Genome analysis and knowledge-driven variant interpretation with TGex

Dahary, Dvir; Golan, Yaron; Mazor, Yaron; Zelig, Ofer; Barshir, Ruth; Twik, Michal; Stein, Tsippi Iny; Rosner, Guy; Kariv, Revital; Chen, Fei; Zhang, Qiang; Shen, Yiping; Lancet, Doron; Fishilevich, Simon

doi:10.1186/s12920-019-0647-8

Cited by 36 publications

(23 citation statements)

References 98 publications

(100 reference statements)

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“…A range of commercial software has been reported to perform variant annotation and interpretation [ 26 , 41 – 43 ]. Compared with above mentioned software, Cruxome offers unique advantages (Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

Cruxome: a powerful tool for annotating, interpreting and reporting genetic variants

Han

Yang

et al. 2021

BMC Genomics

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Background Next-generation sequencing (NGS) is an efficient tool used for identifying pathogenic variants that cause Mendelian disorders. However, the lack of bioinformatics training of researchers makes the interpretation of identified variants a challenge in terms of precision and efficiency. In addition, the non-standardized phenotypic description of human diseases also makes it difficult to establish an integrated analysis pathway for variant annotation and interpretation. Solutions to these bottlenecks are urgently needed. Results We develop a tool named “Cruxome” to automatically annotate and interpret single nucleotide variants (SNVs) and small insertions and deletions (InDels). Our approach greatly simplifies the current burdensome task of clinical geneticists and scientists to identify the causative pathogenic variants and build personal knowledge reference bases. The integrated architecture of Cruxome offers key advantages such as an interactive and user-friendly interface and the assimilation of electronic health records of the patient. By combining a natural language processing algorithm, Cruxome can efficiently process the clinical description of diseases to HPO standardized vocabularies. By using machine learning, in silico predictive algorithms, integrated multiple databases and supplementary tools, Cruxome can automatically process SNVs and InDels variants (trio-family or proband-only cases) and clinical diagnosis records, then annotate, score, identify and interpret pathogenic variants to finally generate a standardized clinical report following American College of Medical Genetics and Genomics/ Association for Molecular Pathology (ACMG/AMP) guidelines. Cruxome also provides supplementary tools to examine and visualize the genes or variations in historical cases, which can help to better understand the genetic basis of the disease. Conclusions Cruxome is an efficient tool for annotation and interpretation of variations and dramatically reduces the workload for clinical geneticists and researchers to interpret NGS results, simplifying their decision-making processes. We present an online version of Cruxome, which is freely available to academics and clinical researchers. The site is accessible at http://114.251.61.49:10024/cruxome/.

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Section: Resultsmentioning

confidence: 99%

Cruxome: a powerful tool for annotating, interpreting and reporting genetic variants

Han

Yang

et al. 2021

BMC Genomics

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“…The FASTQs were uploaded into the Geneyx (previously TGex) Analysis platform. 13 Alignment and variant calling of single nucleotide variations, structural variants, CNVs and repeats were called using Illumina DRAGEN Bio-IT. The resulting VCF files were comprehensively annotated on the Geneyx Analysis annotation engine, and presented for analysis, filtering and interpretation.…”

Section: Methodsmentioning

confidence: 99%

Levodopa-responsive dystonia caused by biallelic PRKN exon inversion invisible to exome sequencing

Mor‐Shaked

Paz-Ebstein

Basal

et al. 2021

Brain Communications

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Biallelic pathogenic variants in PRKN (PARK2), encoding the E3 ubiquitin ligase parkin, lead to early-onset Parkinson's disease. Structural variants, including duplications or deletions, are common in PRKN due to its location within the fragile site FRA6E. These variants are readily detectable by copy number variation analysis. We studied four siblings with levodopa-responsive dystonia by exome sequencing followed by genome sequencing. Affected individuals developed juvenile levodopa-responsive dystonia with subsequent appearance of parkinsonism and motor fluctuations that improved by subthalamic stimulation. Exome sequencing and copy number variation analysis were not diagnostic, yet revealed a shared homozygous block including PRKN. Genome sequencing revealed an inversion within PRKN, with intronic breakpoints flanking exon 5. Breakpoint junction analysis implicated non-homologous end joining and possibly replicative mechanisms as the repair pathways involved. Analysis of cDNA indicated skipping of exon 5 (84 bp) that was replaced by 93 bp of retained intronic sequence, preserving the reading frame yet altering a significant number of residues. Balanced copy number inversions in PRKN are associated with a severe phenotype. Such structural variants, undetected by exome analysis and by copy number variation analysis, should be considered in the relevant clinical setting. These findings raise the possibility that PRKN structural variants are more common than currently estimated.

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“…Sequences were generated on an Illumina NovaSeq 6000 sequencing platform as 150 bp paired-end reads, to a final depth of 30X coverage. The FASTQs were uploaded into the Geneyx (previously TGex) Analysis platform (Dahary et al, 2019). Alignment and variant calling of single nucleotide variants (SNVs), copy number variants (CNVs) and structural variants (SVs), and repeats were called using Illumina DRAGEN Bio-IT.…”

Section: Whole Genome Sequencingmentioning

confidence: 99%

Bi‐allelic PAGR1 variants are associated with microcephaly and a severe neurodevelopmental disorder: Genetic evidence from two families

Daum

Ganapathi

Hirsch³

et al. 2021

American J of Med Genetics Pt A

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Exome and genome sequencing were used to identify the genetic etiology of a severe neurodevelopmental disorder in two unrelated Ashkenazi Jewish families with three affected individuals. The clinical findings included a prenatal presentation of microcephaly, polyhydramnios and clenched hands while postnatal findings included microcephaly, severe developmental delay, dysmorphism, neurologic deficits, and death in infancy. A shared rare homozygous, missense variant (c.274A > G; p.Ser92Gly, NM_024516.4) was identified in PAGR1, a gene currently not associated with a Mendelian disease. PAGR1 encodes a component of the histone methyltransferase MLL2/ MLL3 complex and may function in the DNA damage response pathway. Complete knockout of the murine Pagr1a is embryonic-lethal. Given the available evidence, PAGR1 is a strong candidate gene for a novel autosomal recessive severe syndromic neurodevelopmental disorder.

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Genome analysis and knowledge-driven variant interpretation with TGex

Cited by 36 publications

References 98 publications

Cruxome: a powerful tool for annotating, interpreting and reporting genetic variants

Cruxome: a powerful tool for annotating, interpreting and reporting genetic variants

Levodopa-responsive dystonia caused by biallelic PRKN exon inversion invisible to exome sequencing

Bi‐allelic PAGR1 variants are associated with microcephaly and a severe neurodevelopmental disorder: Genetic evidence from two families

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