Glycine Encephalopathy Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10129 AMT 81479,81479 Order Options and Pricing
BOLA3 81479,81479
GCSH 81479,81479
GLDC 81479,81479
GLRX5 81479,81479
IBA57 81479,81479
ISCA2 81479,81479
LIAS 81479,81479
LIPT2 81479,81479
NFU1 81479,81479
SLC6A9 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10129Genes x (11)81479 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

Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an inborn error of glycine metabolism caused by defects in the glycine cleavage multi-enzyme system (GCS) (Van Hove et al. 2019. PubMed ID: 20301531). Affected children have a large accumulation of glycine in the body (including hyperglycinemia in the blood) resulting in various neurological symptoms. The majority of patients with glycine encephalopathy present in the neonatal period, while some patients can develop the disease in infancy. Regardless of age at onset, 20% of all affected children present with atypical, less severe phenotypes.

The majority of affected neonates develop severe symptoms such as progressive lethargy, feeding difficulties, central hypotonia, and generalized myoclonic seizures/myoclonic jerks, and breathing problems such as apnea that may lead to death. These patients often will have abnormal metabolic brain imaging by MRS, EEG with burst suppression, hypoplasia of the corpus callosum, and recurrent singultus (recurrent hiccup). Surviving infants have hypotonia, profound intellectual disability, developmental delay and intractable seizures. The atypical form has disease onset from late infancy to adulthood and the clinical outcomes range from milder features to rapidly progressive severe disease (Van Hove et al. 2019. PubMed ID: 20301531; GARD: Genetic and Rare Diseases Information Center).

The worldwide prevalence of NKH has been estimated at 1:76,000, although it has been reported with increased frequency in specific populations (for example, 1:12,000 in Northern Finland)(Van Hove et al. 2019. PubMed ID: 20301531).

In addition to the genes responsible for the majority of cases of NKH, we have included additional genes on this panel that may also be associated with hyperglycinemia. Those genes are also associated with the following disorders: multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia (BOLA3), pyridoxine-refractory sideroblastic anemia 3 (GLRX5)multiple mitochondrial dysfunctions syndrome 3 (IBA57), multiple mitochondrial dysfunctions syndrome 4 (ISCA2), hyperglycinemia, lactic acidosis, and seizures (LIAS), severe neonatal encephalopathy with lactic acidosis and brain abnormalities (LIPT2), multiple mitochondrial dysfunctions syndrome 1 (NFU1), glycine encephalopathy with normal serum glycine (SLC6A9). Patients with pathogenic variants in these genes may exhibit some different phenotypic features, such as optic atrophy, pulmonary hypertension, and cardiomyopathy, and testing may also reveal deficient pyruvate dehydrogenase enzyme deficiency (Van Hove et al. 2019. PubMed ID: 20301531).

Molecular testing can be useful for confirmation of a genetic cause of NKH. Molecular diagnosis for a patient with suspected NKH may help with determining appropriate treatment measures, assessment of recurrence risks, and allow for appropriate screening for potential future symptoms. 

Genetics

Glycine encephalopathy is an autosomal recessive disorder. The vast majority of pathogenic variants are inherited, although de novo pathogenic variants have been reported to occur in ~1% of affected individuals (Van Hove et al. 2019. PubMed ID: 20301531). GLDC, AMT and GCSH are the three known genes associated with the disease (Kure et al. 2006. PubMed ID: 16450403). These three genes encode the P, T and H proteins of the glycine cleavage multi-enzyme system (GCS), respectively.

Genetic defects in GLDC account for approximately 70-80% of glycine encephalopathy cases. Documented pathogenic GLDC variants include missense, various types of truncating variant and large deletions. Large deletions within GLDC have been reported as a major cause of the disease (Kanno et al. 2007. PubMed ID: 17361008). Although pathogenic GLDC variants have been found across the whole coding region of the gene, a clustering of missense pathogenic variants in exon 19, which encodes the cofactor-binding site, has been reported (Kure et al. 2006. PubMed ID: 16450403; Van Hove et al. 2019. PubMed ID: 20301531).

Genetic defects of AMT account for approximately 20% of glycine encephalopathy cases. Documented pathogenic AMT variants include missense and various types of truncating variants. Large deletions and duplications within AMT have not been reported (Van Hove et al. 2019. PubMed ID: 20301531; Human Gene Mutation Database).

Genetic defects of GCSH are an extremely rare cause of glycine encephalopathy. To date, only one conclusively pathogenic GCSH variant affecting splicing has been documented for a transient form of glycine encephalopathy (Van Hove et al. 2019. PubMed ID: 20301531; Human Gene Mutation Database).

The LIAS gene encodes lipoic acid synthase, LIPT2 encodes lipoyl(octanoyl) transferase 2, and BOLA3, GLRX5, IBA57, ISCA2, and NFU1 encode proteins involved in the synthesis of the iron-sulfur cluster necessary for the function of lipoic acid synthase. Lipoate is required for the function of the glycine cleavage multi-enzyme system (GCS) (Kikuchi et al. 2008. PubMed ID: 18941301). Pathogenic variants in these genes cause lipoate deficiency and are associated with a variety of clinical disorders, which may be associated with hyperglycinemia (Baker et al. 2014. PubMed ID: 24334290; Van Hove et al. 2019. PubMed ID: 20301531). Documented pathogenic variants in these genes include missense and various types of truncating variants. Large deletions have only been reported in NFU1 (Human Gene Mutation Database).

The SLC6A9 gene encodes the glycine transporter 1 protein, which is located mainly on astrocytes and is essential in clearance of glycine from the extracellular space, terminating glycinergic transmission (Alfallaj and Alfadhel. 2019. PubMed ID: 30815509). To date, missense, nonsense, and small deletion variants have been reported in SLC6A9 (Human Gene Mutation Database).

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

Clinical Sensitivity - Sequencing with CNV PGxome

Genetic defects in GLDC account for 70-80% of glycine encephalopathy (Van Hove et al. 2019. PubMed ID: 20301531) and approximately 20% of GLDC pathogenic alleles are large deletions (Kanno et al. 2007. PubMed ID: 17361008; Van Hove et al. 2019. PubMed ID: 20301531). 

Genetic defects in AMT account for approximately 20% of glycine encephalopathy (Van Hove et al. 2019. PubMed ID: 20301531). Large deletions/duplications within AMT have not been reported (Human Gene Mutation Database).

Genetic defects of GCSH are an extremely rare cause of glycine encephalopathy. In two large studies of families with glycine encephalopathy, no pathogenic GCSH variants were found (Kure et al. 2006. PubMed ID: 16450403; Coughlin et al. 2017. PubMed ID: 27362913).

For the disorders associated with the BOLA3, GLRX5, IBA57, ISCA2, LIAS, LIPT2, NFU1, and SLC6A9 genes, clinical sensitivity cannot be estimated because only a small number of patients with pathogenic variants have been reported.

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

Candidates for this test are patients with clinical features suggestive of glycine encephalopathy, and/or individuals with isolated elevation of glycine in the plasma and CSF and an abnormal CSF-to-plasma glycine ratio (Van Hove et al. 2019. PubMed ID: 20301531).

Genes

Official Gene Symbol OMIM ID
AMT 238310
BOLA3 613183
GCSH 238330
GLDC 238300
GLRX5 609588
IBA57 615316
ISCA2 615317
LIAS 607031
LIPT2 617659
NFU1 608100
SLC6A9 601019
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
PGxome®
AMT-Related Glycine Encephalopathy via the AMT Gene
GLDC-Related Glycine Encephalopathy via the GLDC Gene
Glycine Encephalopathy via the GCSH Gene
Leukodystrophy and Leukoencephalopathy Panel

Citations

  • Alfallaj and Alfadhel. 2019. PubMed ID: 30815509
  • Baker et al. 2014. PubMed ID: 24334290
  • Coughlin et al. 2017. PubMed ID: 27362913
  • Genetic and Rare Diseases Information Center (GARD).
  • Human Gene Mutation Database (Bio-base).
  • Kanno et al. 2007. PubMed ID: 17361008
  • Kikuchi et al. 2008. PubMed ID: 18941301
  • Kure et al. 2006. PubMed ID: 16450403
  • Van Hove et al. 2019. PubMed ID: 20301531

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

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