Although the test is highly accurate there is still a possibility for false positive or false negative results. The lack of disease-causing variants in the targeted genes diminishes but does not exclude the possibility of a disease associated syndrome. Detection of CNVs using NGS has lower sensitivity/specificity than orthogonal quantification methods, therefore the absence of reported CNVs does not guarantee the absence of CNVs. The test cannot detect CNVs at genomic regions with either low mappability or containing repeats, pseudogenes and high/low GC-content. The test can detect CNVs down to a few exons level resolution. Genomic regions are called as variants if their normalized depth of coverage deviates significantly from the expected normalized coverage which is estimated from a set of reference clinical samples. CNVs are detected for a subset of the targeted regions using a depth of sequencing coverage approach by applying GC-content normalization. Copy Number Variations (CNVs) are calculated using high quality, de-duplicated and uniquely aligned sequencing reads. Certain sequence changes (SNVs and INDELS) in targeted regions containing repeats, sequences of high homology such as segmental duplications and pseudogenes, as well as regions of high/low GC-content may not be detected. Certain types of genetic abnormalities such as inversions, rearrangements, polyploidy and epigenetic effects are not covered by this test. In cases where two variants are identified in a gene, the test does not distinguish whether these are on one chromosome (in cis) or on different chromosomes (in trans). Certain sequence changes (SNVs and INDELS) in non-coding regions of selected genes that are of clinical significance are also included in the analysis. Unless otherwise noted, sequence changes (SNVs and INDELS) in the promoter and other non-coding regions are not covered by this assay. Variants that fall outside of the targeted regions are not intended to be detected by this assay. The test aims to detect all variants relevant to the genes listed above by targeting all coding exons, of MANE or/and Canonical transcripts, and 12 bp of adjacent intronic sequence. Seattle (WA): University of Washington, Seattle 1993-2019įH, PH and RAS Kit analyzes 11, 11 and 30 genes and covers Familial Hypercholesterolemia (FH), Pulmonary Hypertension (PH) and RASopathy (RAS) related disorders, respectively.ĪBCA1, ABCG5, ABCG8, APOA5, APOB, APOE, LDLR, LDLRAP1, LIPA, LPL, PCSK9ĪCVRL1, BMPR1B, BMPR2, CAV1, EIF2AK4, ENG, KCNA5, KCNK3, SMAD4, SMAD9, TBX4ĪKT3, BRAF, CBL, CCND2, EPHB4, HRAS, KRAS, LZTR1, MAP2K1, MAP2K2, MRAS, NF1, NF2, NRAS, PIK3CA, PIK3R2, PPP1CB, PTPN11, RAF1, RASA1, RASA2, RIT1, RRAS, SASH1, SHOC2, SMARCB1, SOS1, SOS2, SPRED1, STAMBP 2014, Mol Genet Metab 112(3):210 / Strauss et al., GeneReviews®. Due to the possibility of early detection and therapy with appropriate diet, the prognosis of the disease is favorable.įrazier et al. If positive, the diagnosis can be confirmed by molecular genetics. The patients' urine has a characteristic odor.ĭiagnosis of MSUD is part of newborn screening. Acute metabolic derangements may occur during catabolic stress. The intermediate form is often associated with developmental delay. The classic form of MSUD manifests in the first weeks of life with nonspecific symptoms (poor drinking, vomiting, comatose states, cerebral edema). BCKDHA codes for the E1a subunit, BCKDHB for E1b, and DBT for the E2 subunit.ĭepending on the variant, a distinction is made betweenĬlinical symptoms appear in the first weeks of life and the early childhood years, depending on the form. The disease is rare, with an incidence of approximately 1:150,000, and is caused by pathogenic variants in the BCKDHA, BCKDHB, and DBT genes, which encode three of the four enzymatically active subunits of the BCKAD complex. The defect results in the accumulation of branched-chain amino acids. Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disease caused by a defect in the alpha-keto acid dehydrogenase complex (BCKAD complex), which mediates the breakdown of the branched-chain amino acids, leucine, isoleucine, and valine.
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