Using VAAST to Identify Disease‐Associated Variants in Next‐Generation Sequencing Data

Kennedy, Brett; Kronenberg, Zev; Hu, Hao; Moore, Barry; Flygare, Steven; Reese, Martin G.; Jorde, Lynn B.; Yandell, Mark; Huff, Chad

doi:10.1002/0471142905.hg0614s81

Cited by 26 publications

(26 citation statements)

References 32 publications

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“…Historically, WES has been considered both too complex technically and analytically and too expensive for clinical use. [11] The degree of complexity is rapidly being minimized by technical advances in both hardware and software that have reduced expense and made data generation rapid and analysis relatively straightforward[12, 13]. For example, in the case described herein, WES was performed at a cost of about $600.00 and data was generated and interpreted in a day.…”

Section: Resultsmentioning

confidence: 99%

Exome sequencing for molecular characterization of non-HFE hereditary hemochromatosis

Farrell

Parker

Phillips

2015

Blood Cells, Molecules, and Diseases

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Diagnostic genetic testing for hereditary hemochromatosis is readily available for clinically relevant HFE variants (i.e., those that generate the C282Y, H63D and S65C HFE polymorphisms); however, genetic testing for other known causes of iron overload, including mutations affecting genes encoding hemojuvelin, transferrin receptor 2, HAMP, and ferroportin is not. As an alternative to conventional genetic testing we propose diagnostic use of whole exome sequencing for characterization of non-HFE hemochromatosis. To illustrate the effectiveness of whole exome sequencing as a diagnostic tool, we present the case of an 18-year-old female with a probable case of juvenile hemochromatosis, who was referred for specialty care after testing negative for commonly occurring HFE variants. Whole exome sequencing offered complete coverage of target genes and is a fast, cost effective diagnostic tool for characterization of non-HFE hemochromatosis.

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Section: Resultsmentioning

confidence: 99%

Exome sequencing for molecular characterization of non-HFE hereditary hemochromatosis

Farrell

Parker

Phillips

2015

Blood Cells, Molecules, and Diseases

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“…Data were also analyzed using Omicia Opal 4.15 in a three-person cohort analysis including the proband, mother, and daughter (https://app.omicia.com; Omicia, Inc., Oakland, CA). The software prioritizes variants using the Variant Annotation, Analysis and Search Tool (VAAST) and therefore does not take into account the family relationships between individuals [11]. However, because the analysis was focused on variants shared by all three women, the results are similar to pVAAST.…”

Section: Methodsmentioning

confidence: 99%

POLR2C Mutations Are Associated With Primary Ovarian Insufficiency in Women

Moriwaki

Moore

Mosbruger

et al. 2017

Journal of the Endocrine Society

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ContextPrimary ovarian insufficiency (POI) results from a premature loss of oocytes, causing infertility and early menopause. The etiology of POI remains unknown in a majority of cases.ObjectiveTo identify candidate genes in families affected by POI.DesignThis was a family-based genetic study.SettingThe study was performed at two academic institutions.Patients and Other ParticipantsA family with four generations of women affected by POI (n = 5). Four of these women, three with an associated autoimmune diagnosis, were studied. The controls (n = 387) were recruited for health in old age.InterventionWhole-genome sequencing was performed.Main Outcome MeasureCandidate genes were identified by comparing gene mutations in three family members and 387 control subjects analyzed simultaneously using the pedigree Variant Annotation, Analysis and Search Tool. Data were also compared with that in publicly available databases.ResultsWe identified a heterozygous nonsense mutation in a subunit of RNA polymerase II (POLR2C) that synthesizes messenger RNA. A rare sequence variant in POLR2C was also identified in one of 96 women with sporadic POI. POLR2C expression was decreased in the proband compared with women with POI from another cause. Knockdown in an embryonic carcinoma cell line resulted in decreased protein production and impaired cell proliferation.ConclusionsThese data support a role for RNA polymerase II mutations as candidates in the etiology of POI. The current data also support results from genome-wide association studies that hypothesize a role for RNA polymerase II subunits in age at menopause in the population.

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“…A VCF file containing the same variants as the BED file used with Phenolyzer was then input into similar programs such as wANNOVAR and PhenIX in order to utilize several sources of analysis (Chang and Wang 2012; Zemojtel et al 2014). These same VCF files were input into the Omicia Opal system, with similar results (see Supplemental File 4; Rope et al 2011; Hu et al 2013; Kennedy et al 2014). …”

Section: Methodsmentioning

confidence: 99%

KBG syndrome involving a single-nucleotide duplication in ANKRD11

Kleyner

Malcolmson

Tegay

et al. 2016

Cold Spring Harb Mol Case Stud

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KBG syndrome is a rare autosomal dominant genetic condition characterized by neurological involvement and distinct facial, hand, and skeletal features. More than 70 cases have been reported; however, it is likely that KBG syndrome is underdiagnosed because of lack of comprehensive characterization of the heterogeneous phenotypic features. We describe the clinical manifestations in a male currently 13 years of age, who exhibited symptoms including epilepsy, severe developmental delay, distinct facial features, and hand anomalies, without a positive genetic diagnosis. Subsequent exome sequencing identified a novel de novo heterozygous single base pair duplication (c.6015dupA) in ANKRD11, which was validated by Sanger sequencing. This single-nucleotide duplication is predicted to lead to a premature stop codon and loss of function in ANKRD11, thereby implicating it as contributing to the proband's symptoms and yielding a molecular diagnosis of KBG syndrome. Before molecular diagnosis, this syndrome was not recognized in the proband, as several key features of the disorder were mild and were not recognized by clinicians, further supporting the concept of variable expressivity in many disorders. Although a diagnosis of cerebral folate deficiency has also been given, its significance for the proband's condition remains uncertain.

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Using VAAST to Identify Disease‐Associated Variants in Next‐Generation Sequencing Data

Cited by 26 publications

References 32 publications

Exome sequencing for molecular characterization of non-HFE hereditary hemochromatosis

Exome sequencing for molecular characterization of non-HFE hereditary hemochromatosis

POLR2C Mutations Are Associated With Primary Ovarian Insufficiency in Women

KBG syndrome involving a single-nucleotide duplication in ANKRD11

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