molecular autopsy
Recently Published Documents


TOTAL DOCUMENTS

109
(FIVE YEARS 32)

H-INDEX

23
(FIVE YEARS 2)

2021 ◽  
Vol 79 (12) ◽  
pp. 1368-1371
Author(s):  
Agnieszka Zienciuk-Krajka ◽  
Magdalena Chmara ◽  
Monika Lica-Gorzynska ◽  
Karolina Dorniak ◽  
Joanna Kwiatkowska ◽  
...  

2021 ◽  
Vol 64 (11) ◽  
pp. 104322
Author(s):  
Eline Simons ◽  
Alain Labro ◽  
Johan Saenen ◽  
Aleksandra Nijak ◽  
Ewa Sieliwonczyk ◽  
...  

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Hanan E. Shamseldin ◽  
Lama AlAbdi ◽  
Sateesh Maddirevula ◽  
Hessa S. Alsaif ◽  
Fatema Alzahrani ◽  
...  

Abstract Background Molecular autopsy refers to DNA-based identification of the cause of death. Despite recent attempts to broaden its scope, the term remains typically reserved to sudden unexplained death in young adults. In this study, we aim to showcase the utility of molecular autopsy in defining lethal variants in humans. Methods We describe our experience with a cohort of 481 cases in whom the cause of premature death was investigated using DNA from the index or relatives (molecular autopsy by proxy). Molecular autopsy tool was typically exome sequencing although some were investigated using targeted approaches in the earlier stages of the study; these include positional mapping, targeted gene sequencing, chromosomal microarray, and gene panels. Results The study includes 449 cases from consanguineous families and 141 lacked family history (simplex). The age range was embryos to 18 years. A likely causal variant (pathogenic/likely pathogenic) was identified in 63.8% (307/481), a much higher yield compared to the general diagnostic yield (43%) from the same population. The predominance of recessive lethal alleles allowed us to implement molecular autopsy by proxy in 55 couples, and the yield was similarly high (63.6%). We also note the occurrence of biallelic lethal forms of typically non-lethal dominant disorders, sometimes representing a novel bona fide biallelic recessive disease trait. Forty-six disease genes with no OMIM phenotype were identified in the course of this study. The presented data support the candidacy of two other previously reported novel disease genes (FAAH2 and MSN). The focus on lethal phenotypes revealed many examples of interesting phenotypic expansion as well as remarkable variability in clinical presentation. Furthermore, important insights into population genetics and variant interpretation are highlighted based on the results. Conclusions Molecular autopsy, broadly defined, proved to be a helpful clinical approach that provides unique insights into lethal variants and the clinical annotation of the human genome.


2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
J M Murphy ◽  
C W Kirk ◽  
J Galvin ◽  
D Ward ◽  
T Prendiville ◽  
...  

Abstract Background Inherited cardiomyopathies (hypertrophic, dilated and arrhythmogenic) and cardiac ion channelopathies (long QT, Brugada and CPVT) predispose to sudden cardiac death/sudden arrhythmic death syndrome. Given their genetically heterogenous nature, multi-gene DNA sequencing panels are useful to aid genetic diagnosis. Purpose Investigate the diagnostic yield from cardiac gene panel testing undertaken in patients (including molecular autopsy in deceased patients) referred to four clinical services from 2002 to 2020. Methods Data was collected by interrogation of departmental databases, family charts, and review of molecular genetic diagnostic reports. Results We evaluated molecular genetic diagnostic results from 835 individuals (461 males, 374 females) from 824 families, including 58 deceased patients who underwent molecular autopsy. The median age of the cohort was 44 years (range 0.1–86 years). Testing for hypertrophic cardiomyopathy (HCM) and long QT syndrome (LQT) genes represented 36% and 32% of the cohort, respectively, with the remaining 32% accounting for other cardiomyopathies, arrhythmia syndromes or metabolic/syndromic diseases. The overall variant detection rate was 50% across all panel types. Three hundred and fifty patients (42%) carried a single variant, 68 patients (8%) carried multiple variants (up to a maximum of four), including two individuals who carried two actionable (pathogenic/likely pathogenic) variants each and 30 individuals (5%) with one actionable variant plus a variant of uncertain significance (VUS). The overall diagnostic yield of at least one actionable variant was 28%. At least one VUS was detected in 27% of the cohort. Molecular autopsy yielded an actionable variant in 10% of patients, while 30% of the subcohort carried at least one VUS (up to maximum of two). We found a positive association between female sex and the likelihood of detecting an actionable variant. By decade of age, detection of actionable variants ranged from 19% (60–69 years) to 41% (0–9 years). By panel type, actionable variants ranged from 14% (Brugada) to 35% (cardiomyopathy). The burden of VUS ranged from 22% (LQT) to 46% (dilated cardiomyopathy). Altogether 234 actionable variants were detected in 26 genes, including seven metabolic or syndromic disease genes. From those with non-metabolic/syndromic forms of disease, 84% of actionable variants were detected in well established ICC genes. Analysis of gene-disease associations for VUS detected from HCM and LQT panels revealed that 10–25% were detected in genes now deemed to have only moderate or limited evidence of disease causation. Conclusion Most actionable variants in this cohort were detected in well-established ICC genes, suggesting that large gene panels offer little extra sensitivity compared to historic smaller gene panels. Despite recent gene curation efforts, the high burden of VUS remains a considerable challenge in ICC management. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): National Children's Research Centre


2021 ◽  
Author(s):  
Malak Alghamdi ◽  
Ameinah Alrasheedi ◽  
Esra Alghamdi ◽  
Nouran Adly ◽  
Wajeih Y. AlAali ◽  
...  

Diagnostics ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1378
Author(s):  
Vincenzo Castiglione ◽  
Martina Modena ◽  
Alberto Aimo ◽  
Enrica Chiti ◽  
Nicoletta Botto ◽  
...  

Molecular autopsy is the process of investigating sudden death through genetic analysis. It is particularly useful in cases where traditional autopsy is negative or only shows non-diagnostic features, i.e., in sudden unexplained deaths (SUDs), which are often due to an underlying inherited arrhythmogenic cardiac disease. The final goal of molecular autopsy in SUD cases is to aid medico-legal inquiries and to guide cascade genetic screening of the victim’s relatives. Early attempts of molecular autopsy relied on Sanger sequencing, which, despite being accurate and easy to use, has a low throughput and can only be employed to analyse a small panel of genes. Conversely, the recent adoption of next-generation sequencing (NGS) technologies has allowed exome/genome wide examination, providing an increase in detection of pathogenic variants and the discovery of newer genotype-phenotype associations. NGS has nonetheless brought new challenges to molecular autopsy, especially regarding the clinical interpretation of the large number of variants of unknown significance detected in each individual.


2021 ◽  
Vol 8 ◽  
Author(s):  
Maria Pia Leone ◽  
Pietro Palumbo ◽  
Johan Saenen ◽  
Sandra Mastroianno ◽  
Stefano Castellana ◽  
...  

Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder with an estimated prevalence between 1:2,000 and 1:5,000 and is characterized by the fibrofatty replacement of cardiomyocytes that predisposes to malignant arrhythmias, heart failure, and sudden cardiac death. The diagnosis is based on the 2010 Task Force Criteria including family history, electrocardiographic traits and arrhythmogenic pattern, specific gene mutations, and structural and/or histological abnormalities. Most ACMs display an autosomal dominant mode of inheritance often with incomplete penetrance and variable expressivity. Genetic screening of patients with ACM identifies pathogenic or likely pathogenic variants, prevalently in genes encoding the cardiac desmosome (PKP2, DSP, DSC2, DSG2, and JUP) or less frequently in non-desmosomal genes (CTNNA3, PLN, TMEM43, RYR2, SCN5A, CDH2, and DES).Methods: In the present study, we performed molecular autopsy in a boy who died suddenly during physical exertion. In addition to post-mortem examination, a DNA sample was analyzed with next-generation sequencing (NGS).Results: The genetic analysis revealed the presence of pathogenic heterozygous c.314del (p.Pro105Leufs*7) frameshift variant in the PKP2 gene. Cascade screening of family members allowed us to identify 12 mutation carriers and to intervene on subjects at risk, many of whom were athletes.Conclusions: Molecular autopsy can establish cardiogenetic diagnosis and allow appropriate preventative measures in high-risk relatives.


EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
AM Delgado-Vega ◽  
J Klar ◽  
V Kommata ◽  
N Dahl ◽  
A Wisten ◽  
...  

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Uppsala University Hospital (ALF) and Marcus Börgström Foundation Background The post-mortem investigation of cases with sudden cardiac death (SCD) is critical for risk stratification and adequate care of surviving relatives. Genetic testing is limited by access to DNA from the proband, as blood samples are not routinely collected at the time of death, or DNA of poor quality obtained from formalin-fixed paraffin-embedded (FFPE) tissues. Whole exome sequencing (WES) on minute amounts of DNA has opened up for the possibility to use DNA from Dried Blood Spots (DBS). Purpose To evaluate the feasibility of WES on DNA from archived DBS collected at the time of newborn screening in cases of SCD.  Methods Through National Health Databases and Registries, we identified all cases of SCD in the young (<35 y.o.a.) in Sweden with a post-mortem diagnosis of ARVC between 2000 and 2010 (n = 22). Clinical records, medical and family histories, and autopsy findings were collected. Surviving parents were invited to participate. DNA was extracted from samples in National Biobanks such as DBS collected at birth (n = 19), formalin-fixed paraffin-embedded (FFPE) heart tissues (n = 8) from autopsies, and frozen blood samples (n = 3). Patient and parental DNA samples (when available) underwent WES. DNA- and sequencing-quality check (QC) metrics were compared between two different sequencing platforms and specimen types. We analysed 392 cardiomyopathy and arrhythmia genes and variants were classified as pathogenic or likely pathogenic according to the criteria from the American College of Medical Genetics. Results A higher quality but a lower yield of DNA (7.3 – 140 ng) was obtained from DBS when compared to FFPE samples (515 – 3065 ng). However, 100% of DBS vs. 62,5% of FFPE samples passed QC before sequencing. The average mean target depth for DBS samples (160X) was similar to that in blood samples (155X) and higher than FFPE (82X). Furthermore, >97% of target regions were covered with read depths >30X in DNA from DBS and blood compared to 88% for FFPE samples (Min 63%; Max 97%). Analysis of WES data uncovered clinically relevant variants in 12 out of 19 families (63%), of which four were located in ARVC genes. In six cases, the molecular autopsy identified another arrhythmogenic syndrome. Additionally, we identified one SCD with hemochromatosis and one with myotonic dystrophy as a possible contributing cause. In two additional families, variants of unknown significance fulfilled criteria for further segregation analysis. The concordance of positive results between different tissue samples was 100%. Conclusions DNA obtained from DBS has a quality comparable to that of blood and is a reliable source for WES-based molecular autopsy that may improve the diagnostic yield in cases of SCD. In a proportion of cases diagnosed post-mortem with ARVC, our molecular autopsy analysis pointed to a different diagnosis, highlighting its importance for the correct medical care of surviving relatives.


2021 ◽  
Vol 10 (9) ◽  
pp. 1806
Author(s):  
Mercedes Iglesias ◽  
Tomas Ripoll-Vera ◽  
Consuelo Perez-Luengo ◽  
Ana Belen García ◽  
Susana Moyano ◽  
...  

Background: Sudden death (SD) in the young usually has an underlying genetic cause. In many cases, autopsy reveals unspecific and inconclusive results, like idiopathic left ventricular hypertrophy (LVH), nonsignificant coronary atherosclerosis (CA), and primary myocardial fibrosis (PMF). Their pathogenicity and their relation to SD cause is unknown. This study aims to evaluate the diagnostic yield of genetic testing in these cases. Methods: SD cases, between 1 and 50 years old, with findings of uncertain significance (idiopathic LVH, nonsignificant CA and PMF) on autopsy were evaluated prospectively, including information about medical and family history and circumstances of death. Genetic testing was performed. Results: In a series of 195 SD cases, we selected 31 cases presenting idiopathic LVH (n = 16, 51.61%), nonsignificant CA (n = 17, 54.84%), and/or PMF (n = 24, 77.42%) in the autopsy. Mean age was 41 ± 7.2 years. Diagnostic yield of genetic test was 67.74%, considering variants of unknown significance (VUS), pathogenic variants (PV) and likely pathogenic variants (LPV); 6.45% including only PV and LPV. Structural genes represented 41,93% (n = 13) of cases, while 38,7% (n = 12) were related to channelopathies. Conclusion: Molecular autopsy in SD cases between 1 and 50 years old, with findings of uncertain significance, has a low diagnostic yield, being VUS the most frequent variant observed.


Author(s):  
Laura Jane Heathfield ◽  
Hugh Watkins ◽  
Lorna Jean Martin ◽  
Raj Ramesar

AbstractSudden unexpected death in infants (SUDI) is a devastating event, and unfortunately occurs frequently in developing countries. The emerging molecular autopsy has added value to post-mortem investigations, where genetic variants were able to explain the unexpected demise. Many of these variants have been found in genes involved in arrythmia pathways. The aim of this study was to sequence 43 genes previously associated with cardiac arrhythmia in a selected cohort of SUDI cases (n = 19) in South Africa. A total of 335 variants were found among the 19 infants, of which four were novel. The variants were classified as “likely pathogenic” (n = 1), “variant of unknown significance” (n = 54), “likely benign” (n = 56) or “benign” (n = 224). The likely pathogenic variant was LMNA NM_170707.2:c.1279C > T (p.Arg427Cys) and was found in a 3-week-old male infant of African ancestry. Variants in LMNA have previously been associated with dilated cardiomyopathy, with a typical age of onset in adulthood; therefore, this may be the first report in an infant. The yield of pathogenic or likely pathogenic variants in the classic genes typically associated with channelopathies and sudden death, was less in this study compared with other settings. This finding highlights the importance of population-specific research to develop a molecular autopsy which is locally relevant.


Sign in / Sign up

Export Citation Format

Share Document