The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants

Reuter, Miriam S.; Walker, Susan; Thiruvahindrapuram, Bhooma; Whitney, J. Andrew; Cohn, Iris; Sondheimer, Neal; Yuen, Ryan K. C.; Trost, Brett; Paton, Tara; Pereira, Sérgio Luiz; Herbrick, Jo Anne; Wintle, Richard F.; Merico, Daniele; Howe, Jennifer; MacDonald, Jeffrey R.; Lü, Chao; Nalpathamkalam, Thomas; Sung, Wilson W L; Wang, Zhuozhi; Patel, Rohan; Pellecchia, Giovanna; Wei, John; Strug, Lisa J.; Bell, Sherilyn L.; Kellam, Barbara; Mahtani, Melanie M.; Bassett, Anne S.; Bombard, Yvonne; Weksberg, Rosanna; Shuman, Cheryl; Cohn, Ronald D.; Stavropoulos, Dimitri J.; Bowdin, Sarah; Hildebrandt, Matthew R.; Wei, Wei; Romm, Asli; Pasceri, Peter; Ellis, James; Ray, Peter N.; Meyn, Stephen; Monfared, Nasim; Hosseini, S. Mohsen; Joseph-George, Ann M.; Keeley, Fred W.; Cook, Ryan; Fiume, Marc; Lee, Hin C.; Marshall, Christian R.; Davies, Jill; Hazell, Allison; Buchanan, Janet A.; Szego, Michael J.; Scherer, Stephen W.

doi:10.1503/cmaj.171151

Cited by 58 publications

(60 citation statements)

References 70 publications

(49 reference statements)

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“…Across all five samples, 89-96% of the genome was covered at least 20× (quality metrics in Table S4). We interpreted likely pathogenic variants, loss-of-function constraint gene variants and variants of unknown significance (VUS) as previously described (Reuter et al, 2018) (Supp. Excel files).…”

Section: Resultsmentioning

confidence: 99%

“…Apart from their versatility, the main advantage of these blood-derived footprint-free lines is the clinical annotation of potentially disease-associated variants that may impact cellular phenotypes. Variant analysis in the PGPC participants’ blood had revealed heterozygous variants of unknown significance in all individuals (Reuter et al, 2018). This observation suggests that it may not be possible to isolate universal control lines and reinforces the importance for WGS in characterizing control lines, especially as clinical annotation gains precision with ongoing variant discoveries.…”

Section: Discussionmentioning

confidence: 99%

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Control iPSC lines with clinically annotated genetic variants for versatile multi-lineage differentiation

Hildebrandt

Reuter

Wei

et al. 2019

Preprint

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SummaryInduced Pluripotent Stem Cells (iPSC) derived from healthy individuals are important controls for disease modeling studies. To create a resource of genetically annotated iPSCs, we reprogrammed footprint-free lines from four volunteers in the Personal Genome Project Canada (PGPC). Multilineage directed differentiation efficiently produced functional cortical neurons, cardiomyocytes and hepatocytes. Pilot users further demonstrated line versatility by generating kidney organoids, T-lymphocytes and sensory neurons. A frameshift knockout was introduced into MYBPC3 and these cardiomyocytes exhibited the expected hypertrophic phenotype. Whole genome sequencing (WGS) based annotation of PGPC lines revealed on average 20 coding variants. Importantly, nearly all annotated PGPC and HipSci lines harboured at least one pre-existing or acquired variant with cardiac, neurological or other disease associations. Overall, PGPC lines were efficiently differentiated by multiple users into cell types found in six tissues for disease modeling, and clinical annotation highlighted variant-preferred lines for use as unaffected controls in specific disease settings.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Control iPSC lines with clinically annotated genetic variants for versatile multi-lineage differentiation

Hildebrandt

Reuter

Wei

et al. 2019

Preprint

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“…Non-coding variants and structural variants, which can be detected using whole genome data (47), were not studied. For rare non-coding variants, access to large samples of whole genome data may offer interesting opportunities, especially if analyzing better understood functional elements like promoters.…”

Section: Discussionmentioning

confidence: 99%

Genes and pathways implicated in tetralogy of Fallot revealed by ultra-rare variant burden analysis in 231 genome sequences

Manshaei

Merico

Reuter

et al. 2020

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Recent genome-wide studies of rare genetic variants have begun to implicate novel mechanisms for tetralogy of Fallot (TOF), a severe congenital heart defect (CHD).To provide statistical support for case-only data without parental genomes, we re-analyzed genome sequences of 231 individuals with TOF or related CHD. We adapted a burden test originally developed for de novo variants to assess singleton variant burden in individual genes, and in gene-sets corresponding to functional pathways and mouse phenotypes, accounting for highly correlated gene-sets, and for multiple testing.The gene burden test identified a significant burden of deleterious missense variants in NOTCH1 (Bonferroni-corrected p-value <0.01). These NOTCH1 variants showed significant enrichment for those affecting the extracellular domain, and especially for disruption of cysteine residues forming disulfide bonds (OR 39.8 vs gnomAD). Individuals with NOTCH1 variants, all with TOF, were enriched for positive family history of CHD. Other genes not previously implicated in TOF had more modest statistical support and singleton missense variant results were non-significant for gene-set burden. For singleton truncating variants, the gene burden test confirmed significant burden in FLT4. Gene-set burden tests identified a cluster of pathways corresponding to VEGF signaling (FDR=0%), and of mouse phenotypes corresponding to abnormal vasculature (FDR=0.8%), that suggested additional candidate genes not previously identified (e.g., WNT5A and ZFAND5). Analyses using unrelated sequencing datasets supported specificity of the findings for CHD.The findings support the importance of ultra-rare variants disrupting genes involved in VEGF and NOTCH signaling in the genetic architecture of TOF. These proof-of-principle data indicate that this statistical methodology could assist in analyzing case-only sequencing data in which ultra-rare variants, whether de novo or inherited, contribute to the genetic etiopathogenesis of a complex disorder.Author summaryWe analyzed the ultra-rare nonsynonymous variant burden for genome sequencing data from 231 individuals with congenital heart defects, most with tetralogy of Fallot. We adapted a burden test originally developed for de novo variants. In line with other studies, we identified a significant truncating variant burden for FLT4 and deleterious missense burden for NOTCH1, both passing a stringent Bonferroni multiple-test correction. For NOTCH1, we observed frequent disruption of cysteine residues establishing disulfide bonds in the extracellular domain. We also identified genes with BH-FDR <10% that were not previously implicated. To overcome limited power for individual genes, we tested gene-sets corresponding to functional pathways and mouse phenotypes. Gene-set burden of truncating variants was significant for vascular endothelial growth factor signaling and abnormal vasculature phenotypes. These results confirmed previous findings and suggested additional candidate genes for experimental validation in future studies. This methodology can be extended to other case-only sequencing data in which ultra-rare variants make a substantial contribution to genetic etiology.

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“…Several screening programs are initiating genomic sequencing for healthy or unselected populations, irrespective of health status or family history. [3][4][5][6][7][8][9] Amongst these population screening programs there is consensus to return genomic results which are medically significant however there is less concordance regarding which genes fall into this category.…”

Section: Introductionmentioning

confidence: 99%

Family History Assessment Significantly Enhances Delivery of Precision Medicine in the Genomics Era

Bylstra

Lim²,

Kam

et al. 2020

Preprint

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Background Family history has traditionally been an essential part of clinical care to assess health risks.However, declining sequencing costs have precipitated a shift towards genomics-first approaches in population screening programs, with less emphasis on family history assessment. We evaluated the utility of family history for genomic sequencing selection. MethodsWe analysed whole genome sequences of 1750 healthy research participants, with and without preselection based on standardised family history collection, screening 95 cancer genes. ResultsThe frequency of likely pathogenic/ pathogenic (LP/P) variants in 884 participants with no family history available (FH not available group) (2%) versus 866 participants with family history available (FH available group) (3.1%) was not significant (p=0.158). However, within the FH available group, amongst 73 participants with an increased family history cancer risk (increased FH risk), 1 in 7 participants carried a LP/P variant inferring a six-fold increase compared with 1 in 47 participants assessed at average family history cancer risk (average FH risk) and a seven-fold increase compared to the FH not available group.The enrichment was further pronounced (up to 18-fold) when assessing the 25 cancer genes in the ACMG 59-gene panel. Furthermore, 63 participants had an increased family history cancer risk in absence of an apparent LP/P variant. ConclusionOur findings show that systematic family history collection remains critical for health risk assessment, providing important actionable data and augmenting the yield from genomic data. Family history also highlights the potential impact of additional hereditary, environmental and behavioural influences not reflected by genomic sequencing.

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The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants

Cited by 58 publications

References 70 publications

Control iPSC lines with clinically annotated genetic variants for versatile multi-lineage differentiation

Control iPSC lines with clinically annotated genetic variants for versatile multi-lineage differentiation

Genes and pathways implicated in tetralogy of Fallot revealed by ultra-rare variant burden analysis in 231 genome sequences

Family History Assessment Significantly Enhances Delivery of Precision Medicine in the Genomics Era

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