scholarly journals Lethal variants in humans: lessons learned from a large molecular autopsy cohort

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Hanan E. Shamseldin ◽  
Lama AlAbdi ◽  
Sateesh Maddirevula ◽  
Hessa S. Alsaif ◽  
Fatema Alzahrani ◽  
...  
Keyword(s):  
Diagnostic Yield ◽  
Premature Death ◽  
Causal Variant ◽  
Lessons Learned ◽  
Chromosomal Microarray ◽  
Disease Genes ◽  
Clinical Approach ◽  
Molecular Autopsy ◽  
Targeted Gene Sequencing ◽  
Gene Panels

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.

scholarly journals Diagnostic yield from cardiac gene panel testing for inherited cardiac conditions in a large Irish cohort

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
J M Murphy ◽  
C W Kirk ◽  
J Galvin ◽  
D Ward ◽  
T Prendiville ◽  
...  
Keyword(s):  
Diagnostic Yield ◽  
Molecular Genetic ◽  
Gene Panel ◽  
Long Qt ◽  
Molecular Autopsy ◽  
Panel Testing ◽  
Gene Panel Testing ◽  
Cardiac Gene ◽  
Gene Panels ◽  
Actionable Variants

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

scholarly journals Uptake and Diagnostic Yield of Chromosomal Microarray in an Australian Child Development Clinic

Children ◽  
2014 ◽  
Vol 1 (1) ◽  
pp. 21-30
Author(s):  
Dylan Mordaunt ◽  
Michael Gabbett ◽  
Melanie Waugh ◽  
Karen O'Brien ◽  
Helen Heussler
Keyword(s):  
Child Development ◽  
Diagnostic Yield ◽  
Chromosomal Microarray ◽  
Australian Child

scholarly journals Next-Generation Sequencing Gene Panels and “Solo” Clinical Exome Sequencing Applied in Structurally Abnormal Fetuses

2021 ◽  
pp. 1-11
Author(s):  
Montse Pauta ◽  
Berta Campos ◽  
Maria Segura-Puimedon ◽  
Gemma Arca ◽  
Alfons Nadal ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Exome Sequencing ◽  
Diagnostic Yield ◽  
Monogenic Disease ◽  
Chromosomal Microarray Analysis ◽  
Next Generation ◽  
Clinical Exome Sequencing ◽  
Gene Panels ◽  
Generation Sequencing ◽  
Structural Anomalies

<b><i>Objective:</i></b> The aim of the study was to assess the diagnostic yield of 2 different next-generation sequencing (NGS) approaches: gene panel and “solo” clinical exome sequencing (solo-CES), in fetuses with structural anomalies and normal chromosomal microarray analysis (CMA), in the absence of a known familial mutation. <b><i>Methodology:</i></b> Gene panels encompassing from 2 to 140 genes, were applied mainly in persistent nuchal fold/fetal hydrops and in large hyperechogenic kidneys. Solo-CES, which entails sequencing the fetus alone and only interpreting the Online Mendelian Inheritance in Man genes, was performed in multisystem or recurrent structural anomalies. <b><i>Results:</i></b> During the study period (2015–2020), 153 NGS studies were performed in 148 structurally abnormal fetuses with a normal CMA. The overall diagnostic yield accounted for 35% (53/153) of samples and 36% (53/148) of the fetuses. Diagnostic yield with the gene panels was 31% (15/49), similar to 37% (38/104) in solo-CES. <b><i>Conclusions:</i></b> A monogenic disease was established as the underlying cause in 35% of selected fetal structural anomalies by gene panels and solo-CES.

scholarly journals Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test

2017 ◽  
Vol 20 (4) ◽  
pp. 435-443 ◽  
Author(s):  
Anath C Lionel ◽  
Gregory Costain ◽  
Nasim Monfared ◽  
Susan Walker ◽  
Miriam S Reuter ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genetic Test ◽  
Diagnostic Yield ◽  
Gene Sequencing ◽  
Whole Genome ◽  
Targeted Gene Sequencing

scholarly journals 4258Re-evaluating the genetic contribution of monogenic dilated cardiomyopathy

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
F Mazzarotto ◽  
U Tayal ◽  
R Buchan ◽  
W Midwinter ◽  
A Wilk ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Rare Variants ◽  
Diagnostic Yield ◽  
Meta Analysis ◽  
Diagnostic Testing ◽  
Reference Population ◽  
Population Variation ◽  
Disease Genes ◽  
Specific Patient ◽  
Background Population

Abstract Background Dilated cardiomyopathy (DCM) is genetically heterogeneous, with >100 purported disease genes tested in clinical laboratories. However, many genes were originally identified based on candidate-gene studies that did not adequately account for background population variation. Here we define the frequency of rare variation in 2538 DCM patients across protein-coding regions of 56 commonly tested genes and compare this to both 912 confirmed healthy controls and a reference population of 60,706 individuals. Purpose To identify clinically interpretable genes robustly associated with dominant monogenic DCM. Methods We used the TruSight Cardio sequencing panel to evaluate the burden of rare variants in 56 putative DCM genes in 1040 DCM patients and 912 healthy volunteers processed with identical sequencing and bioinformatics pipelines. We further aggregated data from 1498 DCM patients sequenced in diagnostic laboratories and the ExAC database for replication and meta-analysis. Results Specific variant classes in TTN, DSP, MYH7 and LMNA were associated with DCM in all comparisons. Variants in BAG3, TNNT2, TPM1, NEXN and VCL were significantly enriched specific patient subsets, with the last 3 genes likely contributing primarily to early-onset forms of DCM. Overall, rare variants in these 9 genes potentially explained 19–26% of cases. Whilst the absence of a significant excess in other genes cannot preclude a role in disease, such genes have limited diagnostic value since novel variants will be uninterpretable and therefore non-actionable, and their diagnostic yield is minimal. Conclusion In the largest sequenced DCM cohort yet described, we observe robust disease association only with a limited number of genes, highlighting their importance in DCM and translating into high interpretability in diagnostic testing. The other genes evaluated have limited value in diagnostic testing in DCM. This data will contribute to community gene curation efforts, and will reduce erroneous and inconclusive findings in diagnostic testing. Acknowledgement/Funding Wellcome Trust (107469/Z/15/Z), BHF (SP/10/10/28431), MRC (MR/M003191/1), Fondation Leducq (11-CVD01), Italian Ministry of Health (RF-2013-02356787)

scholarly journals The genetic landscape of intellectual disability and epilepsy in adults and the elderly: a systematic genetic work-up of 150 individuals

2021 ◽  
Author(s):  
Pia Zacher ◽  
Thomas Mayer ◽  
Frank Brandhoff ◽  
Tobias Bartolomaeus ◽  
Diana Le Duc ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Diagnostic Yield ◽  
Fragile X ◽  
Genetic Diagnostics ◽  
High Yield ◽  
Chromosomal Microarray ◽  
Limited Information ◽  
Single Nucleotide Variants ◽  
Elderly Individuals

Abstract Purpose Genetic diagnostics of neurodevelopmental disorders with epilepsy (NDDE) are predominantly applied in children, thus limited information is available regarding adults or elderly. Methods We investigated 150 adult/elderly individuals with NDDE by conventional karyotyping, FMR1 testing, chromosomal microarray, panel sequencing, and for unresolved cases, also by exome sequencing (nsingle = 71, ntrios = 24). Results We identified (likely) pathogenic variants in 71 cases (47.3%) comprising fragile X syndrome (n = 1), disease-causing copy number (n = 23), and single-nucleotide variants (n = 49). Seven individuals displayed multiple independent genetic diagnoses. The diagnostic yield correlated with the severity of intellectual disability. Individuals with anecdotal evidence of exogenic early-life events (e.g., nuchal cord, complications at delivery) with alleged/unproven association to the disorder had a particularly high yield of 58.3%. Screening for disease-specific comorbidities was indicated in 45.1% and direct treatment consequences arose in 11.8% of diagnosed individuals. Conclusion Panel/exome sequencing displayed the highest yield and should be considered as first-tier diagnostics in NDDE. This high yield and the numerous indications for additional screening or treatment modifications arising from genetic diagnoses indicate a current medical undersupply of genetically undiagnosed adult/elderly individuals with NDDE. Moreover, knowledge of the course of elderly individuals will ultimately help in counseling newly diagnosed individuals with NDDE.

scholarly journals Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing

EP Europace ◽  
2015 ◽  
Vol 18 (6) ◽  
pp. 888-896 ◽  
Author(s):  
Laurence M. Nunn ◽  
Luis R. Lopes ◽  
Petros Syrris ◽  
Cian Murphy ◽  
Vincent Plagnol ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Diagnostic Yield ◽  
Molecular Autopsy ◽  
Targeted Exome Sequencing ◽  
Arrhythmic Death ◽  
Sudden Arrhythmic Death Syndrome

Comprehensive analysis of the mutation spectrum in 301 German ALS families

2018 ◽  
Vol 89 (8) ◽  
pp. 817-827 ◽  
Author(s):  
Kathrin Müller ◽  
David Brenner ◽  
Patrick Weydt ◽  
Thomas Meyer ◽  
Torsten Grehl ◽  
...  
Keyword(s):  
Genetic Counselling ◽  
Rare Variants ◽  
Therapeutic Interventions ◽  
Disease Genes ◽  
Detailed Knowledge ◽  
Protein Coding ◽  
Relative Contribution ◽  
Pathogenic Variants ◽  
Familial Als ◽  
Gene Panels

ObjectivesRecent advances in amyotrophic lateral sclerosis (ALS) genetics have revealed that mutations in any of more than 25 genes can cause ALS, mostly as an autosomal-dominant Mendelian trait. Detailed knowledge about the genetic architecture of ALS in a specific population will be important for genetic counselling but also for genotype-specific therapeutic interventions.MethodsHere we combined fragment length analysis, repeat-primed PCR, Southern blotting, Sanger sequencing and whole exome sequencing to obtain a comprehensive profile of genetic variants in ALS disease genes in 301 German pedigrees with familial ALS. We report C9orf72 mutations as well as variants in consensus splice sites and non-synonymous variants in protein-coding regions of ALS genes. We furthermore estimate their pathogenicity by taking into account type and frequency of the respective variant as well as segregation within the families.Results49% of our German ALS families carried a likely pathogenic variant in at least one of the earlier identified ALS genes. In 45% of the ALS families, likely pathogenic variants were detected in C9orf72, SOD1, FUS, TARDBP or TBK1, whereas the relative contribution of the other ALS genes in this familial ALS cohort was 4%. We identified several previously unreported rare variants and demonstrated the absence of likely pathogenic variants in some of the recently described ALS disease genes.ConclusionsWe here present a comprehensive genetic characterisation of German familial ALS. The present findings are of importance for genetic counselling in clinical practice, for molecular research and for the design of diagnostic gene panels or genotype-specific therapeutic interventions in Europe.

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