Hypermethioninemia Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10133 ADK 81479,81479 Order Options and Pricing
AHCY 81479,81479
GNMT 81479,81479
MAT1A 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10133Genes x (4)81479 81479 $890 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Hypermethioninemia can be caused by defects in any one of at least six proteins, and may be detected by newborn screening programs in early infancy (Mudd et al. 2000. PubMed ID: 11145114; Mudd et al. 2001. PubMed ID: 11596649; Mudd. 2011. PubMed ID: 21308989; Mudd 2014). Defects in the methionine adenosyltransferase I/III (MATI/III), glycine N-methyltransferase (GNMT) and S-adenosylhomocysteine hydrolase (AHCY) enzymes are responsible for persistent, isolated hypermethioninemia.

Individuals with defects in MAT I/III, GNMT or AHCY enzymes all exhibit persistent, isolated hypermethioninemia, which may or may not be apparent in early infancy (Mudd. 2011. PubMed ID: 21308989). Clinical presentations may differ as well, although a complete clinical spectrum is not well defined for these diseases. The majority of MAT I/III deficient patients are asymptomatic, but they may occasionally present with unusual breath odor and neurologic abnormalities, including intellectual impairment, increased tendon reflexes, dystonia, and nystagmus (Mudd et al. 1995. PubMed ID: 7573050; Chamberlin et al. 1996. PubMed ID: 8770875; Hazelwood et al. 1998. PubMed ID: 9482646; Mudd et al. 2001. PubMed ID: 11596649; Mudd et al. 2014; Chien et al. 2015. PubMed ID: 26289392). Individuals diagnosed with GNMT Deficiency have presented with hepatomegaly and chronic elevation of serum transaminases indicative of liver disease, not attributable to typical causes of liver disease (Mudd et al. 2001. PubMed ID: 11596649; Luka et al. 2009. PubMed ID: 19483083; Augoustides-Savvopoulou et al. 2003. PubMed ID: 14739680). Patients with AHCY deficiency are generally more severely affected, and all have presented with hypotonia and myopathy along with increased creatine kinase (CK) levels. Other common clinical features of AHCY deficiency have included lethargy, poor head control, white matter or other brain abnormalities, microcephaly, developmental delay, strabismus, coagulopathy, liver abnormalities, behavioral issues (including severe attention deficit, self-injurious behavior and aggression), poor feeding, and in one family, fetal hydrops (Baric et al. 2004. PubMed ID: 15024124; Buist et al. 2006. PubMed ID: 16736098; Grubbs et al. 2010. PubMed ID: 20852937; Mudd. 2011. PubMed ID: 21308989; Honzík et al. 2012. PubMed ID: 22959829; Strauss et al. 2015. PubMed ID: 26095522). Additional details regarding these disorders can be found on the individual gene test description pages.

Hypermethioninemia with mild homocystinuria has also been reported in patients with defects in the adenosine kinase enzyme, encoded by the ADK gene. These patients can present with mild to severe liver dysfunction beginning in the neonatal period, muscular hypotonia, global developmental delays, dysmorphism, epilepsy, and recurrent hypoglycemia. Biochemically, they exhibit intermittent hypermethioninemia, increased S-adenosylmethionine and S-adenosylhomocysteine in plasma and increased adenosine in urine (Bjursell et al. 2011. PubMed ID: 21963049; Shakiba et al. 2016. PubMed ID: 27500280; Staufner et al. 2016. PubMed ID: 26642971).

Hypermethioninemia may also be caused by defects in the cystathionine β -synthase (encoded by the CBS gene), fumarylacetoacetate hydrolase (encoded by the FAH gene) and citrin (encoded by the SLC25A13 gene) proteins, as well as by liver disease (Mudd et al. 2000; Mudd et al. 2001; Mudd et al. 2011; Mudd 2014). As defects in the genes encoding CBS, FAH and citrin lead to biochemically distinguishable profiles, testing for these genes is not included in this NextGen sequencing panel.

Genetics

MAT I/III, GNMT, AHCY, and ADK deficiencies are all autosomal recessive disorders, caused by pathogenic variants in the MAT1A, GNMT, AHCY, and ADK genes, respectively. Pathogenic variants in the MAT1A gene are the most common genetic cause of persistent, isolated hypermethioninemia, with nearly 60 reported causative variants in the literature to date. Pathogenic variants in the ADK, AHCY and GNMT genes are more rare, with fewer than ~15 variants reported in each gene (Human Gene Mutation Database). The majority of reported pathogenic variants in these genes are missense variants, although one nonsense variant has been reported in each AHCY and GNMT, nonsense and small deletion variants have been reported in ADK, and small numbers of nonsense, splicing, small deletions and duplications and three large deletions have been reported in the MAT1A gene (Baric et al. 2004. PubMed ID: 15024124; Human Gene Mutation Database).

The enzymes encoded by these genes are responsible for the catabolism of methionine. The MAT I/III enzyme catalyzes the biosynthesis of S-adenosylmethionine (also known as AdoMet or SAM) from methionine and ATP (Catoni 1953). AdoMet is subsequently converted to S-adenosylhomocysteine (AdoHcy) via the action of GNMT, then the AHCY enzyme hydrolyzes AdoHcy to adenosine and homocysteine (Mudd et al. 2001. PubMed ID: 11596649; Baric et al. 2004. PubMed ID: 15024124; Luka et al. 2009. PubMed ID: 19483083: Mudd. 2011. PubMed ID: 21308989). These reactions make up part of the transmethylation and transsulfuration pathways (Mudd et al. 2014). Adenosine kinase converts adenosine to adenosine monophosphate, and a defect in the ADK enzyme leads to disruption of the methionine cycle due to a resulting accumulation of adenosine that reverses the reaction balance of the AHCY enzyme (Staufner et al. 2016. PubMed ID: 26642971).

Clinical Sensitivity - Sequencing with CNV PGxome

Although the overall sensitivity of this test panel is not precisely known, most pathogenic variants reported for the genes in this panel are of the type which can be detected by sequencing.

In two recent reports of patients with MAT1A deficiency, clinical sensitivity was >95% for variants detectable via direct sequencing (Couce et al. 2013. PubMed ID: 23993429; Chien et al. 2015. PubMed ID: 26289392).

The clinical sensitivity of this test for ADK, AHCY and GNMT deficiencies is currently difficult to estimate due to the low number of cases reported in the literature. However, sensitivity is expected to be high as all patients with biochemically and/or enzymatically confirmed ADK, AHCY and GNMT deficiency and molecular analysis have been found to carry two pathogenic variants in the appropriate gene (Luka et al. 2002. PubMed ID: 11810299; Augoustides-Savvopoulou et al. 2003. PubMed ID: 14739680; Baric et al. 2004. PubMed ID: 15024124; Buist et al. 2006. PubMed ID: 16736098; Bjursell et al. 2011. PubMed ID: 21963049; Strauss et al. 2015. PubMed ID: 26095522; Staufner et al. 2016. PubMed ID: 26642971).

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes listed plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Individuals with biochemical test results consistent with persistent hypermethioninemia are good candidates for this test, as are those with clinical symptoms of a hypermethioninemia disorder.

Genes

Official Gene Symbol OMIM ID
ADK 102750
AHCY 180960
GNMT 606628
MAT1A 610550
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Augoustides-Savvopoulou et al. 2003. PubMed ID: 14739680
  • Baric et al. 2004. PubMed ID: 15024124
  • Bjursell et al. 2011. PubMed ID: 21963049
  • Buist et al. 2006. PubMed ID: 16736098
  • Chamberlin et al. 1996. PubMed ID: 8770875
  • Chien et al. 2015. PubMed ID: 26289392
  • Couce et al. 2013. PubMed ID: 23993429
  • Grubbs et al. 2010. PubMed ID: 20852937
  • Hazelwood et al. 1998. PubMed ID: 9482646
  • Honzík et al. 2012. PubMed ID: 22959829
  • Human Gene Mutation Database (Bio-base).
  • Luka et al. 2002. PubMed ID: 11810299
  • Luka et al. 2009. PubMed ID: 19483083
  • Mudd et al. 1995. PubMed ID: 7573050
  • Mudd et al. 2000. PubMed ID: 11145114
  • Mudd et al. 2001. PubMed ID: 11596649
  • Mudd et al. 2014. Disorders of Transsulfuration. In: Valle D, Beaudet AL, Vogelstein B, et al., editors.New York, NY: McGraw-Hill. OMMBID. 
  • Mudd. 2011. PubMed ID: 21308989
  • Shakiba et al. 2016. PubMed ID: 27500280
  • Staufner et al. 2016. PubMed ID: 26642971
  • Strauss et al. 2015. PubMed ID: 26095522

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

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