The Invitae Elevated Succinylacetone test analyzes the FAH gene, which is associated with elevated succinylacetone (the biochemical hallmark of tyrosinemia type 1) on newborn screening (NBS) or blood and urine organic acid analysis. Genetic testing of this gene may confirm a diagnosis of fumarylacetoacetate hydrolase (FAH) deficiency and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives.
Fumarylacetoacetate hydrolase (FAH) deficiency
The enzyme encoded by the FAH gene is required for the degradation of the amino acid tyrosine. Pathogenic variants in the FAH gene cause FAH deficiency and tyrosinemia type I, an inherited metabolic disorder. Elevated succinylacetone is the biochemical hallmark for tyrosinemia type I. Affected infants may or may not show elevated plasma tyrosine. An elevated plasma tyrosine can also be a nonspecific indicator of liver damage or immaturity. Clinical manifestations are highly variable and can present at any age, from the neonatal period to adulthood. Symptoms and age of onset broadly correlate with disease severity. Affected patients typically present with either an acute or chronic form of the disorder.
Infants affected with acute tyrosinemia type I usually begin with failure to thrive; if left untreated, it often develops to life-threatening liver failure within a few months after birth. Additional symptoms include fever, feeding difficulty, increased tendency to bleeding, diarrhea or bloody stools, hepatosplenomegaly, and kidney disease. Untreated infants and children are also at an increased risk for liver cancer.
Detection rate of biallelic pathogenic variants in FAH is greater than 95% in individuals who have characteristic biochemical findings of FAH deficiency.
Tyrosinemia type I is an autosomal recessive condition.
Tyrosinemia type 1 occurs in an estimated 1 in 100,000–120,000 US births. Higher birth incidences have been reported in one region of the Canadian province of Quebec (approximately 1 in 1,850) and in Norway (1 in 60,000).
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Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.
Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|