP1 and PRDM1 , corresponding in aggregate to 8% of participants; all variants were absent from public databases 6 .…”

Section: Introductionmentioning

confidence: 99%

“…In this study, we undertook a comprehensive statistical re-analysis of the cohort with WGS data previously investigated for ultra-rare variants in the VEGF pathway (6). In an attempt to boost power, we included the sequencing data available for 56 CHD cases as well as for the original 175 TOF cases (n=231 total).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Genes and pathways implicated in tetralogy of Fallot revealed by ultra-rare variant burden analysis in 231 genome sequences

Manshaei

Merico

Reuter

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Recent genome-wide studies of rare genetic variants have begun to implicate novel mechanisms for tetralogy of Fallot (TOF), a severe congenital heart defect (CHD).To provide statistical support for case-only data without parental genomes, we re-analyzed genome sequences of 231 individuals with TOF or related CHD. We adapted a burden test originally developed for de novo variants to assess singleton variant burden in individual genes, and in gene-sets corresponding to functional pathways and mouse phenotypes, accounting for highly correlated gene-sets, and for multiple testing.The gene burden test identified a significant burden of deleterious missense variants in NOTCH1 (Bonferroni-corrected p-value <0.01). These NOTCH1 variants showed significant enrichment for those affecting the extracellular domain, and especially for disruption of cysteine residues forming disulfide bonds (OR 39.8 vs gnomAD). Individuals with NOTCH1 variants, all with TOF, were enriched for positive family history of CHD. Other genes not previously implicated in TOF had more modest statistical support and singleton missense variant results were non-significant for gene-set burden. For singleton truncating variants, the gene burden test confirmed significant burden in FLT4. Gene-set burden tests identified a cluster of pathways corresponding to VEGF signaling (FDR=0%), and of mouse phenotypes corresponding to abnormal vasculature (FDR=0.8%), that suggested additional candidate genes not previously identified (e.g., WNT5A and ZFAND5). Analyses using unrelated sequencing datasets supported specificity of the findings for CHD.The findings support the importance of ultra-rare variants disrupting genes involved in VEGF and NOTCH signaling in the genetic architecture of TOF. These proof-of-principle data indicate that this statistical methodology could assist in analyzing case-only sequencing data in which ultra-rare variants, whether de novo or inherited, contribute to the genetic etiopathogenesis of a complex disorder.Author summaryWe analyzed the ultra-rare nonsynonymous variant burden for genome sequencing data from 231 individuals with congenital heart defects, most with tetralogy of Fallot. We adapted a burden test originally developed for de novo variants. In line with other studies, we identified a significant truncating variant burden for FLT4 and deleterious missense burden for NOTCH1, both passing a stringent Bonferroni multiple-test correction. For NOTCH1, we observed frequent disruption of cysteine residues establishing disulfide bonds in the extracellular domain. We also identified genes with BH-FDR <10% that were not previously implicated. To overcome limited power for individual genes, we tested gene-sets corresponding to functional pathways and mouse phenotypes. Gene-set burden of truncating variants was significant for vascular endothelial growth factor signaling and abnormal vasculature phenotypes. These results confirmed previous findings and suggested additional candidate genes for experimental validation in future studies. This methodology can be extended to other case-only sequencing data in which ultra-rare variants make a substantial contribution to genetic etiology.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Genes and pathways implicated in tetralogy of Fallot revealed by ultra-rare variant burden analysis in 231 genome sequences

Manshaei

Merico

Reuter

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…CTDs exist among several syndromic diseases along with extracardiac symptoms and 22q11.2 deletion syndrome is a notable one . According to recent studies, many gene mutations, including those that encode transcription factors, structural proteins and signaling molecules related to heart formation, have been identified and suspected to be responsible for CTD . However, the etiology of a majority of CTDs is still far from distinct.…”

Section: Introductionmentioning

confidence: 99%

“…6 According to recent studies, many gene mutations, including those that encode transcription factors, structural proteins and signaling molecules related to heart formation, have been identified and suspected to be responsible for CTD. [7][8][9] However, the etiology of a majority of CTDs is still far from distinct. This underlines the importance of further research on correlation mechanism.…”

Section: Introductionmentioning

confidence: 99%

Identification of FOXH1 mutations in patients with sporadic conotruncal heart defect

Wei

et al. 2020

Clinical Genetics

View full text Add to dashboard Cite

Conotruncal heart defects (CTD) are an important subtype of congenital heart disease that occur due to abnormality in the development of the cardiac outflow tract (OFT). FOXH1 is a transcription factor that participates in the morphogenesis of the right ventricle and OFT. In this study, we confirmed the expression of FOXH1 in mouse and human embryos during OFT development. We also scanned the coding exons and splicing regions of the FOXH1 gene in 605 patients with sporadic CTD and 300 unaffected controls, from which we identified seven heterozygous FOXH1 gene mutations. According to bioinformatics analysis results, they were predicted potentially deleterious at conserved amino acid sites. Western blot was used to show that all the variants decreased the expression of FOXH1 protein, while dual‐luciferase reporter assay showed that six of them, with an exception of p.P35R, had enhanced abilities to modulate the expression of MEF2C, which interacts with NKX2.5 and is involved in cardiac growth. The electrophoretic mobility shift assays result showed that two mutations altered DNA‐binding abilities of mutant FOXH1 proteins. Phenotype heterogeneity was found in patients with the same mutation. These results indicate that FOXH1 mutations lead to disease‐causing functional changes that contribute to the occurrence of CTD.

show abstract

Two novel variations p.(Ser1275Thr) and p.(Ser1275Arg) in FLT4 causing prenatal hereditary lymphedema type 1

Lajmi

Lœuillet²,

Petrilli³

et al. 2022

Birth Defects Research

View full text Add to dashboard Cite

Background Hereditary lymphedema 1 is a rare congenital condition, characterized by the development of chronic swelling in body parts. It is highly variable in expression and age of onset with different presentations: from feet edema to hydrops fetalis. This affection is genetically heterogeneous with autosomal dominant inheritance and incomplete penetrance due to a mutation in the FLT4 gene in most cases. Cases In our study, we report on two fetuses harboring congenital lymphedema with FLT4 variation and review the prenatal confirmed ones of the literatures. Our cases were selected within fetuses explored by exome sequencing in a diagnosis setting. Prenatal ultrasonography showed hydrops fetalis in one case and an increased nuchal translucency with hydrothorax in the other. Comparative genomic hybridization array on amniocentesis was normal in both cases. Exome sequencing identified a variation p.(Ser1275Thr) and p.(Ser1275Arg) in fetus 1 and fetus 2 in the FLT4 gene, respectively. A de novo mutation at the same codon was reported in prenatal literature suggesting possible genotype phenotype correlation. Conclusion Cystic hygroma/hydrops fetalis are possible manifestations of several disorders. This study illustrates how the integration of exome sequencing in prenatal clinical practice can facilitate the diagnosis and genetic counseling of heterogeneous developmental affections.

show abstract

Haploinsufficiency of vascular endothelial growth factor related signaling genes is associated with tetralogy of Fallot

Abstract: Loss-of-function variants in FLT4 and KDR contribute substantially to the genetic basis of TOF. The findings support dysregulated VEGF signaling as a novel mechanism contributing to the pathogenesis of TOF.

Cited by 59 publications

References 20 publications

Genes and pathways implicated in tetralogy of Fallot revealed by ultra-rare variant burden analysis in 231 genome sequences

Genes and pathways implicated in tetralogy of Fallot revealed by ultra-rare variant burden analysis in 231 genome sequences

Identification of FOXH1 mutations in patients with sporadic conotruncal heart defect

Two novel variations p.(Ser1275Thr) and p.(Ser1275Arg) in FLT4 causing prenatal hereditary lymphedema type 1

Contact Info

Product

Resources

About