SPC365

Different variants, same gene: similar or different evolutionary behavior throughout life?

Session: Sessão de Posters 17 - Genética em Cardiologia 2
Speaker: Catarina Gregório

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: Catarina Gregório; Ana Beatriz Garcia; Marta Vilela; Daniel Cazeiro; Oana Moldovan; Hugo Madeira; Fausto J. Pinto; Dulce Brito

<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:11.0pt"><span style="color:black"><strong>Introduction:</strong> Pathogenic mutations in the <em>MYH7</em> gene are widely recognized as a cause of hypertrophic cardiomyopathy (HCM), demonstrating a spectrum of effect sizes, as evident in different penetrance and regarding the diverse phenotypic expression of HCM. Despite the knowledge about the different causal genes, the relationship between individual variants and phenotypes is incomplete.</span></span></span></span></p>

<p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:11.0pt"><span style="color:black"><strong>Aim: </strong>The aim of this study was to determine the phenotype expression and outcomes of different variants in the <em>MYH7</em> gene.</span></span></span></span></p>

<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:11.0pt"><span style="color:black"><strong>Methods: </strong>This study was a single center retrospective/prospective analysis of 29 unrelated families with sarcomeric HCM and pathogenic or likely pathogenic (P/LP) mutations<em> </em>in the<em> MYH7</em> gene. We analyzed the most common variants identified in the cohort. Patient&acute;s (pts) characteristics (clinical, ECG, echocardiographic) were evaluated at the time of diagnosis and at the last follow up (FUP) visit. Kaplan-Meier survival analysis was used to estimate disease progression.</span></span></span></span></p>

<p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:11.0pt"><span style="color:black"><strong>Results: </strong>The authors studied 115 pts from 29 families with P/LP MYH7 gene mutations. From 75 genetic carriers (51 pts G+Ph+; 24 pts G+Ph-), the most common variants (16 in total) identified by Next Generation Sequencing were: A) p.Ile263Thr </span></span><span style="font-size:11.0pt"><span style="color:black">[</span></span><span style="font-size:11.0pt"><span style="color:black">4Families (F), n=28</span></span><span style="font-size:11.0pt"><span style="color:black">]</span></span><span style="font-size:11.0pt"><span style="color:black">; B) p.Ala797Thr (4F, n=8); C) p.Glu1356Lys (3F, n=8); and D) p.Arg663His (1F, n=7). Globally median follow up was 14.3&plusmn;2 years (0.2-47) years. In total population, 25 pts were male, mean age at diagnosis was 35.7&plusmn;2.5 years, and 7 pts present outflow left ventricular obstruction (LVOTO) at diagnosis. Median maximal wall thickness was 13.5&plusmn;9 mm and left atrial dimension was 37.2&plusmn;9 mm. Regarding functional capacity, 25.5% of pts were at class II or III of NYHA at diagnosis. Most pts were diagnosed in the context of family screening (30 patients, 59%). Comparation of clinical characteristics between variants is described in Figure 1. </span></span></span></span></p>

<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:11.0pt"><span style="color:black">Behavior of mutations were similar regarding atrial fibrillation (new diagnosis in 5 pts), PMK implantation (7 pts) and ICD implantation for primary prevention (A: 1 pt; C: 1 pt). In total, 3 pts progress to LVOTO (A: 1pt, B:1 pt). All pts evolved with mild progression of LV hypertrophy, independently of the variant (p=0.06). No differences were observed between variants (p=0.86) regarding LV ejection fraction during FUP. </span></span></span></span></p>

<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:11.0pt"><span style="color:black">A clinical composite endpoint of Heart Failure hospitalization, CV hospital admission (arrythmia, acute coronary syndrome or stroke) and death were analyzed and no differences occurred between the 4 variants (LogRank 7.3, p=0.06 &ndash; Figure 1), despite the different FUP time of pts with different variants. During the global mean follow-up time of 14.3&plusmn;2 years penetrance of all variants was 64.7%.</span></span></span></span></p>

<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:11.0pt"><span style="color:black"><strong>Conclusion: </strong>The four variants exhibit a similar evolutive pattern and a relatively benign prognosis showing progression to mild/moderate left ventricular hypertrophy during follow-up, accompanied by a limited number of clinical events.</span></span></span></span></p>