#MEDIAN XL LEVEL CHALLENGE 0 FULL#

#MEDIAN XL LEVEL CHALLENGE 0 FULL#

Nevertheless, genome sequencing has not yet fulfilled its full potential for clinical genomics as current information of the noncoding elements in IBD is still restricted and its analysis is complex ( 21). Due to a more even sequencing coverage of the sequence reads compared with exome sequencing, it allows to investigate copy number variation (CNV, deletions or duplications).

In addition to the protein-coding regions, it allows analysis of regulatory elements and intronic regions. Genome sequencing investigates the entire genome of approximately 3 billion base pairs of which most are biallelic ( 20). The technology does have limitations in the diagnostic setting because of read coverage deficiencies in some regions but newer exon capture assays compensate for uneven coverage. Exome sequencing aims to investigate the whole range of protein-coding variants in approximately 20,000 genes ( 20). This technology results comparably in high coverage of the sequencing reads and the analysis is relatively simple compared with an exome-wide or genome-wide analysis.

Panel sequencing is a cost-effective technology to screen for variants in a limited number of genes (typically 10s to few hundred genes). The technologies and analytic approaches are standardised to meet clinical diagnostic needs ( 20). Next-generation sequencing technologies including targeted panel sequencing, exome and genome sequencing are increasingly used in the research and in the clinical setting to screen for monogenic disorders associated with IBD ( 10, 11, 19). Incomplete penetrance of most causative genes suggests that additional factors, such as environmental factors, the microbiome, and additional genetic risk factors contribute to the phenotype of monogenic IBD ( 17, 18). Monogenic IBDs have a higher morbidity compared with classical IBD ( 15, 16). Whereas some of these monogenic disorders present with almost pathognomonic features (such as immunodysregulation polyendocrinopathy enteropathy X-linked syndrome or Trichohepatoenteric syndrome), others do not. It can be challenging to distinguish monogenic IBD from classical IBD based on clinical phenotype alone. The group of monogenic IBD defects includes a large number of primary immunodeficiencies as well as intestinal epithelial cell defects.

In these patients, IBD is caused by high penetrance genetic variants in a single gene (monogenic IBD). A growing number of rare monogenic disorders presenting with IBD-like intestinal inflammation have been identified ( 10вЂ“ 14). Use of genomic sequencing technologies allows identification of previously undiagnosed disorders in patients with multiple conditions, including gastrointestinal, immunological, and rheumatologic diseases ( 9). In most patients with IBD, a large number of common genetic variants (>1% allelic frequency in the general population) contribute to disease susceptibility in a polygenic setting ( 3вЂ“ 8). The genetics of IBD is complex with 3 major areas arising: complex genetics based on hundreds of common polygenic risk variants, rare monogenic IBD genetics, and pharmacogenetics. Genetic technologies have revolutionized the understanding of the genetic basis and subsequent functional understanding of immune-mediated disorders, such as inflammatory bowel diseases (IBD), which encompasses CrohnвЂ™s disease, ulcerative colitis, and IBD unclassified (IBDU) ( 1, 2).

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