The Invitae Elevated Citrulline Panel analyzes three genes that are associated with elevated citrulline on newborn screening (NBS) or plasma amino acids. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives.
ASL ASS1 SLC25A13
ASL ASS1 SLC25A13
The Invitae Urea Cycle Disorders Panel has been designed to provide a broad genetic analysis of this class of disorders. Depending on the individual’s clinical and family history, this broader panel may be appropriate. It can be ordered at no additional cost.
Elevated citrulline detected during newborn screening may be associated with argininosuccinate synthetase (ASS1) deficiency, argininosuccinate lyase (ASL) deficiency, and the neonatal form of citrin (SLC25A13) deficiency.
Argininosuccinate Lyase (ASL) deficiency can present either as a severe neonatal-onset form with hyperammonemia within the first few days of life, or as a late-onset form with episodic hyperammonemia or long-term complications, including liver dysfunction, neurocognitive deficits, and hypertension. These long-term complications can occur in the absence of hyperammonemic episodes. The biochemical diagnosis of ASL deficiency is typically established with elevation of plasma citrulline together with elevated argininosuccinic acid in the plasma or urine.
ASS1 deficiency causes citrullinemia type 1 (CTLN1). CTLN1 presents as a clinical spectrum with a severe neonatal form, a milder later-onset form, and some individuals who are asymptomatic. Increased intracranial pressure can occur secondarily to hyperammonemia, resulting in increased neuromuscular tone, spasticity, and ankle clonus. Initial plasma ammonia concentration may be 1000–3000 µmol/L (normal: 40–50 µmol/L). In the milder form, symptoms manifest as recurrent lethargy and somnolence, intellectual disability, and chronic or recurrent hyperammonemia. A lower plasma ammonia concentration may be seen than in the classic form (adult upper limit of normal: <35 µmol/L). A rare form of CTLN1 occurs during and after pregnancy, with affected women experiencing vomiting, lethargy, seizures, confusion, hallucinations, behavioral changes (e.g., manic episodes, psychosis), and swelling of the brain.
The SLC25A13 gene encodes the aspartate/glutamate transporter called citrin. Citrin deficiency impairs the shuttling of aspartate and glutamate across the mitochondria, causing a mild hyperammonemia and citrullinemia (also known as citrullinemia type II [CTLN2]). The clinical presentation in adults with citrin deficiency is milder than that of CTLN1, and asymptomatic or presymptomatic individuals with citrin deficiency do not always show biochemical abnormalities. For this reason, definitive diagnosis of at-risk relatives may be dependent on the molecular genetic findings of SLC25A13 in the index case.
Citrin deficiency can manifest in newborns as neonatal intrahepatic cholestasis (NICCD), in older children as failure to thrive and lipid abnormalities, and in adults as recurrent hyperammonemia with neuropsychiatric symptoms.
Analysis of the genes on this panel will identify pathogenic variants in 90% of patients who are diagnosed with CTLN1 or CTLN2. ASL is the only gene in which pathogenic variants are known to cause argininosuccinate lyase deficiency.
All genetic causes of elevated citrulline are inherited in an autosomal recessive manner.
The prevalence of CTLN1 is 1 in 57,000 births in the US, 1 in 22,150 births in Korea, 1 in 118,543 births in Taiwan, and 1 in 77,811 births in Austria. The prevalence of CTLN2 is unknown, though most identified patients are Japanese. The prevalence of ASL deficiency is approximately 1 in 70,000 live births.
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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.
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