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. 2022 Sep 1;24(8):1307-1367.
doi: 10.1093/europace/euac030.

European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases

Arthur A M Wilde  1 , Christopher Semsarian  2 , Manlio F Márquez  3   4 , Alireza Sepehri Shamloo  5 , Michael J Ackerman  6 , Euan A Ashley  7 , Eduardo Back Sternick  8 , Héctor Barajas-Martinez  9 , Elijah R Behr  10 , Connie R Bezzina  11 , Jeroen Breckpot  12 , Philippe Charron  13 , Priya Chockalingam  14 , Lia Crotti  15   16   17 , Michael H Gollob  18 , Steven Lubitz  19 , Naomasa Makita  20 , Seiko Ohno  21 , Martín Ortiz-Genga  22 , Luciana Sacilotto  23 , Eric Schulze-Bahr  24 , Wataru Shimizu  25 , Nona Sotoodehnia  26 , Rafik Tadros  27 , James S Ware  28   29 , David S Winlaw  30 , Elizabeth S Kaufman  31 ; Document Reviewers; Takeshi Aiba  32 , Andreas Bollmann  33   34 , Jong Il Choi  35 , Aarti Dalal  36 , Francisco Darrieux  37 , John Giudicessi  38 , Mariana Guerchicoff  39 , Kui Hong  40 , Andrew D Krahn  41 , Ciorsti MacIntyre  42 , Judith A Mackall  43 , Lluís Mont  44   45 , Carlo Napolitano  46   47 , Juan Pablo Ochoa  48   49   50 , Petr Peichl  51 , Alexandre C Pereira  52   53 , Peter J Schwartz  15 , Jon Skinner  54 , Christoph Stellbrink  55 , Jacob Tfelt-Hansen  56   57 , Thomas Deneke  58 ; Developed in partnership with and endorsed by the European Heart Rhythm Association (EHRA), a branch of the European Society of Cardiology (ESC), the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), and the Latin American Heart Rhythm Society (LAHRS).
Affiliations

European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases

Arthur A M Wilde et al. Europace. .

Erratum in

No abstract available

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Conflict of interest statement

Conflict of interest: none declared.

Figures

Figure 1
Figure 1
The genetic aetiology of cardiovascular diseases. Mendelian disease variants (upper left panel) are ultra-rare in the population and have large effect sizes, though often not sufficient in isolation to yield a disease phenotype. Mendelian genes and variants can be identified through analysis of family pedigrees or burden analysis in case–control studies and further validated with functional assays. Common variants (upper right panel) with individually small effect sizes may collectively contribute to disease burden or modulate the effects of Mendelian variants. Intermediate effect variants (upper middle panel) are emerging variant classes that usually have population frequencies and effect sizes between rare Mendelian and common variants and may act to increase severity and penetrance. Such variants can be identified by demonstrating enrichment in case cohorts and deleterious effects in established functional assays. These different variant classes can combine to reach the threshold of disease in patients with rare cardiovascular diseases and contribute to the variable severity observed in patients. Diseases such as HCM and LQTS are often Mendelian [1] or near-Mendelian where Mendelian variants of large effect sizes can combine with other variant classes to cause disease [2] or act as protective modifiers (e.g. regulatory variants affecting the expression ratio of the mutant vs. non-mutant alleles) [3]. In contrast, diseases such as BrS and DCM may exhibit a more complex aetiology where substantial non-Mendelian genetic and non-genetic factors are required to reach disease threshold in the presence of a low penetrance rare variant [4] or in a non-Mendelian disease model [5]. blue −, individual does not harbour the familial rare pathogenic variant; blue +, individual harbours the familial rare pathogenic variant; green −, individual does not harbour that intermediate effect variant; green +, individual harbours a given intermediate effect variant; GWAS, genome-wide association study; MAF, minor allele frequency; PRS, polygenic risk score; SNP, single-nucleotide polymorphism. Adapted from Walsh et al.
Figure 2
Figure 2
Genome-wide association studies (GWAS) test the association of common genetic variants with traits or diseases. Results are shown as a Manhattan plot (A) where the P-value (y-axis) is plotted against the genomic position (x-axis) for millions of common variants across the genome (blue markers). Polygenic risk scores (B) are generally derived from GWAS and calculated for an individual i (PRSi) as the sum of the products of allelic dosage (dosageij) by the regression coefficient/weight (bj) for all M genetic variants (j). Created with Biorender.com.
Figure 3
Figure 3
Clinical algorithm for genetic testing and family screening in long-QT syndrome.
Figure 4
Figure 4
Clinical algorithm for genetic testing and family screening in Brugada syndrome.
Figure 5
Figure 5
Clinical algorithm for genetic testing and family screening in short-QT syndrome. aAdapted from HRS/EHRA/APHRS Expert consensus recommendations on diagnosis of SQTS.  bAdapted from Gollob et al., see Supplementary material online, Table S9.
Figure 6
Figure 6
Flowchart of the work up of a sudden cardiac death or non-fatal cardiac arrest.
Figure 7
Figure 7
Genetic causes of congenital heart defects. Non-syndromic (lower panel) and syndromic (upper panel) cohorts. The diagram in the left panel displays the relative prevalence of the three broad CHD subgroups, namely syndromic CHD, sporadic non-syndromic CHD, and familial non-syndromic CHD. The diagrams in the central panel display the current yield of standard karyotyping, CMA and WES/WGS in the non-syndromic (lower panel) and syndromic (upper panel) cohorts, respectively, illustrating the low diagnostic yield in sporadic non-syndromic CHD, compared to the syndromic cohort. The pie diagrams at the right display the most common causes of aneuploidies and of CNVs, and the inheritance pattern of single gene defects. The percentages displayed in the diagrams are based on.,,,, CHD, congenital heart defect; CNV, copy number variant; T13, trisomy 13; T18, Trisomy 18; T21, trisomy 21; WBS, Williams–Beuren syndrome.
See this image and copyright information in PMC

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