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Editorial
. 2018 Jun;10(Suppl 17):S1923-S1929.
doi: 10.21037/jtd.2018.05.56.

The new era of whole-exome sequencing in congenital heart disease: brand-new insights into rare pathogenic variants

Ares Pasipoularides  1
Affiliations
Editorial

The new era of whole-exome sequencing in congenital heart disease: brand-new insights into rare pathogenic variants

Ares Pasipoularides. J Thorac Dis. 2018 Jun.
No abstract available

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Conflict of interest statement

Conflicts of Interest: The author has no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Genetic variants affecting CHD risk can be characterized by the frequency of the pathogenic allele and the size of the phenotypic effect that it has, as shown. Crossed out are two portions of the figure space that we can practically disregard straightaway: In the lower left, near the origin of both the coordinate axes, are variant alleles that have very small effects and are present in very low frequencies, which would require enormous population samples for reliable detection. In the upper right are variant alleles that have very large effects and are common; generally, pathogenic variants with very large effects are under negative selection and are almost certainly uncommon. In consequence, most emphasis/interest lies in ascertaining associations with characteristics displayed within the diagonal dotted lines, which reflect current understanding of the genetic architecture of complex diseases. Different from Mendelian diseases that are monogenic and caused by high-impact rare pathogenic mutations, complex diseases are largely polygenic and arise from cumulative effects of many low-to-modest impact genetic variants interacting with modifier-gene background, epigenetic, and environmental factors. Furthermore, certain risk-variants might not be located in protein-coding exome-regions amenable to WES and EWAS and, consequently, might require GWAS for identification/characterization, as shown in the graphic. CHD, congenital heart disease; WES, whole-exome sequencing; EWAS, exome-wide association study/studies; GWA/GWAS, genome-wide association study/studies.
Figure 2
Figure 2
Left-heart, high-fidelity, solid-state multisensor catheterization in hypertrophic cardiomyopathy (HCM). (A) Deep left ventricular (LVP) and aortic root pressures (AOP) in HCM at rest and during supine bicycle exercise, which elicits an abnormal LVP diastolic decay, suggesting impaired ventricular relaxation; LVP decays throughout diastole, in sharp contrast to the normal pattern shown on the lower right. (B) Pressure-flow relationship with large early and enormous mid- and late-systolic dynamic gradients in hypertrophic cardiomyopathy. From top downward: aortic velocity signal, and deep left ventricular (LV), left ventricular outflow tract (LVOT), and aortic root (AO) micromanometric signals, measured by retrograde triple-tip pressure plus velocity multisensor left-heart catheter. Left atrial (LA) micromanometric signal was measured simultaneously by trans-septal catheter. The vertical straight line identifies the onset of SAM-septal contact, determined from a simultaneous M-mode mitral valve echocardiogram (not shown); most of the aortic ejection flow is already completed by this time. The huge mid- and late- systolic gradient (hatched area) is maintained in the face of minuscule remaining forward or even negative aortic velocities. (C) Normal left-heart hemodynamics at rest and exercise. Adapted from Pasipoularides (1,7), with permission of PMPH-USA, and the Journal of Molecular and Cellular Cardiology and Elsevier, respectively. SAM, systolic anterior motion of the mitral valve.
See this image and copyright information in PMC

Comment on

  • Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.
    Jin SC, Homsy J, Zaidi S, Lu Q, Morton S, DePalma SR, Zeng X, Qi H, Chang W, Sierant MC, Hung WC, Haider S, Zhang J, Knight J, Bjornson RD, Castaldi C, Tikhonoa IR, Bilguvar K, Mane SM, Sanders SJ, Mital S, Russell MW, Gaynor JW, Deanfield J, Giardini A, Porter GA Jr, Srivastava D, Lo CW, Shen Y, Watkins WS, Yandell M, Yost HJ, Tristani-Firouzi M, Newburger JW, Roberts AE, Kim R, Zhao H, Kaltman JR, Goldmuntz E, Chung WK, Seidman JG, Gelb BD, Seidman CE, Lifton RP, Brueckner M. Jin SC, et al. Nat Genet. 2017 Nov;49(11):1593-1601. doi: 10.1038/ng.3970. Epub 2017 Oct 9. Nat Genet. 2017. PMID: 28991257 Free PMC article.

References

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