Genetic diagnosis of infantile‐onset epilepsy in the clinic: Application of whole‐exome sequencing following epilepsy gene panel testing

AbstractMotivationWhole exome sequencing (WES) is widely adopted in clinical and research settings. However, there is potential for false negatives due to incomplete breadth and depth of coverage for several exons in clinically implicated genes. In some cases, a targeted gene panel testing may be a dependable option to ascertain true negatives for genomic variants in known phenotype associated genes. We developed a tool for quickly gauging whether all genes of interest would be reliably covered by WES or whether targeted gene panel testing should instead be considered to minimize false negatives in candidate genes.ResultsWEScover is a novel web application that provides an interface for discovering breadth and depth of coverage across population scale WES datasets, searching either by phenotype, by targeted gene panels and by gene(s). Moreover, the application shows metrics from the Genome Aggregation Database to provide gene-centric view on breadth of coverage.ConclusionWEScover allows users to efficiently query genes and phenotype for exome coverage of associated exons, and recommends use of panel tests for genes that are potentially not well covered by WES.

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WEScover: selection between clinical whole exome sequencing and gene panel testing

BMC Bioinformatics ◽

10.1186/s12859-021-04178-5 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

In-Hee Lee ◽

Yufei Lin ◽

William Jefferson Alvarez ◽

Carles Hernandez-Ferrer ◽

Kenneth D. Mandl ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Web Application ◽

Gene Panel ◽

False Negatives ◽

Panel Testing ◽

Whole Exome ◽

Gene Panel Testing ◽

Disease Associated Genes ◽

Targeted Gene Panel Testing

Abstract Background Whole exome sequencing (WES) is widely adopted in clinical and research settings; however, one of the practical concerns is the potential false negatives due to incomplete breadth and depth of coverage for several exons in clinically implicated genes. In some cases, a targeted gene panel testing may be a dependable option to ascertain true negatives for genomic variants in known disease-associated genes. We developed a web-based tool to quickly gauge whether all genes of interest would be reliably covered by WES or whether targeted gene panel testing should be considered instead to minimize false negatives in candidate genes. Results WEScover is a novel web application that provides an intuitive user interface for discovering breadth and depth of coverage across population-scale WES datasets, searching either by phenotype, by targeted gene panel(s) or by gene(s). Moreover, the application shows metrics from the Genome Aggregation Database to provide gene-centric view on breadth of coverage. Conclusions WEScover allows users to efficiently query genes and phenotypes for the coverage of associated exons by WES and recommends use of panel tests for the genes with potential incomplete coverage by WES.

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Dealing With Unspecific Clinical Phenotypes in Molecular Autopsy - HPO-Driven Whole Exome Sequencing Analysis Versus Gene Panel Testing

10.21203/rs.3.rs-122014/v1 ◽

2020 ◽

Author(s):

Ulrike Schoen ◽

Anna Holzer ◽

Andreas Laner ◽

Stephanie Kleinle ◽

Florentine Scharf ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Gene Panel ◽

Sequencing Analysis ◽

Tissue Samples ◽

Human Phenotype ◽

Versus Gene ◽

Molecular Autopsy ◽

Whole Exome ◽

Gene Panel Testing

Abstract Background: Molecular autopsy represents an efficient tool to save the diagnosis in up to one-third of sudden unexplained death (SUD). A defined gene panel is usually used for the examination. Alternatively, it is possible to carry out a comprehensive genetic assessment (Whole Exome Sequencing, WES), which also identifies rare, previously unknown variants. The disadvantage is that a dramatic number of variants must be assessed to identify the causal variant. To improve the evaluation of WES, the Human Phenotype Ontology (HPO) annotation is used internationally for deep phenotyping in the field of rare disease. However, a HPO-based evaluation of WES in SUD has not been described before.Methods: We performed WES in tissue samples from 16 people after SUD. Instead of a fixed gene panel, we defined a set of HPO terms and thus created a flexible “virtual gene panel”, with the advantage, that recently identified genes are automatically associated by HPO terms in the HPO database.Results: We obtained a median value of 68,947 variants per sample. Stringent filtering ended up in a median value of 276 variants per sample. Using the HPO-driven virtual gene panel we developed an algorithm that prioritized 1.4% of the variants. Variant interpretation resulted in eleven potentially causative variants in 16 individuals. Conclusion: Our data introduce an effective diagnostic procedure in molecular autopsy of SUD with a non-specific clinical phenotype.

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Behr syndrome and hypertrophic cardiomyopathy in a family with a novel UCHL1 deletion

Journal of Neurology ◽

10.1007/s00415-020-10059-3 ◽

2020 ◽

Vol 267 (12) ◽

pp. 3643-3649

Author(s):

Grace McMacken ◽

Hanns Lochmüller ◽

Boglarka Bansagi ◽

Angela Pyle ◽

Angela Lochmüller ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Spastic Paraparesis ◽

Clinical Syndrome ◽

Motor Neuropathy ◽

Respiratory Problems ◽

Panel Testing ◽

Whole Exome ◽

Gene Panel Testing

Abstract Background Behr syndrome is a clinically distinct, but genetically heterogeneous disorder characterized by optic atrophy, progressive spastic paraparesis, and motor neuropathy often associated with ataxia. The molecular diagnosis is based on gene panel testing or whole-exome/genome sequencing. Methods Here, we report the clinical presentation of two siblings with a novel genetic form of Behr syndrome. We performed whole-exome sequencing in the two patients and their mother. Results Both patients had a childhood-onset, slowly progressive disease resembling Behr syndrome, starting with visual impairment, followed by progressive spasticity, weakness, and atrophy of the lower legs and ataxia. They also developed scoliosis, leading to respiratory problems. In their late 30’s, both siblings developed a hypertrophic cardiomyopathy and died of sudden cardiac death at age 43 and 40, respectively. Whole-exome sequencing identified the novel homozygous c.627_629del; p.(Gly210del) deletion in UCHL1. Conclusions The presentation of our patients raises the possibility that hypertrophic cardiomyopathy may be an additional feature of the clinical syndrome associated with UCHL1 mutations, and highlights the importance of cardiac follow-up and treatment in neurodegenerative disease associated with UCHL1 mutations.

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