Disorders Related to Metabolism of Cobalamin, Folate and Homocysteine Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10397 ABCD4 81479,81479 Order Options and Pricing
ACSF3 81479,81479
ADK 81479,81479
AHCY 81479,81479
ALDH6A1 81479,81479
AMN 81479,81479
CBLIF 81479,81479
CBS 81406,81479
CD320 81479,81479
CUBN 81479,81479
DHFR 81479,81479
FOLR1 81479,81479
FTCD 81479,81479
GNMT 81479,81479
HCFC1 81479,81479
HIBCH 81479,81479
LMBRD1 81479,81479
MAT1A 81479,81479
MCEE 81479,81479
MLYCD 81479,81479
MMAA 81405,81479
MMAB 81405,81479
MMACHC 81404,81479
MMADHC 81479,81479
MMUT 81406,81479
MTHFD1 81479,81479
MTHFR 81479,81479
MTR 81479,81479
MTRR 81479,81479
PCCA 81406,81405
PCCB 81406,81479
PRDX1 81479,81479
SLC46A1 81479,81479
SUCLA2 81479,81479
SUCLG1 81479,81479
TCN1 81479,81479
TCN2 81479,81479
THAP11 81479,81479
ZNF143 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10397Genes x (39)81479 81404, 81405, 81406, 81479 $960 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

The disorders caused by defects in the genes in this sequencing panel are all inborn errors of metabolism related to the transport and metabolism of cobalamin, propionic acid, methylmalonyl-CoA, folate and methionine. Clinical features vary with the different disorders, but can include symptoms such as feeding difficulties, vomiting, failure to thrive, lethargy, hypotonia and myopathy along with increased creatine kinase (CK) levels. Liver abnormalities, such as hepatomegaly and elevation of serum transaminases, are also common. Neurologic abnormalities often occur, and may include intellectual impairment, cerebral atrophy and developmental delay, seizures, microcephaly, increased tendon reflexes, ataxia, dystonia, and nystagmus. Hematological abnormalities are also common, and may include megaloblastic anemia, neutropenia and/or coagulopathy. Visual defects such as ectopia lentis, strabismus, severe myopia or blindness may occur. Less common features may include skeletal abnormalities, vascular disease, behavioral issues, and dysmorphic features. Biochemically, patients may have hypoglycemia, ketosis, metabolic acidosis, hyperammonemia, and abnormally low or high levels of serum and/or urine homocysteine, methylmalonic acid, methionine, and/or propionic acid; the specific biochemical profile will vary with each of the different disorders. Onset for the majority of patients is early in life, though later-onset cases do occur. See Sloan et al. 2018. (PubMed ID: 20301503) for a review of a number of these disorders.

The disorders included in this panel are very rare in most populations, with a frequency of ~1/50,000 or less, depending on the disorder (Sloan et al. 2018. PubMed ID: 20301503).

Obtaining an accurate molecular diagnosis may help in determining the patient’s prognosis, planning for the best treatment and/or management of symptoms, and allow for reproductive planning. For details on specific disorders, please visit the individual gene summary page.

Genetics

This sequencing panel currently includes genes that have been associated with inborn errors of cobalamin, propionic acid, methylmalonyl-CoA, folate and methionine metabolism. The majority of the disorders associated with these genes are inherited in an autosomal recessive manner, with the exception of methionine adenosyltransferase I/III deficiency, which primarily autosomal recessive but is sometimes associated with autosomal dominant inheritance, and cblX type methylmalonic aciduria and homocystinuria, which is an X-linked disorder caused by pathogenic variants in the HCFC1 gene. Of note, female carriers of HCFC1 genes are generally unaffected (Sloan et al. 2018. PubMed ID: 20301503). Pathogenic de novo variants have occasionally been reported in HCFC1. To our knowledge, de novo variants are not a common cause of disease for the remaining genes in this panel.

It has been recently reported that patients compound heterozygous for a pathogenic variant in MMACHC and a variant that disrupts the intron 5 splice acceptor site of the PRDX1 gene (which is adjacent to the MMACHC gene) present with cblC type methylmalonic aciduria and homocystinuria. Disruption of the splice site at the junction of intron 5 and exon 6 of PRDX1 was shown to lead to PRDX1 exon 6 skipping, transcription of antisense MMACHC RNA, and resultant hypermethylation of the MMACHC promoter and exon 1. This lead to silencing of MMACHC gene expression (Guéant et al. 2018. PubMed ID: 29302025).

See individual gene summaries for information about molecular biology of gene products and spectra of pathogenic variants.

Clinical Sensitivity - Sequencing with CNV PGxome

The clinical sensitivity of this specific grouping of genes is difficult to estimate as we are unaware of any reports in the literature in which all of these genes have been sequenced together in a patient cohort. One study of 131 patients with elevated methylmalonic acid in the blood or urine but no molecular diagnosis based on initial testing has been published. A 24 gene sequencing panel, of which 22 genes overlap with our test, was run for each of these patients to attempt to obtain a diagnosis. Eight patients (6%) were reported with pathogenic variants consistent with their diagnosis (Pupavac et al. 2016. PubMed ID: 26827111).

The clinical sensitivity of sequencing the individual genes in this test is high in patient groups with biochemical and/or enzymatic diagnoses of the relevant disorders; details are available on the individual gene summary pages. Analytical sensitivity is expected to be high as nearly all variants reported in these genes are detectable via direct sequencing.

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 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

Patients with biochemical and/or clinical features consistent with inborn errors of cobalamin, propionic acid, methylmalonyl-CoA, folate and methionine metabolism are good candidates for this test.

Diseases

Name Inheritance OMIM ID
Beta-Hydroxyisobutyryl-CoA Deacylase Deficiency AR 250620
Cerebral Folate Deficiency AR 613068
Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia AR 617780
Combined Malonic And Methylmalonic Aciduria AR 614265
Folate Malabsorption, Hereditary AR 229050
Glutamate Formiminotransferase Deficiency AR 229100
Glycine N-Methyltransferase Deficiency AR 606664
Homocystinuria Due To Cbs Deficiency AR 236200
Homocystinuria due to MTHFR Deficiency AR 236250
Homocystinuria-Megaloblastic Anemia Due To Defect In Cobalamin Metabolism, cblE Complementation Type AR 236270
Homocystinuria-Megaloblastic Anemia Due To Defect In Cobalamin Metabolism, cblG Complementation Type AR 250940
Hypermethioninemia Due To Adenosine Kinase Deficiency AR 614300
Hypermethioninemia With S-Adenosylhomocysteine Hydrolase Deficiency AR 613752
Intrinsic Factor Deficiency AR 261000
Malonyl-CoA Decarboxylase Deficiency AR 248360
Megaloblastic Anemia Due To Dihydrofolate Reductase Deficiency AR 613839
Megaloblastic Anemia Due To Inborn Errors Of Metabolism AR 261100
Mental Retardation, X-Linked 3 (Methylmalonic Acidemia and Homocysteinemia, cblX Type) XL 309541
Methionine Adenosyltransferase I/III Deficiency AD,AR 250850
Methylmalonate Semialdehyde Dehydrogenase Deficiency AR 614105
Methylmalonic Aciduria and Homocystinuria, cblC Type AR 277400
Methylmalonic Aciduria and Homocystinuria, cblD Type AR 277410
Methylmalonic Aciduria and Homocystinuria, cblF Type AR 277380
Methylmalonic Aciduria and Homocystinuria, cblJ Type AR 614857
Methylmalonic Aciduria Cbla Type AR 251100
Methylmalonic Aciduria Cblb Type AR 251110
Methylmalonic Aciduria Due To Methylmalonyl-CoA Mutase Deficiency AR 251000
Methylmalonic Aciduria Due To Transcobalamin Receptor Defect AR 613646
Methylmalonyl-CoA Epimerase Deficiency AR 251120
Mitochondrial DNA Depletion Syndrome 5 (Encephalomyopathic with or without Methylmalonic Aciduria) AR 612073
Mitochondrial DNA Depletion Syndrome 9 (Encephalomyopathic With Methylmalonic Aciduria) AR 245400
Neural Tube Defects, Folate-Sensitive AR 601634
Propionic Acidemia AR 606054
Transcobalamin II Deficiency AR 275350

Related Tests

Name
PGxome®
Homocystinuria Panel
Methylmalonic Acidemia Panel
Propionic Acidemia Panel

Citations

  • Guéant et al. 2018. PubMed ID: 29302025
  • Pupavac et al. 2016. PubMed ID: 26827111
  • Sloan et al. 2018. PubMed ID: 20301503

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

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2) Select Additional Test Options

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

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