- 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. - The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. - If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. - To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.. - The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.. - Currently, in the order of Mendelian disorders have been recorded by Global Genes (https://globalgenes.org. - Online Mendelian Inheritance in Man (OMIM, https://omim.org/) and Orphadata (http://www.orphadata.org/) databases and ap- proximately 300 new Mendelian phenotypes are updated each year [4]. - Thus, an important step is to choose the appropriate analysis tools to efficiently and precisely mine the causative variants, especially when the analysis team lacks training in the use of sophisticated bioinformatic programs. - Combined Annota- tion Dependent Depletion (CADD) is used to score the deleteriousness of SNV as well as InDel variants in the human genome. - When a set of candidate variants are identified, the aim of follow-up analysis is to establish a strong relationship between the candidate genes and known diseases by using information in the published literature and databases. - HPO uses standardized vocabulary for describing pheno- typic abnormalities in human disease, drawing on over 13,000 terms and over 156,000 annotations to hereditary diseases (https://hpo.jax.org/) [29, 32]. - To enhance the functionality of Cruxome, improve efficiency and simplify code mainten- ance, a layered pattern was used in the basic architecture. - of Cruxome (Fig. - Minimum requirements of Cruxome (available on all modern computers):. - 1 Architecture of Cruxome. - The report of the analysis is then exported in a PDF or Word format, and the personal knowledge base is automatically updated to store all the interpretation information. - The clinical diagnosis of the six-month-old pro- band was “decreased fetal movement in the prenatal period and increased head circumference (45.7 cm), glo- bal developmental delay, periventricular leukomalacia, hip dysplasia, motor deterioration and impaired pursuit initiation and maintenance post birth”. - The final interpretation results can be accessed in the. - If candidate pathogenic gene variants are found (AHDC1 gene in this case), users should mark the corresponding variants as “Positive” in the conclusion column (Fig. - T: p.R925*) in the AHDC1 gene, which has been reported to be responsible for autosomal dominant Xia-Gibbs syndrome [39]. - T: p.R73X) variant in the MMACHC gene, which is responsible for methylmalonic aciduria and homocystinuria [40] (Supplemental Table 1). - Third, the “locus searching” tool can be used to calculate frequency of variants in all samples in the personal knowledge base (Fig. - users can easily re-analyze cases stored in the knowledge base, and potentially identify novel pathogenic variants.. - However, in the current version of Cruxome, only variants from WES and panel data are supported, and file. - 3 Interface of Cruxome. - Users enter the submodule by clicking the corresponding text in the left panel. - To perform an interpretation, click “ Add ” button in “ Sample Management ” module, and input the patient ’ s information in the pop-out window. - 4 Extra tools Interface of Cruxome. - Getting sequence ” tools: displays flanking sequence of a given site in the reference genome.. - The position, reference sequence and the type of variants are shown in the above three rows. - Locus search ” tool: calculates the frequency of variants in a given region in all samples in the personal knowledge base. - 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