The Invitae Elevated Glycine Panel analyzes genes that are associated with elevated plasma and/or CSF glycine levels. This test is useful for the diagnosis of patients in whom glycine encephalopathy is suspected due to clinical symptoms or biochemical findings. Additionally, this test may help distinguish neonatal patients with glycine encephalopathy from those with transient glycine encephalopathy.
AMT GCSH GLDC LIAS NFU1 SLC6A9
ACAD8 ACADSB ACAT1 ACSF3 ASPA AUH BCKDHA BCKDHB BTD D2HGDH DBT DHTKD1 DLD DNAJC19 ETFA ETFB ETFDH ETHE1 FBP1 FH FTCD GCDH GSS HIBCH HLCS HMGCL HSD17B10 IDH2 IVD L2HGDH MCCC1 MCCC2 MCEE MLYCD MMAA MMAB MMACHC MMADHC MUT NFU1 OGDH OPA3 OPLAH OXCT1 PCCA PCCB POLG PPM1K SERAC1 SLC13A5 SLC25A1 SLC25A19 SUCLA2 SUCLG1 TAZ TMEM70
The organic acidemias can also cause elevations of glycine on plasma amino acid analysis. However, these disorders will have characteristic abnormalities on urine organic acid analysis. If urine organic acid analysis has not been performed in a patient with elevated glycine on plasma amino acids, it may be appropriate to analyze the genes associated with organic acidemias. These genes can be included at no additional charge.
AMT GCSH GLDC LIAS NFU1 SLC6A9
The organic acidemias can also cause elevations of glycine on plasma amino acid analysis. However, these disorders will have characteristic abnormalities on urine organic acid analysis. If urine organic acid analysis has not been performed in a patient with elevated glycine on plasma amino acids, it may be appropriate to analyze the genes associated with organic acidemias. These genes can be included at no additional charge.
ACAD8 ACADSB ACAT1 ACSF3 ASPA AUH BCKDHA BCKDHB BTD D2HGDH DBT DHTKD1 DLD DNAJC19 ETFA ETFB ETFDH ETHE1 FBP1 FH FTCD GCDH GSS HIBCH HLCS HMGCL HSD17B10 IDH2 IVD L2HGDH MCCC1 MCCC2 MCEE MLYCD MMAA MMAB MMACHC MMADHC MUT NFU1 OGDH OPA3 OPLAH OXCT1 PCCA PCCB POLG PPM1K SERAC1 SLC13A5 SLC25A1 SLC25A19 SUCLA2 SUCLG1 TAZ TMEM70
Glycine encephalopathy including neonatal, late-onset and variant forms.
Gene | Disorder | Inheritance pattern |
---|---|---|
AMT | Glycine encephalopathy (GCE) | Autosomal recessive |
GCSH | ||
GLDC | ||
LIAS | Hyperglycinemia, lactic acidosis, and seizures (HGCLAS), also known as pyruvate dehydrogenase lipoic acid synthetase deficiency (PDHLD) | |
NFU1 | multiple mitochondrial dysfunctions syndrome 1 (MMDS1) | |
SLC6A9 | Glycine encephalopathy with normal serum glycine |
Glycine encephalopathy is an inborn error of glycine metabolism that most commonly presents in the neonatal period. Patients with this disorder are not able to metabolize glycine properly due to a defect in the glycine cleavage system. This defect leads to toxic accumulation of glycine, especially in the brain. The age of onset in patients with glycine encephalopathy can range from neonatal to adulthood, with the most severely affected individuals presenting in the neonatal period.
Patients with glycine encephalopathy have hyperglycinemia that is detectable in both plasma and CSF. These patients will also have an elevated CSF-to-plasma glycine ratio (>0.08 in severe patients; note that this value can be lower in late-onset patients). The absence of acidosis and ketosis is important in distinguishing this disorder from other causes of hyperglycinemia (e.g., propionic acidemia, methylmalonic acidemia).
Neonatal glycine encephalopathy
This is the most common clinical subtype of glycine encephalopathy. Most patients are normal at birth but can present as early as a few hours of life. Symptoms include progressive encephalopathy leading to lethargy, muscular hypotonia, apneic attacks, hiccups, seizures, burst suppression pattern on EEG, coma, and early death. The vast majority of patients that do survive the first 15 months of life show severe intellectual impairment (IQ<20) and motor disability (inability to sit or grasp objects).
Late-onset glycine encephalopathy
This phenotype presents anytime from infancy to adulthood and has a heterogeneous clinical picture. The late-onset form may include features such as intellectual disability, hypotonia, choreic movement disorder, aggressiveness, attention deficit hyperactivity disorder (ADHD), confusion triggered by fever, and, although rarely, seizures.
Transient glycine encephalopathy
This phenotype has been reported in a few patients. These patients may present with symptoms similar to neonatal glycine encephalopathy, though the biochemical elevations typically normalize by the third month of life. Differentiating neonatal glycine encephalopathy from transient glycine encephalopathy based on biochemical findings alone is difficult. Transient glycine encephalopathy may be due to delayed maturation of the glycine cleavage system, high residual activity of the glycine cleavage system in the presence of two pathogenic variants, or a heterozygous individual.
Variant glycine encephalopathy
This form of glycine encephalopathy occurs due to defects in cofactors for the glycine cleavage system or a glycine transporter. Without functioning enzymatic cofactors, the glycine cleavage system cannot properly metabolize glycine and results in a glycine encephalopathy. Individuals with LIAS-related glycine encephalopathy present with extremely elevated plasma glycine levels but minimally CSF glycine. Clinical symptoms can be similar to those observed in neonatal and late-onset glycine encephalopathy. Individuals with NFU1 pathogenic variants present with a much more severe phenotype as the cofactor encoded by this gene is involved in mitochondrial respiratory complexes I and II in addition to the glycine cleavage system. The reported clinical phenotype is broad, but common features include onset before 1 year of age, failure to thrive, pulmonary hypertension, encephalopathy, neurologic regression and infantile death. There is marked plasma glycine elevation and elevated CSF glycine.
For patients with a biochemical diagnosis of glycine encephalopathy (elevated plasma and CSF glycine with an increased CSF-to-plasma glycine ratio), approximately 90%–95% will have two pathogenic variants in one of these genes. GLDC is the most commonly mutated gene in glycine encephalopathy patients (70%–75%), followed by AMT (20%) and GCSH (<1%). Approximately 5% of individuals with an enzymatically confirmed diagnosis of glycine encephalopathy do not have a pathogenic variant in any of the aforementioned genes, and may have a variant form of glycine encephalopathy.
All the conditions on this panel causing elevated glycine levels follow autosomal recessive inheritance.
The general prevalence of glycine encephalopathy is unknown. The birth incidence in several subpopulations have been estimated as follows:
Some small, consanguineous Arab villages in Israel have a higher incidence of glycine encephalopathy.
The incidence of variant forms of glycine encephalopathy is not known, but these forms are very rare.
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 |
---|---|---|---|
ACAD8 | NM_014384.2 | ||
ACADSB | NM_001609.3 | ||
ACAT1 | NM_000019.3 | ||
ACSF3 | NM_174917.4 | ||
AMT | NM_000481.3 | ||
ASPA | NM_000049.2 | ||
AUH | NM_001698.2 | ||
BCKDHA | NM_000709.3 | ||
BCKDHB | NM_183050.2 | ||
BTD | NM_000060.3 | ||
D2HGDH | NM_152783.4 | ||
DBT | NM_001918.3 | ||
DHTKD1 | NM_018706.6 | ||
DLD | NM_000108.4 | ||
DNAJC19 | NM_145261.3 | ||
ETFA | NM_000126.3 | ||
ETFB | NM_001985.2 | ||
ETFDH | NM_004453.3 | ||
ETHE1 | NM_014297.3 | ||
FBP1 | NM_000507.3 | ||
FH | NM_000143.3 | ||
FTCD | NM_006657.2 | ||
GCDH | NM_000159.3 | ||
GCSH | NM_004483.4 | ||
GLDC | NM_000170.2 | ||
GSS | NM_000178.2 | ||
HIBCH | NM_014362.3 | ||
HLCS | NM_000411.6 | ||
HMGCL | NM_000191.2 | ||
HSD17B10 | NM_004493.2 | ||
IDH2 | NM_002168.3 | ||
IVD | NM_002225.3 | ||
L2HGDH | NM_024884.2 | ||
LIAS | NM_006859.3 | ||
MCCC1 | NM_020166.4 | ||
MCCC2 | NM_022132.4 | ||
MCEE | NM_032601.3 | ||
MLYCD | NM_012213.2 | ||
MMAA | NM_172250.2 | ||
MMAB | NM_052845.3 | ||
MMACHC | NM_015506.2 | ||
MMADHC | NM_015702.2 | ||
MUT | NM_000255.3 | ||
NFU1 | NM_001002755.2 | ||
OGDH | NM_002541.3 | ||
OPA3 | NM_025136.3 | ||
OPLAH | NM_017570.4 | ||
OXCT1 | NM_000436.3 | ||
PCCA | NM_000282.3 | ||
PCCB | NM_000532.4 | ||
POLG | NM_002693.2 | ||
PPM1K | NM_152542.4 | ||
SERAC1 | NM_032861.3 | ||
SLC13A5 | NM_177550.4 | ||
SLC25A1 | NM_005984.4 | ||
SLC25A19 | NM_021734.4 | ||
SLC6A9 | NM_201649.3 | ||
SUCLA2 | NM_003850.2 | ||
SUCLG1 | NM_003849.3 | ||
TAZ | NM_000116.4 | ||
TMEM70 | NM_017866.5 |