Diagnostic yield of genetic testing in heart transplant recipients with prior cardiomyopathy

Boen, Hanne M; Loeys, Bart; Alaerts, Maaike; Saenen, Johan; Goovaerts, Inge; Laer, Lut Van; Vorlat, Anne; Vermeulen, Tom; Franssen, Constantijn; Pauwels, Patrick; Rodrigus, Inez; Heidbüchel, Hein; Craenenbroeck, Emeline M. Van

doi:10.1016/j.healun.2022.03.020

Cited by 11 publications

(13 citation statements)

References 39 publications

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“…To date, only a few studies have provided genetic information about the genetic status of heart transplant recipients. They all provided interesting information about inherited cardiomyopathies, with a high genetic yield that improves depending on the cohort selection and the genes included in their NGS genetic panels [2,[40][41][42][43][44][45]. However, all such studies focused on inherited cardiomyopathies behind non-ischemic DCM, and none provided additional genetic information.…”

Section: Discussionmentioning

confidence: 99%

Opportunistic Genetic Screening for Familial Hypercholesterolemia in Heart Transplant Patients

Salgado

Díaz‐Molina

Cuesta‐Llavona

et al. 2023

JCM

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Heart transplantation remains the gold standard for the treatment of advanced heart failure (HF). Identification of the etiology of HF is mandatory, as the specific pathology can determine subsequent treatment. Early identification of familial hypercholesterolemia (FH), the most common genetic disorder associated with premature cardiovascular disease, has a potential important impact on clinical management and public health. We evaluated the genetic information in the genes associated with FH in a cohort of 140 heart-transplanted patients. All patients underwent NGS genetic testing including LDLR, APOB, and PCSK9. We identified four carriers of rare pathogenic variants in LDLR and APOB. Although all four identified carriers had dyslipidemia, only the one carrying the pathogenic variant LDLR c.676T>C was transplanted due to CAD. Another patient with heart valvular disease was carrier of the controversial LDLR c.2096C>T. Two additional patients with non-ischemic dilated cardiomyopathy were carriers of variants in APOB (c.4672A>G and c.5600G>A). In our cohort, we identified the genetic cause of FH in patients that otherwise would not have been diagnosed. Opportunistic genetic testing for FH provides important information to perform personalized medicine and risk stratification not only for patients but also for relatives at concealed high cardiovascular risk. Including the LDLR gene in standard NGS cardiovascular diagnostics panels should be considered.

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Section: Discussionmentioning

confidence: 99%

Opportunistic Genetic Screening for Familial Hypercholesterolemia in Heart Transplant Patients

Salgado

Díaz‐Molina

Cuesta‐Llavona

et al. 2023

JCM

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“…Em um estudo que identificou variantes patogênicas ou provavelmente patogênicas em pacientes transplantados cardíacos por CMD, o rastreamento familiar identificou variantes patogênicas em 39,6% dos familiares, e destes, a maioria (52,6%) não tinha fenótipo clínico da doença. 32 O diagnóstico em familiares é útil para iniciar o tratamento precoce, evitando a progressão da doença e morte súbita. 3 , 4 , 14 Os principais dados estão resumidos na figura central .…”

Section: Introductionunclassified

Desafios e Aplicações dos Testes Genéticos na Cardiomiopatia Dilatada: Genótipo, Fenótipo e Implicações Clínicas

Furquim,

Linnenkamp,

Olivetti

et al. 2023

Arquivos Brasileiros De Cardiologia

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Resumo Os testes genéticos para cardiomiopatia dilatada (CMD) apresentam uma positividade de até 40%, mas há uma grande heterogeneidade genética e outros desafios decorrentes de expressividade variável e penetrância incompleta. O heredograma é fundamental para diferenciar os casos de CMD esporádica e familiar, por meio da avaliação do histórico familiar. A CMD familiar apresenta um rendimento maior nos testes genéticos, mas a CMD esporádica não exclui a possibilidade de causa genética. Alguns genes têm fenótipos específicos, sendo o gene da Lamina ( LMNA ) o mais fortemente associado a um fenótipo de arritmias malignas e quadros de insuficiência cardíaca (IC) avançada. A presença de uma variante genética causal também pode ajudar na avaliação prognóstica, identificando quadros mais graves e com menores taxas de remodelamento reverso em comparação com indivíduos com genótipo negativo. As diretrizes atuais recomendam a avaliação e aconselhamento genético em indivíduos com CMD, além do rastreamento em cascata nos familiares de primeiro grau nos casos em que há uma ou mais variantes identificadas, sendo uma oportunidade para o diagnóstico e tratamento precoces. Familiares com genótipo positivo e fenótipo negativo são candidatos à avaliação seriada, com periodicidade que varia conforme a idade. O genótipo também auxilia na indicação individualizada de cardiodesfibrilador implantável e em recomendações quanto à atividade física e planejamento familiar. Estudos em curso esclarecem progressivamente os detalhes das relações genótipo/fenótipo de um grande número de variantes e fazem com que a genética molecular esteja cada vez mais presente na prática clínica.

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“…5 Another study reported 10 of 26 (38%) patients with DCM who had pathogenic variants. 6 Numerous other recent helpful DCM genetics studies with larger numbers of patients have been published, 2,3,[7][8][9][10][11][12] but these studies had few patients with advanced disease or were limited by patient selection on the basis of analysis of specific genes 7,9,11,12 or sequence availability, 10 or by a study design focused on reverse remodeling not conducive to inclusion of advanced cases of DCM. 8 Moreover, most had no information regarding race or ethnicity, 2,3,7,8,[10][11][12] or if information regarding race was provided, 9 had very few non-White participants.…”

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confidence: 99%

Rare Variant Genetics and Dilated Cardiomyopathy Severity: The DCM Precision Medicine Study

Hofmeyer,

Haas,

Jordan

et al. 2023

Circulation

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BACKGROUND: Dilated cardiomyopathy (DCM) can lead to advanced disease, defined herein as necessitating a durable left ventricular assist device or a heart transplant (LVAD/HT). DCM is known to have a genetic basis, but the association of rare variant genetics with advanced DCM has not been studied. METHODS: We analyzed clinical and genetic sequence data from patients enrolled between 2016 and 2021 in the US multisite DCM Precision Medicine Study, which was a geographically diverse, multiracial, multiethnic cohort. Clinical evaluation included standardized patient interview and medical record query forms. DCM severity was classified into 3 groups: patients with advanced disease with LVAD/HT; patients with an implantable cardioverter defibrillator (ICD) only; or patients with no ICD or LVAD/HT. Rare variants in 36 DCM genes were classified as pathogenic or likely pathogenic or variants of uncertain significance. Confounding factors we considered included demographic characteristics, lifestyle factors, access to care, DCM duration, and comorbidities. Crude and adjusted associations between DCM severity and rare variant genetic findings were assessed using multinomial models with generalized logit link. RESULTS: Patients’ mean (SD) age was 51.9 (13.6) years; 42% were of African ancestry, 56% were of European ancestry, and 44% were female. Of 1198 patients, 347 had LVAD/HT, 511 had an ICD, and 340 had no LVAD/HT or ICD. The percentage of patients with pathogenic or likely pathogenic variants was 26.2%, 15.9%, and 15.0% for those with LVAD/HT, ICD only, or neither, respectively. After controlling for sociodemographic characteristics and comorbidities, patients with DCM with LVAD/HT were more likely than those without LVAD/HT or ICD to have DCM-related pathogenic or likely pathogenic rare variants (odds ratio, 2.3 [95% CI, 1.5–3.6]). The association did not differ by ancestry. Rare variant genetic findings were similar between patients with DCM with an ICD and those without LVAD/HT or ICD. CONCLUSIONS: Advanced DCM was associated with higher odds of rare variants in DCM genes adjudicated as pathogenic or likely pathogenic, compared with individuals with less severe DCM. This finding may help assess the risk of outcomes in management of patients with DCM and their at-risk family members. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03037632.

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Diagnostic yield of genetic testing in heart transplant recipients with prior cardiomyopathy

Cited by 11 publications

References 39 publications

Opportunistic Genetic Screening for Familial Hypercholesterolemia in Heart Transplant Patients

Opportunistic Genetic Screening for Familial Hypercholesterolemia in Heart Transplant Patients

Desafios e Aplicações dos Testes Genéticos na Cardiomiopatia Dilatada: Genótipo, Fenótipo e Implicações Clínicas

Rare Variant Genetics and Dilated Cardiomyopathy Severity: The DCM Precision Medicine Study

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