scholarly journals Anticipating uncertainty and irrevocable decisions: provider perspectives on implementing whole-genome sequencing in critically ill children with heart disease

2018 ◽  
Vol 20 (11) ◽  
pp. 1455-1461 ◽  
Author(s):  
Danton S Char ◽  
Sandra Soo-Jin Lee ◽  
David Magnus ◽  
Mildred Cho
Keyword(s):  
Heart Disease ◽  
Whole Genome Sequencing ◽  
Critically Ill ◽  
Genome Sequencing ◽  
Critically Ill Children ◽  
Whole Genome ◽  
Provider Perspectives

Coming up to Speed on Whole Genome Sequencing in Critically Ill Children

2018 ◽  
Vol 1 (1) ◽  
pp. 1-8
Author(s):  
Isabelle Thiffault ◽  
Emily Farrow ◽  
Maxime Cadieux-Dion ◽  
Carol J. Saunders
Keyword(s):  
Whole Genome Sequencing ◽  
Critically Ill ◽  
Genome Sequencing ◽  
Critically Ill Children ◽  
Whole Genome

Whole genome sequencing in critically ill children

2015 ◽  
Vol 3 (4) ◽  
pp. 264-266 ◽  
Author(s):  
Danton S Char ◽  
Mildred Cho ◽  
David Magnus
Keyword(s):  
Whole Genome Sequencing ◽  
Critically Ill ◽  
Genome Sequencing ◽  
Critically Ill Children ◽  
Whole Genome

scholarly journals Rapid whole genome sequencing impacts care and resource utilization in infants with congenital heart disease

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Nathaly M. Sweeney ◽  
Shareef A. Nahas ◽  
Sh. Chowdhury ◽  
Sergey Batalov ◽  
Michelle Clark ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genetic Disease ◽  
Congenital Heart ◽  
Cost Of Care ◽  
Morbidity And Mortality ◽  
Whole Genome ◽  
Microarray Gene

AbstractCongenital heart disease (CHD) is the most common congenital anomaly and a major cause of infant morbidity and mortality. While morbidity and mortality are highest in infants with underlying genetic conditions, molecular diagnoses are ascertained in only ~20% of cases using widely adopted genetic tests. Furthermore, cost of care for children and adults with CHD has increased dramatically. Rapid whole genome sequencing (rWGS) of newborns in intensive care units with suspected genetic diseases has been associated with increased rate of diagnosis and a net reduction in cost of care. In this study, we explored whether the clinical utility of rWGS extends to critically ill infants with structural CHD through a retrospective review of rWGS study data obtained from inpatient infants < 1 year with structural CHD at a regional children’s hospital. rWGS diagnosed genetic disease in 46% of the enrolled infants. Moreover, genetic disease was identified five times more frequently with rWGS than microarray ± gene panel testing in 21 of these infants (rWGS diagnosed 43% versus 10% with microarray ± gene panels, p = 0.02). Molecular diagnoses ranged from syndromes affecting multiple organ systems to disorders limited to the cardiovascular system. The average daily hospital spending was lower in the time period post blood collection for rWGS compared to prior (p = 0.003) and further decreased after rWGS results (p = 0.000). The cost was not prohibitive to rWGS implementation in the care of this cohort of infants. rWGS provided timely actionable information that impacted care and there was evidence of decreased hospital spending around rWGS implementation.

scholarly journals Whole genome sequencing identifies multiple loci for critical illness caused by COVID-19

2021 ◽  
Author(s):  
Athanasios Kousathanas ◽  
Erola Pairo-Castineira ◽  
Konrad Rawlik ◽  
Alex Stuckey ◽  
Christopher A Odhams ◽  
...  
Keyword(s):  
Critical Care ◽  
Critical Illness ◽  
Whole Genome Sequencing ◽  
Critically Ill ◽  
Genome Sequencing ◽  
Blood Type ◽  
Host Immune System ◽  
Whole Genome ◽  
Mucin Expression ◽  
Population Controls

Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care or hospitalisation following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study is designed to compare genetic variants in critically-ill cases with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identified 15 new independent associations with severe COVID-19, including variants within genes involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating expression of multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in severe disease. We show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials.

Precision medicine validation: identifying the MYBPC3 A31P variant with whole-genome sequencing in two Maine Coon cats with hypertrophic cardiomyopathy

2018 ◽  
Vol 21 (12) ◽  
pp. 1086-1093 ◽  
Author(s):  
Eric S Ontiveros ◽  
Yu Ueda ◽  
Samantha P Harris ◽  
Joshua A Stern ◽  
Keyword(s):  
Heart Disease ◽  
Hypertrophic Cardiomyopathy ◽  
Whole Genome Sequencing ◽  
Precision Medicine ◽  
Allele Frequency ◽  
Genome Sequencing ◽  
Disease Status ◽  
Whole Genome ◽  
Proof Of Concept ◽  
Separate Cohort

Objectives The objective of this study was to perform a proof-of-concept experiment that validates a precision medicine approach to identify variants associated with hypertrophic cardiomyopathy (HCM). We hypothesized that whole-genome sequencing would identify variant(s) associated with HCM in two affected Maine Coon/Maine Coon cross cats when compared with 79 controls of various breeds. Methods Two affected and two control Maine Coon/Maine Coon cross cats had whole-genome sequencing performed at approximately × 30 coverage. Variants were called in these four cats and 77 cats of various breeds as part of the 99 Lives Cat Genome Sequencing Initiative ( http://felinegenetics.missouri.edu/99lives ) using Platypus v0.7.9.1, annotated with dbSNP ID, and variants’ effect predicted by SnpEff. Strict filtering criteria (alternate allele frequency >49%) were applied to identify homozygous-alternate or heterozygous variants in the two HCM-affected samples when compared with 79 controls of various breeds. Results A total of four variants were identified in the two Maine Coon/Maine Coon cross cats with HCM when compared with 79 controls after strict filtering. Three of the variants identified in genes MFSD12, BTN1A1 and SLITRK5 did not segregate with disease in a separate cohort of seven HCM-affected and five control Maine Coon/Maine Coon cross cats. The remaining variant MYBPC3 segregated with disease status. Furthermore, this gene was previously associated with heart disease and encodes for a protein with sarcomeric function. Conclusions and relevance This proof-of-concept experiment identified the previously reported MYBPC3 A31P Maine Coon variant in two HCM-affected cases. This result validates and highlights the power of whole-genome sequencing for feline precision medicine.

scholarly journals Genetic Association between Hypoplastic Left Heart Syndrome and Cardiomyopathies

2020 ◽  
Author(s):  
Jeanne L. Theis ◽  
Jessie J. Hu ◽  
Rhianna S. Sundsbak ◽  
Jared M. Evans ◽  
William R. Bamlet ◽  
...  
Keyword(s):  
Heart Disease ◽  
Whole Genome Sequencing ◽  
Hypoplastic Left Heart Syndrome ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Left Heart ◽  
Hypoplastic Left Heart ◽  
Degree Relative ◽  
Fourth Degree ◽  
Left Heart Syndrome

Background - Hypoplastic left heart syndrome (HLHS) with risk of poor outcome has been linked to MYH6 variants, implicating overlap in genetic etiologies of structural and myopathic heart disease. Methods - Whole genome sequencing (WGS) was performed in 197 probands with HLHS, 43 family members, and 813 controls. Data were filtered for rare, segregating variants in three index families comprised of an HLHS proband and relative(s) with cardiomyopathy. WGS data from cases and controls were compared for rare variant burden across 56 cardiomyopathy genes utilizing a weighted burden test approach, accounting for multiple testing using a Bonferroni correction. Results - A pathogenic MYBPC3 nonsense variant was identified in the first proband who underwent cardiac transplantation for diastolic heart failure, her father with left ventricular non-compaction (LVNC), and two fourth-degree relatives with hypertrophic cardiomyopathy. A likely pathogenic RYR2 missense variant was identified in the second proband, a second-degree relative with aortic dilation, and a fourth-degree relative with dilated cardiomyopathy. A pathogenic RYR2 exon 3 in-frame deletion was identified in the third proband diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) and his father with LVNC and CPVT. To further investigate HLHS-cardiomyopathy gene associations in cases versus controls, rare variant burden testing of 56 genes revealed enrichment in MYH6 ( P =0.000068). Rare, predicted-damaging MYH6 variants were identified in 10% of probands in our cohort-four with familial congenital heart disease, four with compound heterozygosity (three with systolic ventricular dysfunction), and four with MYH6-FLNC synergistic heterozygosity. Conclusions - Whole genome sequencing in multiplex families, proband-parent trios, and case-control cohorts revealed defects in cardiomyopathy-associated genes in patients with HLHS, which may portend impaired functional reserve of the single-ventricle circulation.

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