Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings

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.

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Abstract 16066: Genomic Autopsy of 103 Sudden Deaths in the Young Reveals the Importance of Cardiomyopathy Genes and Non-Mendelian Risk

Circulation ◽

10.1161/circ.142.suppl_3.16066 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Gregory Webster ◽

Megan Puckelwartz ◽

Lorenzo Pesce ◽

Dellefave-Castillo Lisa ◽

Carlos Vanoye ◽

...

Keyword(s):

Sudden Death ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

De Novo ◽

Multivariable Analysis ◽

Clinical Analysis ◽

Clinical Findings ◽

Whole Genome ◽

Age At Death ◽

Clinical Genetic

Introduction: Genetic testing after sudden death in the young can identify pathogenic cardiac gene variants. Hypothesis: Genomic methods, coupled with phenotype evaluation, reveal non-Mendalian risks. Methods: We conducted clinical analysis and whole genome sequencing on 103 decedents aged 1-40 (mean age at death 23.7 years) accrued prospectively from 2015 to 2019 across 22 states. Postmortem pathological findings were classified as: known cardiac disorders, findings of uncertain significance (FUS), or sudden unexplained death (SUD, indicating no postmortem pathological diagnosis). Parental DNA and clinical data were obtained where possible. Variants were classified by an independent clinical genetic laboratory. Results: Among the 103 decedents, 34 had a postmortem clinical diagnosis, 23 had FUS, and 46 were classified as SUD. Pathogenic/likely pathogenic (P/LP) variants in arrhythmia or cardiomyopathy genes were identified in 17 (16.5%) decedents. The distribution of P/LP variants was not associated with age at death (OR 1.01 [0.97, 1.05], p=0.54); however, a multivariable analysis including decedent phenotype, ancestry and sex demonstrated that younger decedents had a higher burden of curated P/LP/VUS variants (effect size -1.5, p=0.0019). DNA from 31 parent-decedent trios and 14 parent-decedent dyads revealed 9 transmitted P/LP variants and 1 de novo P/LP variant. More than half of parents transmitting a P/LP variant (5/9) did not have clinical findings associated with the genotype. Conclusions: Whole genome sequencing effectively revealed P/LP variants in cases of sudden death in the young, implicating both arrhythmia and cardiomyopathy genes. In addition, both genotype and phenotype analyses suggest additional non-Mendelian risk mechanisms.

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