Outcomes of post mortem genetic diagnosis in SCD victims and primary prevention of cardiac arrest in relatives: a nationwide multidisciplinary and multicentric collaboration in the Czechia

2021 ◽  
Vol 28 (Supplement_1) ◽  
Author(s):  
A Krebsova ◽  
P Votypka ◽  
P Peldova ◽  
K Rucklova ◽  
M Kulvajtova ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Primary Prevention ◽  
Genetic Analysis ◽  
Massively Parallel Sequencing ◽  
Family Members ◽  
Genetic Diagnosis ◽  
Sudden Infant ◽  
Post Mortem ◽  
Custom Made ◽  
Acute Dissection

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Supported by Ministry of Health of the Czech Republic Introduction Post mortem genetic analysis in sudden cardiac death (SCD) represents an important diagnostic tool for the primary prevention of cardiac arrest in victim´s relatives.  Purpose To assess the underlying molecular pathogenesis of SCD in a representative Czech cohort and to evaluate the effects of primary prevention of SCD in genetic relatives.  Patients and Methods Between 2016 and 2020 we have ascertained 100 SCD cases (29 females/71 males; age range 0-52 years). According to autopsy protocols, cases with SCD were divided into categories of sudden arrhythmic death (SADS), sudden unexplained death (in infants; SUD/SUDI), thoracic aortic aneurysm/dissection and cardiomyopathy hypertrophic, arrhythmic, dilated (HCM, ACM, DCM) and sudden infant death syndrome (SIDS). DNA was isolated from post mortem biopsies / relatives blood and subjected to massively parallel sequencing (Illumina, USA) comprising custom-made candidate gene panel (100 genes). Genetic counselling and cardiological examinations were carried out in 245 family members.  Results According to post mortem-established diagnosis, we identified 20 victims with SADS and SUD/SUDI, 11 with HCM and DCM, 19 with ACMG, 8 SIDS cases and 9 acute dissection cases. Most of victims died at sleep or at rest, while only 10/100 victims died during strenuous sport activities. About 50% of SCD victims did not report any apparent cardiac complaints. Highly likely or certain molecular etiology (i.e. based on presence of ACMG.net Class 4 to 5 variants) was disclosed in 19/100 (19%) in RYR2, KCNH2, SCN5A, FLNC (stop), TTN, RBM 20, LMNA/C, PRKAG2, MYBPC3, DSC2, FHL1, TGFBR1 and Col3A1 genes (see Tab). Finally, we identified 52/241 phenotype/genotype positive family members who are at risk of cardiac arrest and were offered  corresponding cardiological care. Conclusion Multidisciplinary cooperation, together with centralized and standardized molecular genetic testing, enables the primary prevention of cardiac arrest in relatives of SCD victims. Results of post mortem genetic analysis Post mortem diagnosis Nr. Gender Age (years) Nr. of positive cases (DNA variant class IV or V) Gene Nr. examined relatives/phenotype or genotype positive cases SADS 20 8 females12 males 3-52 5/20 (25%) KCNH2 3x RYR2RANGFR 56/11 SUD/SUDI 20 5 females, 15 males 0-50 1/18 (5%, 2 non informative cases) RYR2 45/9 HCM 11 0 females11 males 14-52 3/11 (27%) MYBPC3FHL1PRKAG2 26/9 DCM 11 3 females8 males 8-48 4/11 (36%) TTN (3x)RBM 20FLNC (stop) 24/7 ACM 19 9 females10 males 17 - 49 4/19 (21%) SCN5AFLNC (stop)DSC2LMNA/C 58/9 SIDS 8 3 females5 males < 1 0/8 - 12/0 Acute dissection 9 1 female8 males 16-49 2/9 (22%) TGFBR1Col3A1 24/7

scholarly journals Comparison of variant detection rate in genes between two cohorts of Czech living patients versus victims of sudden cardiac death with clinical / post mortem diagnosis of non-ischemic cardiomyopathy

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
E Borisincova ◽  
P Votypka ◽  
K Rucklova ◽  
A Pilin ◽  
M Kulvajtova ◽  
...  
Keyword(s):  
At Risk ◽  
Czech Republic ◽  
Primary Prevention ◽  
Sudden Cardiac Death ◽  
Genetic Counselling ◽  
Cardiac Death ◽  
Detection Rate ◽  
Funding Source ◽  
Post Mortem ◽  
Custom Made

Abstract Introduction Hereditary cardiomyopathy is associated with an increased risk of ventricular arrhythmia and sudden cardiac death (SCD). Genetic stratification substantiates risk assessment and enables the primary prevention of SCD in relatives at risk. We have analyzed the genetic aetiology of SCD in a representative Czech cohort with post mortem diagnosis of various forms of cardiomyopathy and compared it to living cases with these cardiac disorders. Patients and methods Between 2018 and 2019, altogether 47 victims of SCD with post mortem diagnosis of hypertrophic- (HCM; 18/47), arrhythmogenic- (ACM; 19/47) and dilated cardiomyopathy (DCM; 10/47) were identified. Concurrently, genetic testing was performed in 114 living patients (HCM 54/114, ACM 22/114, DCM 38/114). Genetic counselling and cardiologic examination had been carried out in first-degree relatives in all patients/SCD victims. Massively parallel sequencing (MiSeq platform; Illumina.com) was utilized for a custom-made panel comprising 100 candidate genes (Sophia Genetics, Switzerland). The presence of pathogenic variants was validated by Sanger DNA sequencing and through family segregation analyses. Results The causative detection rate (according to ACMG.net classes 4 or 5) in SCD victims with DCM was 60% (6/10) and in living patients with DCM 47.4% (18/38). Variants in TTN, RBM20, DES and FLNC (mainly truncating variants) prevailed in both groups. The detection rate in ACM was 5% (1/19 in SCN5A gene) in SCD victims and 31.8% (7/22) in living patients. Interestingly, the most prevalent mutated gene PKP2 in living patients was not detected in SCD victims. The detection rate in SCD victims with post mortem diagnosis of HCM was 16% (3/18) and in living patients 35% (19/54). The most prevalent gene was MYBPC3 in both groups, while PRKAG2 was detected in one SCD victim and in one living case who survived cardiac arrest. Conclusion Post-mortem genetic analysis in DCM yields a high detection rate and allows potentially effective primary prevention of SCD in relatives at risk. In contrast, the molecular autopsy of HCM and ACM renders a much lower yield which is below the mutation detection rate in living phenotype positive individuals. The results help to improve the genetic counselling in affected families in Czech Republic. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Ministry of Health of the Czech Republic

scholarly journals Post-Mortem Review and Genetic Analysis of Sudden Infant Death Syndrome (SIDS) Cases

2012 ◽  
Vol 21 ◽  
pp. S270
Author(s):  
A. Evans ◽  
R. Bagnall ◽  
E. Tu ◽  
J. Duflou ◽  
C. Semsarian
Keyword(s):  
Genetic Analysis ◽  
Sudden Infant Death Syndrome ◽  
Infant Death ◽  
Sudden Infant Death ◽  
Sudden Infant ◽  
Post Mortem

MULTIPLE ENDOCRINE NEOPLASIA IN PRACTICE OF PRIMARY CARE AND FAMILY PHYISICIANS

2020 ◽  
pp. 11-15
Author(s):  
V. I Pozhar ◽  
O. V. Doroshenko ◽  
M. I. Shevchuk
Keyword(s):  
Family History ◽  
Genetic Analysis ◽  
Multiple Endocrine Neoplasia ◽  
Ganglion Cells ◽  
Family Members ◽  
Clinical Manifestations ◽  
Neurofibromatosis Type ◽  
Endocrine Tumors ◽  
Endocrine Neoplasia ◽  
Cutaneous Lichen Amyloidosis

Multiple endocrine neoplasia is characterized with a predisposition to tumors involving two or more endocrine glands. The four main forms of the disease are inherited as an autosomal dominant syndrome or may occur sporadically. In addition to these four forms, six other syndromes are associated with the presence of multiple endocrine and other neoplasms of the organs: hyperparathyroidism − jaw tumors, Carney complex, von Hippel−Lindau disease, neurofibromatosis type 1, Cowden syndrome and McCune − Albright syndrome. The diagnosis of multiple endocrine neoplasia syndrome can be established in humans by one of the three available criteria: clinical features, family history, genetic analysis. Mutation analysis during these syndromes is useful in clinical practice to confirm the clinical diagnosis; identifying family members who tolerate the mutation and need to be screened, and identifying family members who do not tolerate the mutation. Syndrome of multiple endocrine neoplasia (Wermer syndrome) is characterized by the presence of a triad of tumors, including tumors of the parathyroid glands, pheochromocytoma and tumors of the parathyroid gland. It occurs less frequently in combination with Hirschsprung's disease, caused by the absence of vegetative ganglion cells in the intestine terminal parts, that leads to colonic enlargement, severe constipation and obstruction. This syndrome may be associated with cutaneous lichen amyloidosis, the clinical manifestations of which are pruritus and lichenoid lesions, usually located in the upper back. A clinical case of MEN2 syndrome in a 52−year−old patient is presented. It is noted that for such patients, in addition to timely syndromic rather than component diagnosis of this endocrine multipathology, the spread of neoplastic process in medullary thyroid cancer to its capsule and surrounding tissues, as well as the presence of metastases in peripheral lymph nodes are important. As a rule, such patients cannot be timely cured. Key words: multiple endocrine neoplasia, endocrine tumors, genetic analysis, family history.

scholarly journals Ethical issues in genomics research on neurodevelopmental disorders: a critical interpretive review

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
S. Mezinska ◽  
L. Gallagher ◽  
M. Verbrugge ◽  
E.M. Bunnik
Keyword(s):  
Informed Consent ◽  
Neurodevelopmental Disorders ◽  
Cognitive Abilities ◽  
Social Impact ◽  
Mental Health Problems ◽  
Ethical Issues ◽  
Family Members ◽  
Genetic Diagnosis ◽  
Research Participation ◽  
Genomic Research

Abstract Background Genomic research on neurodevelopmental disorders (NDDs), particularly involving minors, combines and amplifies existing research ethics issues for biomedical research. We performed a review of the literature on the ethical issues associated with genomic research involving children affected by NDDs as an aid to researchers to better anticipate and address ethical concerns. Results Qualitative thematic analysis of the included articles revealed themes in three main areas: research design and ethics review, inclusion of research participants, and communication of research results. Ethical issues known to be associated with genomic research in general, such as privacy risks and informed consent/assent, seem especially pressing for NDD participants because of their potentially decreased cognitive abilities, increased vulnerability, and stigma associated with mental health problems. Additionally, there are informational risks: learning genetic information about NDD may have psychological and social impact, not only for the research participant but also for family members. However, there are potential benefits associated with research participation, too: by enrolling in research, the participants may access genetic testing and thus increase their chances of receiving a (genetic) diagnosis for their neurodevelopmental symptoms, prognostic or predictive information about disease progression or the risk of concurrent future disorders. Based on the results of our review, we developed an ethics checklist for genomic research involving children affected by NDDs. Conclusions In setting up and designing genomic research efforts in NDD, researchers should partner with communities of persons with NDDs. Particular attention should be paid to preventing disproportional burdens of research participation of children with NDDs and their siblings, parents and other family members. Researchers should carefully tailor the information and informed consent procedures to avoid therapeutic and diagnostic misconception in NDD research. To better anticipate and address ethical issues in specific NDD studies, we suggest researchers to use the ethics checklist for genomic research involving children affected by NDDs presented in this paper.

Postmortem genetic analysis of sudden unexpected death in infancy: neonatal genetic screening may enable the prevention of sudden infant death

2017 ◽  
Vol 62 (11) ◽  
pp. 989-995 ◽  
Author(s):  
Yuki Oshima ◽  
Takuma Yamamoto ◽  
Taisuke Ishikawa ◽  
Hiroyuki Mishima ◽  
Aya Matsusue ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Infant Death ◽  
Genetic Screening ◽  
Sudden Infant Death ◽  
Sudden Unexpected Death ◽  
Sudden Infant ◽  
Unexpected Death

scholarly journals Early Detection of Widespread Progressive Brain Injury after Cardiac Arrest: A Single Case DTI and Post-Mortem Histology Study

PLoS ONE ◽  
2014 ◽  
Vol 9 (3) ◽  
pp. e92103 ◽  
Author(s):  
Jan S. Gerdes ◽  
Ernst U. Walther ◽  
Suad Jaganjac ◽  
Maria Makrigeorgi-Butera ◽  
Sven G. Meuth ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Brain Injury ◽  
Early Detection ◽  
Single Case ◽  
Post Mortem

Abstract 87: Assessment of Stroke Caregiver Readiness: A Primary Prevention Strategy

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Barbara J Lutz ◽  
Mary Ellen Young
Keyword(s):  
Primary Prevention ◽  
Family Caregivers ◽  
Family Members ◽  
Inpatient Rehabilitation ◽  
Stroke Survivors ◽  
Post Discharge ◽  
Readiness Assessment ◽  
Increased Risk ◽  
Transition Home

Introduction: More than 3.5 million family caregivers provide assistance with activities and instrumental activities of daily living for stroke survivors living at home. Studies consistently indicate that stroke family caregivers are inadequately assessed and under prepared for their new caregiver roles and responsibilities as stroke survivors transition home from inpatient rehabilitation. Several tools exist to assess caregivers once they have assumed the caregiving role, however, there are no tools assess stroke caregiver readiness prior to discharge. Research has indicated the need for a thorough and systematic pre-discharge assessment of the caregiver’s ability to assume the caregiving role. The purpose of this presentation is to describe ten critical stroke caregiver readiness assessment domains and to discuss their relevance for long-term outcomes for stroke survivors and family caregivers. Methods: In this grounded theory study, data were collected from19 persons with stroke and 19 family caregivers. Semi-structured interviews were conducted during inpatient rehabilitation and within 6 months post-discharge. First interviews focused on expectations for recovery and caregiving needs post-discharge. Follow-up interviews focused on how families managed the transition from rehabilitation to home and how their initial expectations matched the reality of their post-discharge experience. Interviews were analyzed using dimensional analysis and coded in NVivo data management software. Findings: Participants indicated that stroke was an overwhelming, life changing crisis event. Family members felt abandoned, isolated, and under prepared to assume the fulltime caregiving role as stroke survivors transitioned home. They described using ineffective or risky caregiving strategies that resulted in safety and health issues for both stroke survivors and caregivers. Ten pre-discharge caregiver readiness assessment domains were identified in the interviews and a corresponding stroke caregiver readiness assessment interview guide was developed. Conclusion: Stroke survivors and family caregivers are extremely vulnerable as they transition home from inpatient rehabilitation leaving them at risk for poorer health, depression, and increased risk for injury. In order to prevent these deleterious outcomes, caregivers should be assessed, and potential areas of risk identified and addressed prior to discharge from inpatient rehabilitation. As new interventions are developed to improve survival rates for persons with stroke, we must also develop and implement primary prevention strategies for family members who are called upon to provide care following discharge to protect their health and improve the long-term recovery outcomes for the stroke survivor.

Concealed cardiomyopathy as a frequent cause of idiopathic ventricular fibrillation in a representative Czech cohort of survivors of sudden cardiac arrest (SCA)

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
A Krebsova ◽  
P Votypka ◽  
P Peldova ◽  
J Haskova ◽  
T Tavacova ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Genetic Testing ◽  
Ventricular Fibrillation ◽  
Dna Sequencing ◽  
Clinical Diagnostics ◽  
Idiopathic Ventricular Fibrillation ◽  
Custom Made ◽  
Diagnostic Work ◽  
Work Up ◽  
Diagnostic Work Up

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Health of the Czech Republic Introduction The complex diagnostic work up in SCA survivors often does not yield a concrete cardiological diagnosis. Moreover, there is conflicting evidence whether genetic testing could support or guide clinical diagnostics. Purpose To assess the molecular architecture of idiopathic ventricular fibrillation in cases without apparent evidence of specific structural or arrhythmic cardiac disease at initial diagnostic work up in a representative Czech cohort. Patients and Methods Between 2013 - 2020 we have ascertained 100 SCA survivors (54 M / 46 F; age range at cardiac arrest 5-69 years). Genetic counselling was followed by massively parallel DNA sequencing using custom-made panels comprising 100 cardiac conditions-related genes. Subsequently, thorough cardiological screening examinations in first degree relatives were carried out. Presence of pathogenic variants was validated by Sanger DNA sequencing and through family segregation analyses. Results Highly likely or certain molecular aetiology (i.e. based on the presence of Class 4 or 5 variants) was disclosed in 20/100 (20%) in PKP2 (3x), SCN5A (4x), RYR2 (3x), TTN (2x), PLN, FLNC, PRKAG2, KCNH2, KCNQ1, SLC4A, TNNT2, and DSP. Interestingly, the KCNE1 p.Asp85Asn (LQT 5 lite) variant, was detected in further 3/100 cases, representing a recognized risk factor for ventricular arrhythmias. Conclusions Genetic testing facilitates stratification of the cause of arrhythmia in a substantial portion of SCA survivors. The utility of positive outcomes of genetic testing was substantiated in 10/20 gene positive patients, where the genetic stratification led to diagnosis of concealed arrhythmogenic cardiomyopathy, whose extent of morphological changes was under the diagnostic sensibility of imaging modalities or ECG. Our results enable individualized care in SCA survivors and assure targeted preventive approaches in their relatives.

Sign in / Sign up

Export Citation Format

Share Document