SPC365

INTERPRETING GENETIC TESTING FOR INHERITED CARDIAC DISORDERS

Session: Sessão de Posters 17 - Genética em Cardiologia 2
Speaker: Diana Antunes

Congress: CPC 2024
Topic: F. Valvular, Myocardial, Pericardial, Pulmonary, Congenital Heart Disease
Theme: 20. Congenital Heart Disease and Pediatric Cardiology
Subtheme: 20.6 Congenital Heart Disease – Clinical
Session Type: Cartazes
FP Number: ---
Authors: Diana Antunes; Rafael Graça; Catarina Silveira; Yuri Chiodo; Silvia Aguiar Rosa; Maria Carmo Fonseca
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:10.0pt"><span style="font-family:&quot;Arial&quot;,sans-serif">Introduction:</span></span></strong></span></span></p>

<p style="text-align:justify">The financial and societal impact of hereditary cardiac diseases (HCD) is widely acknowledged. One of the most prevalent of these conditions is Hypertrophic Cardiomyopathy (HCM) which affects 1:200 to 1:500 people. In 2022 it was published the&ldquo;Expert Consensus Statement on the state of genetic testing for cardiac diseases&rdquo;, which appeared to be converging in a downgrade for genetic testing in hereditary cardiac diseases (HCD).</p>

<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:10.0pt"><span style="font-family:&quot;Arial&quot;,sans-serif">Methods:</span></span></strong></span></span></p>

<p style="text-align:justify">We conducted a retrospective analysis from the results of the genetic testing carried out for suspected HCD between November 2015 and August 2023. The primary goal<br />
was to validate in-house results, as well to evaluate the applicability of the 2022 Consensus.</p>

<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:10.0pt"><span style="font-family:&quot;Arial&quot;,sans-serif">Results:</span></span></strong></span></span></p>

<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="font-family:&quot;Arial&quot;,sans-serif">978 genetic tests were categorized in<u><span style="color:teal">:</span></u> Hypertrophic Cardiomyopathy (HCM, N=395), Dilated Cardiomyopathy (DCM, N=274), Brugada Syndrome (BS, N=117), Arrhythmogenic Cardiomyopathy (ACM, N=48), Unspecified Cardiomyopathy (uCM, N=40), Unexplained Cardiac Arrest (uCA, N=27), Rhythm Disorders (RD, N=26), Non-compaction cardiomyopathy (NCM, N=24), and Long QT Syndrome (LQT, N=23).</span></span></span></span></p>

<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="font-family:&quot;Arial&quot;,sans-serif">Pathogenic (P) or likely pathogenic (LP)&nbsp; variants were identified in 209 patients with an overall diagnostic yield of 21.37% (N=209): ACM 31.25% (N=15), NCM 29,17% (N=6), HCM 25.32% (N=100), RD 23.08% (N=6), DCM 22.71% (N=62), uCA 18.52% (N=5), uCM 12.5% (N=5), LQT 17.39% (N=4), and BS 4.27% (N=5). </span></span></span></span></p>

<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="font-family:&quot;Arial&quot;,sans-serif">P/LP variants were identified in the following genes for HCM: <em>ACTN2, ALPK3, CSRP3, FHOD3, GLA, KCNQ1, MYBPC3</em> (35%, N=35), <em>MYH7</em> (31%, N=31), <em>MYL2, PRKAG2, RBM20, RYR2, SLC25A4, TNNC1, TNNI3, TNNT2, TPM1, TRIM63 &ndash; </em>and for DCM: <em>DSP, FLNC, GLA, LMNA</em> (11.29%, N=7), <em>MYBPC3, MYH7, PKP2, RBM20, RYR2, SCN5A, TCAP, TNNT2, TPM1, TTN </em>(38.71%, N=24), <em>TTR</em> (6.45%, N=5).</span></span></span></span></p>

<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="font-family:&quot;Arial&quot;,sans-serif">Double genetic diagnoses (GD) were found in 2.39% of cases (N=5) - HCM 3% (N=3) and DCM 3.23% (N=2).&nbsp;P/LP Copy Number Variants (CNVs) were identified in 1,4% of&nbsp;&nbsp;cases (N=3).</span></span></span></span></p>

<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="font-size:10.0pt"><span style="font-family:&quot;Arial&quot;,sans-serif">Discussion:</span></span></strong></span></span></p>

<p style="text-align:justify">The results revealed GD for HCM and BS lower than expected. More than half of the HCM GD were attributed to <em>MYBPC3</em> and <em>MYH7</em>, while all BS cases were associated to <em>SCN5A, </em>as previouslyy reported. The most prevalent DCM GD&nbsp;was <em>TTN,&nbsp;</em>as anticipated.&nbsp;P/LP variants were found in genes not covered by the 2022 Consensus, such as <em>GLA</em> in HCM or<em> TTR</em> in DCM. Although the guidelines recommend restraining from genetic testing in non-well defined phenotypes, P/LP variants were detected at significant rates in conditions categorized as less consensual such as uCM, RD and NCM.</p>

<p style="text-align:justify"><strong>Conclusion:</strong></p>

<p style="text-align:justify">An overall diagnostic yield &gt;20% for patients suspected of having HCD, underscores the urgency of mainstreaming genetic testing.&nbsp;The primary focus should be on empowering multidisciplinary teams, comprising cardiologists specialized in HCD, including rhythm disorders and cardiomyopathies, as well as clinical and laboratory geneticists, to facilitate discussions and enhance patient care.</p>