Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands

Jin, Sheng Chih; Homsy, Jason; Zaidi, Samir; Lu, Qiongshi; Morton, Sarah U.; DePalma, Steven R.; Zeng, Xue; Qi, Hongjian; Chang, Wen-I; Sierant, Michael C.; Hung, Wei-Chien; Haider, Shozeb; Zhang, Junhui; Knight, James; Bjornson, Robert; Castaldi, Christopher; Tikhonoa, Irina R; Bilgüvar, Kaya; Mane, Shrikant; Sanders, Stephan; Mital, Seema; Russell, Mark W.; Gaynor, J. William; Deanfield, John; Giardini, Anna; Porter, George A.; Srivastava, Deepak; Lo, Cecilia; Shen, Yufeng; Watkins, W. Scott; Yandell, Mark; Yost, H. Joseph; Tristani‐Firouzi, Martin; Newburger, Jane W.; Roberts, Amy E.; Kim, Richard; Zhao, Hongyu; Kaltman, Jonathan R.; Goldmuntz, Elizabeth; Chung, Wendy K.; Seidman, Jonathan G.; Gelb, Bruce D.; Seidman, Christine E.; Lifton, Richard P.; Brueckner, Martina

doi:10.1038/ng.3970

Nat Genet

2017

DOI: 10.1038/ng.3970

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Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands

Sheng Chih Jin

¹

,

Jason Homsy

²

,

Samir Zaidi

³

et al.

Abstract: Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Exome sequencing of a single cohort of 2,871 CHD probands including 2,645 parent-offspring trios implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ~5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ~11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, inc… Show more

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Cited by 912 publications

(1,337 citation statements)

References 61 publications

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“…RGs were estimated to contribute to 5.4% (CI: 2.1% to 8.6%) of probands with laterality-associated cardiac defects compared to 1.4% (CI: −0.05% to 2.8%) of those without laterality-associated defects ( SI Appendix , Table S16 ). This is consistent with our previously published data ( 19 ). Consistent with these estimates, we identified RGs in known genes in 2.4% of probands with laterality-associated defects, and 0.9% of the remainder.…”

Section: Resultssupporting

confidence: 94%

Recessive genetic contribution to congenital heart disease in 5,424 probands

Dong

¹

,

Jin

²

,

Sierant

³

et al. 2025

Proc. Natl. Acad. Sci. U.S.A.

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Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.

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“…RGs were estimated to contribute to 5.4% (CI: 2.1% to 8.6%) of probands with laterality-associated cardiac defects compared to 1.4% (CI: −0.05% to 2.8%) of those without laterality-associated defects ( SI Appendix , Table S16 ). This is consistent with our previously published data ( 19 ). Consistent with these estimates, we identified RGs in known genes in 2.4% of probands with laterality-associated defects, and 0.9% of the remainder.…”

Section: Resultssupporting

confidence: 94%

Recessive genetic contribution to congenital heart disease in 5,424 probands

Dong

¹

,

Jin

²

,

Sierant

³

et al. 2025

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

Get access via publisher Add to dashboard Cite

Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.

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“…The HTX phenotype class was enriched for damaging recessive/biallelic variants in cilia-related genes (2.6-fold, CI 2.0-3.2) and showed proportionally higher enrichment in the subset of motile cilia genes modulated by FOXJ1 (6.9-fold, 3.3-10.4), findings consistent with previous reports 5,8,17 Patients with FOXJ1 pathway mutations accounted for four of nine HTX patients (44%) in the cilia enrichment subset. Damaged genes in the FOXJ1 pathway were ARMC4 , CCDC151 , DNAI1 , DRC1 , IFT172 , and SPEF2 .…”

Section: Resultssupporting

confidence: 91%

“…The HTX phenotype class was enriched for damaging recessive/biallelic variants in cilia-related genes (2.63-fold, CI 2.06-3.20) and showed proportionally higher enrichment in the subset of motile cilia genes modulated by FOXJ1 (6.89-fold, 3.30-10.36), findings consistent with previous reports 5,8,35 . The OTHER phenotype class was enriched for damaging de novo variants in chromatin-modifying genes (1.85-fold, CI 1.44-2.26) and the curated CHD genes (1.59-fold, CI 1.38-1.80) lists.…”

Section: Resultssupporting

confidence: 91%

Genome Sequencing is Critical for Forecasting Outcomes Following Congenital Cardiac Surgery

Watkins

¹

,

Hernández

²

,

Miller

³

et al. 2024

Preprint

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1

0

Get access via publisher Add to dashboard Cite

Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.

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“…As regards expression, de novo genotypes are about twice as likely to occur in embryonic HHE genes than are recessive ones. This trend is slightly more pronounced when gene function is taken into account; for example, P (HighHeart|chromatin, de novo, ¬ recessive)/ P (HighHeart|cilia, recessive, ¬ de novo) = 2.8, in general agreement with previous reports 3–5 .…”

Section: Resultssupporting

confidence: 91%

“…3i). Consistent with prior publications that have documented an excess of de novo variants in chromatin genes 3–5 , the enrichment of de novo variants in the chromatin list exceeds that observed for recessive variants, with VAAST identifying 77 damaged genes in 76 probands (3.2% of all probands) having de novo damaging variants (permutation p value < 1e −5 ; Fig. 3j).…”

Section: Resultssupporting

confidence: 89%

De novo and recessive forms of congenital heart disease have distinct genetic and phenotypic landscapes

Watkins

¹

,

Hernández

²

,

Wesołowski

³

et al. 2019

Self Cite

Get access via publisher Add to dashboard Cite

Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.

show abstract

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