Ordering
  • Test code: 06213
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
Billing
 

Invitae Purine Metabolism Disorders Panel

Test description

The Invitae Purine Metabolism Disorders Panel analyzes up to 10 genes that are associated with abnormalities in the synthesis, interconversion, and degradation of the purines, adenine and guanine. Symptoms can include gout, anemia, epilepsy, developmental delays, intellectual disabilities, kidney problems, and immune deficiencies. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of disease-causing variants provides accurate risk assessment and determines carrier status in at-risk relatives.

Please note that this panel does not include the MOCS2 gene.

Order test

Primary panel (9 genes)

ADA ADSL AMPD1 GPHN HPRT1 MOCOS MOCS1 PNP XDH

Add-on Sulfite Oxidase Deficiency Gene (1 gene)

The enzymes encoded by the GPHN and MOCS1 genes are required for molybdenum cofactor (MoCo) synthesis. MoCo is a cofactor required for the functioning of xanthine dehydrogenase. Biallelic pathogenic mutations in one of these three genes result in MoCo deficiency and lead to xanthine dehydrogenase deficiency. MoCo deficiency and sulfite oxidase deficiency are clinically similar. Both disorders show elevated urinary sulfite, accumulation of sulfocysteine, and elevated levels of thiosulfate as well as taurine. Other biochemical features can distinguish these disorders, but given the clinical and partial biochemical overlap of these conditions, the analysis of SUOX may be appropriate. This gene can be added at no additional charge.

SUOX

  • adenosine deaminase deficiency (ADA)
  • adenylosuccinate lyase deficiency (ADSL)
  • adenosine monophosphate deaminase 1 deficiency (AMPD1)
  • hypoxanthine phosphoribosyltransferase 1 deficiency (HPRT1)
  • molybdenum cofactor deficiency type A (MOCS1)
  • molybdenum cofactor deficiency type C (GPHN)
  • molybdenum cofactor sulphurase deficiency (MOCOS)
  • purine nucleoside phosphorylase deficiency (PNP)
  • xanthine dehydrogenase deficiency (XDH)

The purine nucleotides, their cyclic derivatives (cAMP and cGMP), and their phosphorylated derivatives participate in many aspects of intermediary metabolism. Purine compounds also serve as signal transducers, neurotransmitters, vasodilators and mediators of platelet aggregation. Pathogenic mutations resulting in deficiencies in enzymes in purine metabolism have been associated with specific clinical disorders.

Adenosine deaminase encoded by the ADA gene and purine nucleoside phosphorylase encoded by the PNP gene catalyse sequential steps in the metabolism of purine ribonucleosides and deoxyribonucleosides. ADA and PNP genes are highly expressed in lymphoid cells and deficiency of these enzymes results in the accumulation lymphotoxic metabolites and causes to lymphopenia and immunodeficiency. ADA deficiency most often manifests as severe combined immunodeficiency with lethal infections in infancy or early childhood. Surviving children with bone marrow transplantation or enzyme replacement therapy may develop neurological problems including psychomotor retardation, seizures, or hearing loss. Symptoms of purine nucleoside phosphorylase deficiency involve varying degrees of immunodeficiency and a spectrum of neurological, motor, and cognitive abnormalities. Approximately 30% of affected individuals present autoimmune diseases and 50% of affected individuals manifest neurological problems.

The ADSL gene encodes the adenylosuccinate lyase which catalyzes two steps in the synthesis of purine nucleotides. The biochemical hallmark of adenylosuccinate lyase deficiency is the accumulation of succinyl aminoimidazolecarboxamide riboside and succinyladenosine in cerebrospinal fluid and urine. Adenylosuccinate lyase deficiency is further classified into type 1 and type 2 subtypes. Type 1 can be life threatening and the condition involves hypotonia, microcephaly, epileptic seizures with neonatal or infantile onset, intellectual disability, autistic features, and growth retardation. Individuals affected with type 2 adenylosuccinate lyase deficiency present milder intellectual impairment as compared to those affected with type 1 although delayed motor development and profound hypotonia may be involved.

AMP deaminase deficiency primarily affects adenine nucleotide catabolism in skeletal muscle. The vast majority of individuals with AMP deaminase deficiency are asymptomatic. Individuals who develop symptoms typically involve exercise intolerance accompanied by muscle pain and cramping in late childhood or adulthood.

The HPRT gene encodes the hypoxanthine phosphoribosyltransferase 1 which participates in recycling the purine bases hypoxanthine and guanine back into the purine nucleotide pools. The absence of hypoxanthine phosphoribosyltransferase 1 activity, purine bases cannot be recycled and are metabolized into uric. Hypoxanthine phosphoribosyltransferase 1 deficiency involves a clinical spectrum from isolated hyperuricemia to hyperuricemia with profound neurological disabilities and behavioural disturbances seen in Lesch–Nyhan syndrome. Stones may form in any portion of the urogenital system where uric acid is concentrated by the kidneys, resulting in nephrolithiasis or crystalluria. It may also precipitate in the synovial fluid of the joints, causing gout.

The XDH gene encodes xanthine dehydrogenase which catalyzes the breakdown of purines to uric acid. The xanthine dehydrogenase enzyme functions as homodimers with each subunit containing one molybdenum center requiring the molybdenum cofactor (MoCo) for enzymatic activity. MoCo synthesis is required by the enzymes encoded by the GPHN, MOCS1, and MOCS2 genes. Biallelic pathogenic mutations in one of the three MoCo synthesis genes resulting in MoCo deficiency lead to xanthine dehydrogenase deficiency.

Biallelic pathogenic mutations in the XDH gene cause hereditary xanthinuria type 1, a condition characterized by elevated xanthine and very low levels of uric acid in blood and urine. The functional activity of XDH is dependent on the activity of the MoCo sulfurase encoded by the MOCOS gene. The MoCo sulfurase enzyme sulfurates the MoCo which is a process required for activation of xanthine dehydrogenase. Biallelic pathogenic mutations in the MOCOS gene resulting in MoCo sulfurase deficiency which prevents the activation of xanthine dehydrogenase and leads to hereditary xanthinuria type 2. Clinically, xanthinuria type 1 and type 2 are not distinguishable. Molecular analysis and allopurinol loading test are necessary to differentiate them.

The clinical sensitivity for this test is unknown. Purine metabolism disorders are clinically and genetically heterogeneous, and the percentage of patients with a purine metabolism disorder and a pathogenic variant(s) in one of the genes offered in this panel has not been determined.

The following deficiencies are inherited in an an autosomal recessive manner:

  • ADA deficiency
  • ADSL deficiency
  • AMPD1 deficiency
  • GPHN deficiency
  • MOCOS deficiency
  • MOCS1 deficiency
  • PNP deficiency
  • XDH deficiency

The following deficiency is inherited in an X-linked manner:

  • HPRT deficiency

Adenosine deaminase deficiency is very rare and is estimated to occur in approximately 1: 200,000 live births.

The prevalence of Lesch-Nyhan syndrome is approximately 1: 380,000 individuals.

AMP deaminase deficiency is one of the most common inherited muscle disorders in Caucasian populations, affecting 1: 50 to 1:100. The prevalence is lower in African Americans, affecting an estimated 1: 40,000, and the condition is even less common in the Japanese population.

The frequency of MoCo deficiency is estimated to occur 1:100,000 to 1: 200,000 newborns worldwide although it may be underestimated due to underdiagnosis.

The combined incidence of hereditary xanthinuria types 1 (XDH) and 2 (MOCOS) is estimated to be approximately 1: 69,000 worldwide. The true incidence is likely to be higher due to under diagnosis.

Purine nucleoside phosphorylase deficiency and adenylosuccinate lyase deficiency are rare, prevalence in the population is unknown.

Assay and technical information

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 in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ADA NM_000022.2
ADSL NM_000026.2
AMPD1 NM_000036.2
GPHN NM_020806.4
HPRT1 NM_000194.2
MOCOS NM_017947.2
MOCS1 NM_001075098.3
PNP NM_000270.3
SUOX NM_000456.2
XDH NM_000379.3