Impact of a 22q11.2 Microdeletion on Adult All-Cause Mortality in Tetralogy of Fallot Patients

Mil, Spencer van; Heung, Tracy; Małecki, S; Van, Lily; Chang, Janis; Breetvelt, Elemi J.; Wald, Rachel M.; Oechslin, Erwin; Silversides, Candice K.; Bassett, Anne S.

doi:10.1016/j.cjca.2020.04.019

Cited by 17 publications

(10 citation statements)

References 26 publications

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“…They reported a 5-fold increase in the risk of mortality for subjects with 22q11 after adjusting for the presence of pulmonary atresia. 26 Unlike those results, we found no influence of 22q11 on the risk of mortality in cTOF subjects from birth to 30 years of age, suggesting a shift in the mortality risk of these patients later in life. Our study adds to the current literature by providing stratified survival estimates and morbidity outcomes for TOF-PA and for specific genetic conditions such as T21, 22q11 deletions, and complex syndromes.…”

Section: Prevalence Of Tof Types and Genetic Conditionscontrasting

confidence: 98%

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The 30-Year Outcomes of Tetralogy of Fallot According to Native Anatomy and Genetic Conditions

Blais

Marelli

Vanasse

et al. 2021

Canadian Journal of Cardiology

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Section: Prevalence Of Tof Types and Genetic Conditionscontrasting

confidence: 98%

“…Results: We included 960 subjects. The median follow-up was 17 years (interquartile range, [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. Nonsyndromic cTOF subjects had a 30-year survival of 95% and had undergone a mean of 2.8 interventions and 0.5 hospitalisations per subject.…”

Section: Discussionmentioning

confidence: 99%

The 30-Year Outcomes of Tetralogy of Fallot According to Native Anatomy and Genetic Conditions

Blais

Marelli

Vanasse

et al. 2021

Canadian Journal of Cardiology

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“…[6][7][8][9] The pursuit of determining the genetic underpinnings and recognizing how these may affect late outcomes in TOF has proceeded in parallel with these clinical advances. [10][11][12][13] This research began with the recognition of multisystem syndromes in ≈20% of patients, most commonly caused by 22q11.2 microdeletions, other copy number variants, or aneuploidies, 14 along with some single gene defects. 15 Availability of newer genomic technologies, particularly genome-wide sequencing, has expanded gene discovery studies.…”

mentioning

confidence: 99%

Clinical Genetic Risk Variants Inform a Functional Protein Interaction Network for Tetralogy of Fallot

Reuter

Chaturvedi

Jobling

et al. 2021

Circ: Genomic and Precision Medicine

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Background - Tetralogy of Fallot (TOF), the most common cyanotic heart defect in newborns, has evidence of multiple genetic contributing factors. Identifying variants that are clinically relevant is essential to understand patient-specific disease susceptibility and outcomes, and could contribute to delineating pathomechanisms. Methods - Using a clinically-driven strategy, we re-analyzed exome sequencing data from 811 probands with TOF, to identify rare loss-of-function and other likely pathogenic variants in genes associated with congenital heart disease (CHD). Results - We confirmed a major contribution of likely pathogenic variants in FLT4 (VEGFR3; n=14) and NOTCH1 (n=10), and identified 1-3 variants in each of 21 other genes, including ATRX , DLL4 , EP300 , GATA6 , JAG1 , NF1 , PIK3CA , RAF1 , RASA1 , SMAD2 , and TBX1 . In addition, multiple loss-of-function variants provided support for three emerging CHD/TOF candidate genes: KDR (n=4), IQGAP1 (n=3), and GDF1 (n=8). In total, these variants were identified in 63 probands (7.8%). Using the 26 composite genes in a STRING protein interaction enrichment analysis revealed a biologically relevant network (p-value 3.3e-16), with VEGFR2 ( KDR ) and NOTCH1 representing central nodes. Variants associated with arrhythmias/sudden death and/or heart failure indicated factors that could influence long-term outcomes. Conclusions - The results are relevant to precision medicine for TOF. They suggest considerable clinical yield from genome-wide sequencing, with further evidence for KDR (VEGFR2) as a CHD/TOF gene, and for vascular endothelial growth factor (VEGF) and Notch signaling as mechanisms in human disease. Harnessing the genetic heterogeneity of single gene defects could inform etiopathogenesis and help prioritize novel candidate genes for TOF.

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“…Identifying the genetic etiologies of TOF can improve clinical management, by providing information on outcomes and risks related to the variant, in addition to those related to the cardiac anatomical severity and other clinical parameters 13, 48, 49 . After the surgical repair of TOF, heart failure and arrhythmias are leading causes of morbidity, impaired quality of life, and mortality.…”

Section: Discussionmentioning

confidence: 99%

“…The pursuit of determining the genetic underpinnings and recognizing how these may affect late outcomes in TOF, has proceeded in parallel with these clinical advances 10-13 . This research began with the recognition of multi-system syndromes in approximately 20% of patients, most commonly caused by 22q11.2 microdeletions, other copy number variants, or aneuploidies 14 , along with some single-gene defects 15 .…”

Section: Introductionmentioning

confidence: 99%

Clinical genetic risk variants inform a functional protein interaction network for tetralogy of Fallot

Reuter

Chaturvedi

Jobling

et al. 2021

Preprint

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Background: Tetralogy of Fallot (TOF), the most common cyanotic heart defect in newborns, has evidence of multiple genetic contributing factors. Identifying variants that are clinically relevant is essential to understand patient-specific disease susceptibility and outcomes, and could contribute to delineating pathomechanisms. Methods and Results: We used a clinically-driven strategy and current guidelines to re-analyze exome sequencing data from 811 probands with TOF, focused on identifying rare loss-of-function and other likely pathogenic variants in congenital heart disease (CHD) genes. In addition to confirming a major contribution of likely pathogenic variants in FLT4 (VEGFR3; n=14) and NOTCH1 (n=11), we identified 1-3 such variants in each of 21 other CHD genes, including ATRX, DLL4, EP300, GATA6, JAG1, NF1, PIK3CA, RAF1, RASA1, SMAD2, and TBX1. There were also three emerging CHD/TOF candidate genes with multiple loss-of-function variants in this cohort: KDR (n=4), IQGAP1 (n=3), and GDF1 (n=8). In total, these variants were identified in 64 probands (7.9%). Using the 26 composite genes in a STRING protein interaction enrichment analysis revealed a biologically relevant network (p-value 3.3e-16), with VEGFR2 (KDR) and NOTCH1 representing central nodes. Variants associated with arrhythmias/sudden death and/or heart failure indicated factors that could influence long-term outcomes. Conclusions: The results are relevant to precision medicine for TOF. They suggest considerable clinical yield from genome-wide sequencing, and further evidence for KDR as a CHD/TOF gene and VEGF and Notch signaling as mechanisms in human disease. Harnessing genetic heterogeneity of single gene defects could inform etiopathogenesis and help prioritize novel candidate genes for TOF.

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Impact of a 22q11.2 Microdeletion on Adult All-Cause Mortality in Tetralogy of Fallot Patients

Cited by 17 publications

References 26 publications

The 30-Year Outcomes of Tetralogy of Fallot According to Native Anatomy and Genetic Conditions

The 30-Year Outcomes of Tetralogy of Fallot According to Native Anatomy and Genetic Conditions

Clinical Genetic Risk Variants Inform a Functional Protein Interaction Network for Tetralogy of Fallot

Clinical genetic risk variants inform a functional protein interaction network for tetralogy of Fallot

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