Diagnosis; Drug Response; Mutation Confirmation; Prognostic

Establish or confirm diagnosis

Urea cycle disorders are a family of disorders in which excess ammonia found in the plasma is the result of either failure of ammonia detoxification or overproduction of ammonia. Defects in the urea cycle or its cofactors are not evident at birth, but symptoms frequently appear within days of birth. … Urea cycle disorders are a family of disorders in which excess ammonia found in the plasma is the result of either failure of ammonia detoxification or overproduction of ammonia. Defects in the urea cycle or its cofactors are not evident at birth, but symptoms frequently appear within days of birth. Cerebral edema, poor feeding and vomiting, seizures, hypothermia as well as hyper or hypoventilation. Primary hyperammonemia may be the result of an inherited deficiency of one of the enzymes composing the hepatic urea cycle and membrane transporters. Secondary hyperammonemia is the result of defects in the related pathways responsible for the assembly of ammonia acceptors and associated substrates required in the function of the urea cycle. Heterogeneity in urea cycle disorders supports the use of a multigene panel for genetic testing. London Health Sciences Centre Urea Cycle Panel (LHSC UCD) is a Next Generation Sequencing (NGS) test involving sequence and copy number analysis of coding regions and adjacent intronic regions for 13 genes associated with various forms of urea cycle disorders. The test is designed to provide rule out level assessment for all coding sequence and copy number alterations for 13 genes, which encompass the majority of the known genetic etiologies for urea cycle disorders. This test is useful in the confirmation of a clinical diagnosis, prenatal diagnosis in the presence of a family history of urea cycle disorders, as well as testing individuals with idiopathic hyperammonemia or suspicion of a urea cycle disorder. View more

All coding exons and 20 bp of flanking intronic sequence are enriched using an LHSC custom targeted hybridization protocol (Roche Nimblegen), followed by high throughput sequencing (Illumina). Sequence variants and copy number changes are assessed and interpreted using clinically validated algorithms and commercial software (SoftGenetics: Nextgene, Geneticist Assistant, Mutation Surveyor; … All coding exons and 20 bp of flanking intronic sequence are enriched using an LHSC custom targeted hybridization protocol (Roche Nimblegen), followed by high throughput sequencing (Illumina). Sequence variants and copy number changes are assessed and interpreted using clinically validated algorithms and commercial software (SoftGenetics: Nextgene, Geneticist Assistant, Mutation Surveyor; and Alamut Visual). All exons have >1000x mean read depth coverage, with a minimum 200x coverage at a single nucleotide resolution. This assay meets the sensitivity and specificity of combined Sanger sequencing and MLPA copy number analysis. All variants interpreted as either ACMG category 1, 2, or 3 (pathogenic, likely pathogenic, VUS; PMID: 25741868) are confirmed using Sanger sequencing, MLPA, or other assays. ACMG category 4 and 5 variants (likely benign, benign) are not reported, but are available upon reques View more

Affymetrix CytoScan HD Array

Mutations identified are repeated in an independent assay using either Sanger sequence, MLPA, Q-PCR or other.

Tests performed
Entire test performed in-house

This assay meets the sensitivity and specificity of combined Sanger sequencing and MLPA copy number analysis, >99%

Is proficiency testing performed for this test? Help
Yes

Method used for proficiency testing: Help
Intra-Laboratory

Software used to interpret novel variations Help
SoftGenetics: Nextgene, Geneticist Assistant, Mutation Surveyor; and Alamut Visual with HGMD

Laboratory's policy on reporting novel variations Help
All variants interpreted as either ACMG category 1, 2, or 3 (pathogenic, likely pathogenic, VUS; PMID: 25741868) are confirmed using Sanger sequencing, MLPA, or other assays. ACMG category 4 and 5 variants (likely benign, benign) are not reported, but are available upon request