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  • Test code: 06222
  • 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
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Invitae Treatable Neurometabolic Disorders Panel

Test description

The Invitae Treatable Neurometabolic Disorders Panel analyzes genes that are associated with with inherited neurometabolic disorders that have treatments of varying efficacy. These genes were selected based on the available evidence to date to provide Invitae’s broadest test for treatable inherited neurometabolic disorders. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives.

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Primary panel (102 genes)

ABCD1 ABCD4 ACAT1 AGA ALDH5A1 ALDH7A1 AMN AMT ARG1 ARHGEF9 ARSA ASL ASS1 ATP7A ATP7B AUH BCKDHA BCKDHB BTD CBS CD320 CLN2 (TPP1) CP CPS1 CUBN CYP27A1 DBT DHCR7 DLAT DLD ETFA ETFB ETFDH ETHE1 GALC GAMT GATM GCDH GCH1 GCSH GIF GLA GLDC GLRA1 GLRB GLUD1 GUSB HCFC1 HLCS HMGCL HMGCS2 HSD17B10 IDS IDUA IVD LIPA LMBRD1 MAN2B1 MCCC1 MCCC2 MMAA MMAB MMACHC MMADHC MOCS1 MTHFR MTR MTRR MUT NAGS NPC1 NPC2 OTC OXCT1 PAH PANK2 PCBD1 PCCA PCCB PDHA1 PDHB PDHX PDP1 PHGDH PNPO PPM1K PSAT1 PSPH PTS QDPR SGSH SLC19A3 SLC25A13 SLC25A15 SLC2A1 SLC6A5 SLC6A8 SPR TAT TCN1 TCN2 TH

Add-on Neurometabolic Conditions Genes (42 genes)

Although these neurometabolic disorders are not considered to be treatable, they have symptoms that overlap with the disorders on the primary panel such as intellectual disability, seizures, ataxia, dystonia, and other neurologic symptoms. Given the phenotypic overlap, analyzing the genes associated with other neurometabolic conditions may be appropriate. These genes can be included at no additional charge.

ABAT ADSL AP1S1 ATP13A2 BCKDK C19orf12 CLN3 CLN5 CLN6 CLN8 CLPB COASY CTSD D2HGDH DBH DCAF17 DDC FA2H FTL GAD1 GNS GPHN HEXA HEXB HGSNAT HPRT1 IDH2 KCTD7 L2HGDH MAOA MFSD8 MOCOS NAGLU PLA2G6 POLG PPT1 SLC13A5 SLC33A1 SLC6A3 SUOX WDR45 XDH

Alternative tests to consider

If the clinician desires to make this a treatable disorders panel including non-neurometabolic conditions. The clinician can order this panel plus:












Gene Disorders
Primary Panel
ABCD1 X-linked adrenoleukodystrophy
ABCD4 methylmalonic aciduria with homocystinuria due to cobalamin J (cblJ) deficiency
ACAT1 beta-ketothiolase deficiency
AGA aspartylglucosaminuria
ALDH5A1 succinate semialdehyde dehydrogenase deficiency
ALDH7A1 pyridoxine responsive epilepsy
AMN Imerslund-Gräsbeck syndrome
AMT glycine encephalopathy
ARG1 arginase deficiency
ARSA metachromatic leukodystrophy
ARHGEF9 hyperekplexia
ASL argininosuccinate lyase deficiency
ASS1 citrullinemia type I
ATP7A Menkes disease, occipital horn syndrome and ATP7A-related distal hereditary motor neuropathy
ATP7B Wilson disease
AUH 3-methylglutaconic aciduria type I
BCKDHA maple syrup urine disease
BCKDHB maple syrup urine disease
BTD biotinidase deficiency
CBS homocystinuria due to cystathionine beta-synthase deficiency
CD320 methylmalonic aciduria due to transcobalamin receptor defect
CP aceruloplasminemia
CPS1 carbamoylphosphate synthetase I deficiency
CUBN Imerslund-Gräsbeck syndrome
CYP27A1 cerebrotendinous xanthomatosis
DBT maple syrup urine disease
DHCR7 Smith-Lemli-Opitz syndrome
DLAT pyruvate dehydrogenase complex deficiency
DLD dihydrolipoamide dehydrogenase deficiency
ETFA multiple acyl-CoA dehydrogenase deficiency
ETFB multiple acyl-CoA dehydrogenase deficiency
ETFDH multiple acyl-CoA dehydrogenase deficiency
ETHE1 ethylmalonic encephalopathy
GALC Krabbe disease
GAMT guanidinoacetate N-methyltransferase (GAMT) deficiency
GATM arginine:glycine amidinotransferase (AGAT) deficiency
GCDH glutaric acidemia type I
GCH1 GTP cyclohydrolase deficiency, dopa responsive dystonia
GCSH glycine encephalopathy
GIF intrinsic factor deficiency
GLA Fabry disease
GLDC glycine encephalopathy
GLRA1 hyperekplexia
GLRB hyperekplexia
GLUD1 familial hyperinsulinism-hyperammonemia (HI/HA) syndrome
GUSB mucopolysaccharidosis type  VII
HCFC1 X-linked recessive methylmalonic acidemia and homocysteinemia, cblX type, also known as X-linked intellectual disability 3 (IDX3)
HLCS holocarboxylase synthetase deficiency
HMGCL 3-HMG CoA lyase deficiency
HMGCS2 HMG-CoA synthase deficiency
HSD17B10 2-methyl-3-hydroxybutyric aciduria
IDS mucopolysaccharidosis type  II
IDUA mucopolysaccharidosis type  I
IVD isovaleric acidemia
LIPA lysosomal acid lipase deficiency
LMBRD1 methylmalonic aciduria and homocystinuria cblF type
MAN2B1 alpha-mannosidosis
MCCC1 3-methylcrotonyl-CoA carboxylase deficiency
MCCC2 3-methylcrotonyl-CoA carboxylase deficiency
MMAA cobalamin A type methylmalonic aciduria
MMAB cobalamin B type methylmalonic aciduria
MMACHC methylmalonic aciduria and homocystinuria due to cobalamin C (cblC) deficiency
MMADHC cobalamin D (cbl D) deficiency
MOCS1 molybdenum cofactor deficiency of complementation group A
MTHFR Severe MTHFR deficiency
MTR cobalamin G (cblG) deficiency
MTRR homocystinuria due to cobalamin E deficiency
MUT methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency
NAGS N-acetylglutamate synthase (NAGS) deficiency
NPC1 Niemann-Pick type C
NPC2 Niemann-Pick type C
OTC ornithine transcarbamylase deficiency
OXCT1 succinyl CoA:3-oxoacid CoA transferase (SCOT) deficiency
PAH phenylalanine hydroxylase deficiency
PANK2 pantothenate kinase-associated neurodegeneration (PKAN)
PCBD1 Tetrahydrobiopterin-deficient hyperphenylalinemia due to pterin-4-alpha-carbinolamine dehydratase (PCD) deficiency
PCCA propionic acidemia
PCCB propionic acidemia
PDHA1 X-linked pyruvate dehydrogenase E1-alpha (PDHE1α) deficiency
PDHB pyruvate dehydrogenase complex (PDHC) deficiency
PDHX pyruvate dehydrogenase complex (PDHC) deficiency
PDP1 pyruvate dehydrogenase deficiency
PHGDH phosphoglycerate dehydrogenase deficiency, which includes Neu-Laxova syndrome
PNPO pyridoxal 5’-phosphate dependent epilepsy
PPM1K maple syrup urine disease
PSAT1 phosphoserine aminotransferase (PSAT) deficiency, which includes Neu-Laxova syndrome type 2
PSPH phosphoserine phosphatase (PSPH) deficiency
PTS tetrahydrobiopterin-deficient hyperphenylalaninemia due to 6-pyruvoyltetrahydropterin synthase deficiency
QDPR tetrahydrobiopterin-deficient hyperphenylalaninemia due to quinoid dihydropteridine reductase (DHPR) deficiency
SGSH mucopolysaccharidosis IIIA
SLC19A3 thiamine metabolism dysfunction syndrome 2 (THMD2), also known as biotin-responsive basal ganglia disease (BBGD)
SLC25A13 citrin deficiency
SLC25A15 hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome
SLC2A1 glucose transporter type 1 (GLUT1) deficiency syndrome
SLC6A5 hyperekplexia 3
SLC6A8 X-linked recessive creatine transporter deficiency
SPR sepiapterin reductase deficiency
TAT tyrosinemia type II
TCN1 transcobalamin I (haptocorrin) deficiency
TCN2 transcobalamin II deficiency
TH tyrosine hydroxylase deficiency
TPP1 neuronal ceroid lipofuscinosis 2 (CLN2)

Neurometabolic conditions





Gene Disorder(s)
ABAT GABA-transaminase (GABA-T) deficiency
ADSL adenylosuccinate lyase (ADSL) deficiency
AP1S1 intellectual disability, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma, also known as MEDNIK syndrome
ATP13A2 Kufor Rakeb syndrome, also known as Parkinson’s disease 9 (PARK9), autosomal recessive hereditary spastic paraplegia,neuronal ceroid lipofuscinosis type 12 (CLN12)
BCKDK branched-chain ketoacid dehydrogenase kinase deficiency
C19orf12 Neurodegeneration with Brain Iron Accumulation (NBIA) 4; hereditary spastic paraplegia 43
CLN3 neuronal ceroid lipofuscinosis type 3 (CLN3)
CLN5 neuronal ceroid lipofuscinosis type 5 (CLN5)
CLN6 neuronal ceroid lipofuscinosis type 6 (CLN6)
CLN8 neuronal ceroid lipofuscinosis type 8 (CLN8)
CLPB 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia (MEGCANN)
COASY Neurodegeneration with Brain Iron Accumulation (NBIA) 6
CTSD neuronal ceroid lipofuscinosis type10 (CLN10)
D2HGDH D-2-hydroxyglutaric aciduria
DBH dopamine beta-hydroxylase deficiency
DCAF17 Woodhouse-Sakati syndrome (WSS)
DDC aromatic L-amino acid decarboxylase deficiency
FA2H hereditary spastic paraplegia 35
FTL Neurodegeneration Brain Iron Accumulation 3 (NBIA3); hereditary hyperferritinemia-cataract syndrome; L-ferritin deficiency
GAD1 spastic quadriplegia cerebral palsy 1
GNS mucopolysaccharidosis type IIID (MPS IIID or Sanfilippo D)
GPHN molybdenum cofactor deficiency; autosomal dominant early infantile epileptic encephalopathy
HEXA hexosaminidase A (HEXA) deficiency, also known as Tay-Sachs disease
HEXB Sandhoff disease
HGSNAT mucopolysaccharidosis type IIIC (MPS IIIC or Sanfilippo C)
HPRT1 Lesch-Nyhan syndrome
IDH2 D-2-hydroxyglutaric aciduria 2
KCTD7 Progressive myoclonic epilepsy with or without inclusions (EPM3), also known as neuronal ceroid lipofuscinosis type 14 (CLN14)
L2HGDH L-2-hydroxyglutaric aciduria
MAOA Brunner syndrome
MFSD8 neuronal ceroid lipofuscinosis type 7 (CLN7)
MOCOS xanthinuria
NAGLU mucopolysacharidosis IIIB (MPS IIIB) also known as Sanfilippo B; dominant axonal Charcot-Marie-Tooth disease type 2V
PLA2G6 neuroaxonal dystrophy dystonia-parkinsonism; Neurodegeneration Brain Iron Accumulation 2 (NBIA2)
POLG mitochondrial DNA depletion syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO), spinocerebellar ataxia with epilepsy (SCAE), and progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOB1), progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1)
PPT1 neuronal ceroid lipofuscinosis 1 (CLN1)
SLC13A5 early infantile epileptic encephalopathy type 25 (EIEE25)
SLC25A22 early infantile epileptic encephalopathy 3 (EIEE3)
SLC33A1 Huppke-Brendel Syndrome; autosomal dominant hereditary spastic paraplegia 42
SLC6A3 infantile parkinsonism-dystonia
SUOX sulfite oxidase deficiency
WDR45 Neurodegeneration with Brain Iron Accumulation 5 (NBIA5), early infantile epileptic encephalopathy (EIEE), and Rett syndrome
XDH xanthinuria type I

Inherited metabolic disorders are a group of genetic disorders that result from the deficiency of an enzyme, transporter, or cofactor that is essential to the metabolism of certain substances (protein, carbohydrates, or fats) or that may be essential for the maintenance and health of certain organelles (e.g., lysosomes) in the cell. Many of these disorders can cause symptoms such as intellectual disability, developmental delay, epilepsy, movement disorders, encephalopathy, spasticity, dystonia, and other neurological symptoms. Inherited metabolic disorders with primarily a neurological presentation are called neurometabolic disorders.

Some inherited neurometabolic disorders are treatable. The efficacy of these treatments can vary widely depending on the disorder. Treatments can range from sick day diets, nutritional therapy, and vitamin and cofactor therapy to substrate inhibitors, enzyme replacement therapy, and hematopoietic stem cell transplants. Often, early medical intervention—before the onset of symptoms— has better treatment efficacy than when treatment is started after the onset of irreversible damage. Some disorders that have been included in the primary panel may have treatments which are in clinical trials and are not yet clinically available.

The majority of these treatable conditions are inherited in an autosomal recessive manner.

The following conditions are inherited in an autosomal dominant and autosomal recessive manner:

  • GCH1-related autosomal dominant dopa-responsive dystonia and autosomal recessive GTP cyclohydrolase deficiency
  • GLRA1-associated hyperekplexia
  • NAGLU-related MPS IIIB and Charcot-Marie-Tooth disease type 2V
  • POLG-related conditions
  • SLC33A1-related Huppke-Brende I syndrome and autosomal dominant hereditary spastic paraplegia 42

The following disorders are inherited in an autosomal dominant manner:
  • D-2-hydroxyglutaric aciduria 2
  • GPHN-related early infantile epileptic encephalopathy

The following disorders are inherited in an X-linked manner:
  • 2-methyl-3-hydroxybutyric aciduria
  • ARHGEF9-associated hyperekplexia
  • ATP7A-related disorders
  • Brunner syndrome
  • creatine transporter deficiency
  • cobalamin X
  • Lesch-Nyhan syndrome
  • mucopolysaccharidosis type II
  • ornithine transcarbamylase (OTC) deficiency
  • PDHA1-associated pyruvate dehydrogenase deficiency
  • Smith-Lemli-Opitz syndrome
  • X-linked adrenoleukodystrophy
  • X-linked methylmalonic acidemia and homocysteinemia, cblX type, also known as X-linked intellectual disability 3 (IDX3)
  • WDR45-related Neurodegeneration with Brain Iron Accumulation 5 (NBIA5), early infantile epileptic encephalopathy (EIEE) and Rett syndrome

Individually, treatable inherited metabolic disorders are rare disorders, but when they are considered collectively, the prevalence can be quite common, although the exact prevalence is difficult to determine.

This test may be appropriate for patients with one or any combination of symptoms:

  • intellectual disability
  • regression
  • global developmental delay
  • language/speech delay
  • cerebral palsy like symptoms
  • seizures
  • ataxia
  • spasticity
  • hearing or vision loss
  • neuropathy
  • hypotonia
  • behavioral disturbances
  • psychiatric symptoms
  • encephalopathy
  • movement disorders

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
ABAT NM_020686.5
ABCD1 NM_000033.3
ABCD4 NM_005050.3
ACAT1 NM_000019.3
ADSL NM_000026.2
AGA NM_000027.3
ALDH5A1 NM_001080.3
ALDH7A1 NM_001182.4
AMN NM_030943.3
AMT NM_000481.3
AP1S1 NM_001283.3
ARG1 NM_000045.3
ARHGEF9 NM_015185.2; NM_001173479.1
ARSA NM_000487.5
ASL NM_000048.3
ASS1 NM_000050.4
ATP13A2 NM_022089.3
ATP7A NM_000052.6
ATP7B NM_000053.3
AUH NM_001698.2
BCKDHA NM_000709.3
BCKDHB NM_183050.2
BCKDK NM_005881.3
BTD NM_000060.3
C19orf12 NM_001031726.3
CBS NM_000071.2
CD320 NM_016579.3
CLN2 (TPP1) NM_000391.3
CLN3* NM_001042432.1
CLN5 NM_006493.2
CLN6 NM_017882.2
CLN8 NM_018941.3
CLPB NM_030813.5
COASY NM_025233.6
CP NM_000096.3
CPS1 NM_001875.4
CTSD NM_001909.4
CUBN* NM_001081.3
CYP27A1 NM_000784.3
D2HGDH NM_152783.4
DBH NM_000787.3
DBT NM_001918.3
DCAF17 NM_025000.3
DDC* NM_000790.3
DHCR7 NM_001360.2
DLAT NM_001931.4
DLD NM_000108.4
ETFA NM_000126.3
ETFB NM_001985.2
ETFDH NM_004453.3
ETHE1 NM_014297.3
FA2H NM_024306.4
FTL NM_000146.3
GAD1 NM_000817.2
GALC* NM_000153.3
GAMT NM_000156.5
GATM NM_001482.2
GCDH NM_000159.3
GCH1 NM_000161.2
GCSH NM_004483.4
GIF NM_005142.2
GLA* NM_000169.2
GLDC NM_000170.2
GLRA1 NM_000171.3
GLRB NM_000824.4
GLUD1 NM_005271.4
GNS NM_002076.3
GPHN NM_020806.4
GUSB NM_000181.3
HCFC1 NM_005334.2
HEXA NM_000520.4
HEXB NM_000521.3
HGSNAT NM_152419.2
HLCS NM_000411.6
HMGCL NM_000191.2
HMGCS2 NM_005518.3
HPRT1 NM_000194.2
HSD17B10 NM_004493.2
IDH2 NM_002168.3
IDS* NM_000202.6
IDUA NM_000203.4
IVD NM_002225.3
KCTD7 NM_153033.4
L2HGDH NM_024884.2
LIPA NM_000235.3
LMBRD1 NM_018368.3
MAN2B1 NM_000528.3
MAOA NM_000240.3
MCCC1 NM_020166.4
MCCC2 NM_022132.4
MFSD8 NM_152778.2
MMAA NM_172250.2
MMAB NM_052845.3
MMACHC NM_015506.2
MMADHC NM_015702.2
MOCOS NM_017947.2
MOCS1 NM_001075098.3
MTHFR NM_005957.4
MTR NM_000254.2
MTRR* NM_002454.2
MUT NM_000255.3
NAGLU NM_000263.3
NAGS NM_153006.2
NPC1 NM_000271.4
NPC2 NM_006432.3
OTC* NM_000531.5
OXCT1 NM_000436.3
PAH NM_000277.1
PANK2 NM_153638.2
PCBD1 NM_000281.3
PCCA NM_000282.3
PCCB NM_000532.4
PDHA1 NM_000284.3
PDHB NM_000925.3
PDHX NM_003477.2
PDP1 NM_018444.3
PHGDH NM_006623.3
PLA2G6 NM_003560.2
PNPO NM_018129.3
POLG NM_002693.2
PPM1K NM_152542.4
PPT1* NM_000310.3
PSAT1 NM_058179.3
PSPH* NM_004577.3
PTS NM_000317.2
QDPR NM_000320.2
SGSH NM_000199.3
SLC13A5 NM_177550.4
SLC19A3 NM_025243.3
SLC25A13 NM_014251.2
SLC25A15 NM_014252.3
SLC2A1 NM_006516.2
SLC33A1 NM_004733.3
SLC6A3 NM_001044.4
SLC6A5 NM_004211.3
SLC6A8 NM_005629.3
SPR NM_003124.4
SUOX NM_000456.2
TAT NM_000353.2
TCN1 NM_001062.3
TCN2 NM_000355.3
TH NM_199292.2
WDR45 NM_007075.3
XDH NM_000379.3

CLN3: Analysis includes the intronic variant NM_001042432.1; c.461-13G>C.
CUBN: Analysis includes the intronic variant NM_001081.3: c.3330-439C>G.
DDC: Deletion/duplication analysis is not offered for exons 10-11 (NM_000790.3).
GALC: Analysis includes the large (30 kb) deletion for Krabbe Disease.
GLA: Analysis includes the intronic variant NM_000169.2:c.IVS4+919G>A.
IDS: Detection of complex rearrangements not offered (PMID: 7633410, 20301451).
MTRR: Analysis includes the intronic variant NM_002454.2:c.903+469T>C.
OTC: Analysis includes the intronic variant NM_000531.5:c.540+265G>A.
PPT1: Analysis includes the large, mostly intronic deletion NM_000310.3:c.124+1215_235-102del3627 as well as the intronic variant NM_000310.3:c.125-15T>G.
PSPH: Deletion/duplication and sequencing analysis is not offered for exons 4-5 (NM_004577.3).