PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels

Martin, Antonio Rueda; Williams, Eleanor; Foulger, Rebecca E.; Leigh, Sarah; Daugherty, Louise C.; Niblock, Olivia; Leong, Ivone; Smith, Katherine R.; Герасименко, О. М.; Haraldsdottir, Eik; Thomas, E. R. A.; Scott, Richard; Baple, Emma L.; Tucci, Arianna; Brittain, Helen; Burca, Anna de; Ibáñez, Kristina; Kasperavičiūtė, Dalia; Smedley, Damian; Caulfield, Mark J.; Rendon, Augusto; McDonagh, Ellen M.

doi:10.1038/s41588-019-0528-2

Cited by 382 publications

(377 citation statements)

References 16 publications

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“…To minimize the analytical workload and the risk of incidental findings, only a panel of relevant disease genes is assessed. Obviously, these gene panels need to be constantly updated and various resources for this exist (65).…”

Section: Genetic Testing In Tubulopathiesmentioning

confidence: 99%

Inherited Tubulopathies of the Kidney

Downie

Lopez-Garcia

Kleta

et al. 2020

CJASN

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The kidney tubules provide homeostasis by maintaining the external milieu that is critical for proper cellular function. Without homeostasis, there would be no heartbeat, no muscle movement, no thought, sensation, or emotion. The task is achieved by an orchestra of proteins, directly or indirectly involved in the tubular transport of water and solutes. Inherited tubulopathies are characterized by impaired function of one or more of these specific transport molecules. The clinical consequences can range from isolated alterations in the concentration of specific solutes in blood or urine to serious and life-threatening disorders of homeostasis. In this review, we will focus on genetic aspects of the tubulopathies and how genetic investigations and kidney physiology have crossfertilized each other and facilitated the identification of these disorders and their molecular basis. In turn, clinical investigations of genetically defined patients have shaped our understanding of kidney physiology.

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Section: Genetic Testing In Tubulopathiesmentioning

confidence: 99%

Inherited Tubulopathies of the Kidney

Downie

Lopez-Garcia

Kleta

et al. 2020

CJASN

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“…Our work focused on a different group of disorders, IED, and had a number of differences in terms of study design. To reduce the potential impact of misannotation, we focused on (i) genes for which there is broad consensus for their involvement in disease [12] and (ii) variants that are considered to have strong evidence for pathogenicity (those marked as "DM" in HGMD) [13]. We chose to use HGMD (a pay-for-access resource which relies on curation of published literature) over ClinVar (a freely accessible public database which is based on submissions from researchers and clinical diagnostic laboratories) as, at the time of study design, the breadth of coverage of the former appeared to be greater [33].…”

Section: Discussionmentioning

confidence: 99%

“…IED-implicated genes were obtained through PanelApp, a publicly available knowledgebase that combines expert reviews and manual curation to create diagnostic-grade gene lists [12]. We focused on the genes that are included in the different panels within the "ophthalmological disorders" disease category (as of Only genes with a high level of evidence ("green") were retained as our aim was to study variable penetrance in genes robustly associated with disease (rather than to question gene-disease associations).…”

Section: Obtaining Lists Of Genes and Variants Associated With Inherimentioning

confidence: 99%

Variability in Gene Expression is Associated with Incomplete Penetrance in Inherited Eye Disorders

Green

Sallah

Ellingford

et al. 2020

Genes

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Inherited eye disorders (IED) are a heterogeneous group of Mendelian conditions that are associated with visual impairment. Although these disorders often exhibit incomplete penetrance and variable expressivity, the scale and mechanisms of these phenomena remain largely unknown. Here, we utilize publicly-available genomic and transcriptomic datasets to gain insights into variable penetrance in IED. Variants in a curated set of 340 IED-implicated genes were extracted from the Human Gene Mutation Database (HGMD) 2019.1 and cross-checked with the Genome Aggregation Database (gnomAD) 2.1 control-only dataset. Genes for which >1 variants were encountered in both HGMD and gnomAD were considered to be associated with variable penetrance (n = 56). Variability in gene expression levels was then estimated for the subset of these genes that was found to be adequately expressed in two relevant resources: the Genotype-Tissue Expression (GTEx) and Eye Genotype Expression (EyeGEx) datasets. We found that genes suspected to be associated with variable penetrance tended to have significantly more variability in gene expression levels in the general population (p = 0.0000015); this finding was consistent across tissue types. The results of this study point to the possible influence of cis and/or trans-acting elements on the expressivity of variants causing Mendelian disorders. They also highlight the potential utility of quantifying gene expression as part of the investigation of families showing evidence of variable penetrance.

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“…Orphanet (INSERM, 1999;Rath et al, 2012) (a database centred on rare, typically monogenic disease), expertly curated gene panels used for diagnostics from Genomics England PanelApp (Martin et al, 2019) and results from on-going Deciphering Developmental Disorders Study (DECIPHER) -whose aim is to identify de novo micro genomic rearrangements responsible for undiagnosed developmental delay disorders (Firth et al, 2009).…”

Section: Integration Of Mendelvar Data Sourcesmentioning

confidence: 99%

MendelVar: gene prioritization at GWAS loci using phenotypic enrichment of Mendelian disease genes

Sobczyk

Gaunt

Paternoster

2020

Preprint

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Gene prioritisation at GWAS loci necessities careful assembly and examination of different types of molecular evidence to arrive at a set of plausible candidates. In many human traits, common small-effect mutations may subtly dysregulate the function of the very same genes which are impacted by rare, large-effect mutations causing Mendelian disease of similar phenotype. However, information on gene-Mendelian disease associations, rare pathogenic mutations driving the disease, and the disease phenotype ontology is dispersed across many data sources and does not integrate easily with enrichment analysis.MendelVar is a new webserver facilitating transfer of knowledge from Mendelian disease research into interpretation of genetic associations from GWAS of complex traits.MendelVar allows querying of pre-defined or LD-determined genomic intervals against a comprehensive integrated database to find overlap with genes linked to Mendelian disease. Next, MendelVar looks for enrichment of any Human Phenotype Ontology, DiseaseOntology and other ontology/pathway terms associated with identified Mendelian genes. In addition, MendelVar provides a list of all overlapping pathogenic and likely pathogenic variants for Mendelian disease sourced from ClinVar. Inclusion of information obtained from MendelVar in post-GWAS gene annotation pipelinescan strengthen the case for causal importance of some genes. Moreover, as genes with Mendelian disease evidence may make for more successful drug targets, this may be particularly useful in drug discovery pipelines. Taking GWAS summary statistics for malepattern baldness, intelligence and atopic dermatitis, we demonstrate the use of MendelVar in prioritizing candidate genes at these loci which are linked to relevant enriched ontology terms. MendelVar is freely available at https

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PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels

Cited by 382 publications

References 16 publications

Inherited Tubulopathies of the Kidney

Inherited Tubulopathies of the Kidney

Variability in Gene Expression is Associated with Incomplete Penetrance in Inherited Eye Disorders

MendelVar: gene prioritization at GWAS loci using phenotypic enrichment of Mendelian disease genes

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