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Invitae Mendelian Disorders with Psychiatric Symptoms Panel

Test description

The Invitae Mendelian Disorders with Psychiatric Symptoms Panel analyzes up to 91 genes that are associated with late-onset or atypical presentations of inborn errors of metabolism and neurometabolic conditions that can present with psychiatric symptoms. These symptoms can include: altered mental status, confusion, coma, impaired executive functioning, mood disorders, dissociative episodes, decline in cognitive ability, delusions, visual/auditory hallucinations and schizophrenia-like or psychotic episodes. A subset of these conditions can also be associated with physical features, such as, movement disorders, eye abnormalities and hepatosplenomegaly. Genetic testing of these genes may confirm the diagnosis of an underlying inborn error of metabolism and help guide treatment and management of the condition. Additionally, the identification of disease causing variants provides accurate risk assessment and determines carrier status for relatives.

Please note: This assay does not test for Wolfram syndrome (WFS1), Hartnup disorder (SLC6A19), folate transporter deficiency (FOLR1), Huntington Disease (HTT), or disorders associated with mitochondrial DNA dysfunction, such as MELAS. Genes associated with porphyria are not included on this panel, but can be ordered on a separate panel. Additionally, this assay does not include genes associated with small multifactorial risks for psychiatric disease, but rather focuses on genes that are known to cause Mendelian conditions that result in psychiatric symptoms.

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Primary panel (88 genes)

ABCD1 ADSL ALDH5A1 AMACR AMT AP1S1 ARG1 ARSA ASL ASS1 ATP13A2 ATP7B BCKDHA BCKDHB BCKDK C19orf12 CA5A CBS CLN2 (TPP1) CLN3 CLN5 CLN6 CLN8 COASY CP CPS1 CTSD CYP27A1 DBH DBT DCAF17 DDC DLD FAH FTL FUCA1 GALC GAMT GATM GCH1 GCSH GLA GLB1 GLDC GM2A GNS GSS HEXA HEXB HGSNAT HMGCL HPRT1 MAN2B1 MANBA MAOA MFSD8 MMACHC MTHFR MTR NAGLU NAGS NPC1 NPC2 OTC PAH PANK2 PCCA PCCB PLA2G6 POLG PPT1 PRODH PSAP PTS QDPR SGSH SLC25A13 SLC25A15 SLC52A1 SLC52A2 SLC52A3 SLC6A8 SLC7A7 SPR SUMF1 TBX1 TH WDR45

Add-on Adult-onset Neuronal Ceroid Lipofuscinoses Genes (3 genes)

Individuals under the age of 18 should undergo comprehensive pre-test genetic counseling before considering genetic testing for adult-onset forms of NCL; specifically for the GRN gene, which, along with being associated with autosomal recessive NCL, is also associated with autosomal dominant frontotemporal dementia, a progressive neurodegenerative condition with an age of onset which ranges from the 30s to 80s. For more information on genetic testing in minors, please refer to the ASHG position statement.
http://www.cell.com/ajhg/abstract/S0002-9297(15)00236-0()

CTSF DNAJC5 GRN

Gene Disorder
ABCD1 X-linked adrenoleukodystrophy
ADSL Adenylosuccinate lyase deficiency
ALDH5A1 Succinic semialdehyde dehydrogenase deficiency
AMACR Alpha-methylacyl-CoA racemase deficiency
AMT Glycine encephalopathy
AP1S1 Intellectual disability, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma (MEDNIK) syndrome
ARG1 Arginase deficiency
ARSA Metachromatic leukodystrophy
ASL Argininosuccinate lyase deficiency
ASS1 Citrullinemia I
ATP7B Wilson disease
ATP13A2 Kufor Rakeb syndrome, autosomal recessive hereditary spastic paraplegia,   juvenile neuronal ceroid lipofuscinosis
BCKDHA Maple syrup urine disease
BCKDHB Maple syrup urine disease
BCKDK Branched-chain alpha-keto acid dehydrogenase kinase deficiency
C19orf12 Neurodegeneration with brain iron accumulation 4 (NBIA4)
CA5A Hyperammonemia due to carbonic anhydrase VA deficiency
CBS Homocystinuria due to cystathionine beta-synthase deficiency
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)
COASY Neurodegeneration with brain iron accumulation 6 (NBIA6)
CP Ceruloplasmin deficiency
CPS1 Carbamoyl phosphate synthetase I deficiency
CTSD Neuronal ceroid lipofuscinosis type 10 (CLN10)
CYP27A1 Cerebrotendinous xanthomatosis
DBH Dopamine beta-hydroxylase deficiency
DBT Maple syrup urine disease
DCAF17 Woodhouse-Sakati syndrome
DDC Aromatic L-amino acid decarboxylase deficiency
DLD Dihydrolipoamide dehydrogenase (DLD) deficiency
FAH Tyrosinemia type I
FTL Neurodegeneration with brain iron accumulation 3  (NBIA3), hereditary hyperferritinemia-cataract syndrome,  L-ferritin deficiency
FUCA1 Fucosidosis
GALC Krabbe disease
GAMT Guanidinoacetate methyltransferase (GAMT) deficiency
GATM Cerebral creatine deficiency due to arginine:glycine amidinotransferase (AGAT) deficiency
GCH1 Dopa-responsive dystonia and GTP cyclohydrolase deficiency
GCSH Glycine encephalopathy
GLA Fabry disease
GLB1 GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB, also known as Morquio B)
GLDC Glycine encephalopathy
GM2A GM2-gangliosidosis, AB variant, also known as GM2 activator deficiency
GNS Mucopolysaccharidosis type IIID (MPS IIID or  Sanfilippo D)
GSS Glutathione synthetase deficiency
HEXA Tay Sachs disease
HEXB Sandhoff disease
HGSNAT Mucopolysaccharidosis Type IIIC (MPS IIIC or Sanfilippo C)
HMGCL 3-hydroxy-3-methylglutaryl (3HMG)-CoA lyase deficiency
HPRT1 Lesch-Nyhan syndrome
MAN2B1 Alpha-mannosidosis
MANBA Beta-mannosidosis
MAOA Brunner syndrome
MFSD8 Neuronal ceroid lipofuscinosis type 7 (CLN7)
MMACHC Methylmalonic aciduria and homocystinuria, cblC type
MTHFR Severe N (5,10)-methylenetetrahydrofolate reductase (MTHFR) deficiency
MTR Cobalamin G (cblG) deficiency
NAGLU Mucopolysaccharidosis type IIIB (MPS IIIB or Sanfilippo B); Charcot-Marie-Tooth disease type 2V
NAGS N-acetylglutamate synthase deficiency
NPC1 Niemann-Pick Disease Type C
NPC2 Niemann-Pick Disease Type C
OTC Ornithine transcarbamylase deficiency
PAH Hyperphenylalaninemia
PANK2 Pantothenate kinase-associated neurodegeneration (PKAN)
PCCA Propionic acidemia
PCCB Propionic acidemia
PLA2G6 Neurodegeneration with Brain Iron Accumulation 2B, autosomal recessive Parkinson disease 14
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 type 1 (CLN1)
PRODH Hyperprolinemia type I
PSAP Metachromatic leukodystrophy due to SAP-b deficiency, atypical Gaucher disease, atypical Krabbe disease
PTS Tetrahydrobiopterin-deficient hyperphenylalaninemia due to 6-pyruvoyltetrahydropterin synthase deficiency
QDPR Tetrahydrobiopterin-deficient hyperphenylalaninemia due to quinoid dihydropteridine reductase (DHPR) deficiency
SGSH Mucopolysaccharidosis Type IIIA (MPS IIIA or Sanfilippo A)
SLC6A8 Creatine transporter deficiency
SLC7A7 Lysinuric protein intolerance
SLC25A13 Citrin deficiency
SLC25A15 Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
SLC52A1 Riboflavin transporter deficiency
SLC52A2 Brown-Vialetto-Van Laere syndrome 2
SLC52A3 Brown-Vialetto-Van Laere syndrome 1
SPR Sepiapterin reductase deficiency
SUMF1 Multiple sulfatase deficiency
TBX1 DiGeorge syndrome
TH Tyrosine hydroxylase deficiency
TPP1 Neuronal ceroid lipofuscinosis 2 (CLN2)
WDR45 Neurodegeneration with Brain Iron Accumulation 5, early infantile epileptic encephalopathy, Rett syndrome

This panel has been curated with special attention to atypical presentations of late onset inborn errors of metabolism that can result in psychiatric symptoms. Identification of these conditions, as early as possible, in the diagnostic process provides the best chance to intervene with the appropriate clinical and psychological management to achieve the best possible outcome for the patient. Many of the conditions are treatable with dietary modification to restrict the offending substrate, the use of vitamin cofactors to increase intrinsic enzyme activity, or the use of medication to detoxify the metabolites involved. Some of the conditions, such as the urea cycle defects can present with acute symptoms, while others, such as lysosomal storage diseases, can result in the development of psychiatric symptoms gradually over time.

The pathophysiology underlying the development of psychiatric symptoms can include neurotoxicity, which is common in conditions such as, urea cycle disorders, homocystinuria, defects of cobalamin metabolism, and Maple Syrup Urine disease. In contrast, lysosomal storage disorders, such as metachromatic leukodystrophy, GM2 gangliosidosis and Kuf’s disease are generally associated with progressive neurological deterioration and accompanying dementia, ataxia and psychiatric symptoms. Movement disorders can be a distinctive feature of Wilson disease, dopa-responsive dystonia due to sepiapterin reductase deficiency and the Neurodegeneration with Brain Iron Accumulation disorders.

This assay provides a means to quickly rule out a variety of conditions associated with psychiatric symptoms and gives the medical team extra confidence that they have not missed the opportunity to intervene in the management of a treatable disorder.

Gene Condition Autosomal Recessive Autosomal Dominant X-Linked
ABCD1 X-linked adrenoleukodystrophy X
ADSL Adenylosuccinate lyase deficiency X
ALDH5A1 Succinic semialdehyde dehydrogenase deficiency X
AMACR Alpha-methylacyl-CoA Racemase deficiency X
AMT Glycine encephalopathy X
AP1S1 Intellectual disability, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma (MEDNIK) syndrome X
ARG1 Arginase deficiency X
ARSA Metachromatic leukodystrophy X
ASL Argininosuccinic aciduria X
ASS1 Citrullinemia I X
ATP7B Wilson disease X
ATP13A2 Kufor Rakeb syndrome, autosomal recessive hereditary spastic paraplegia,   juvenile neuronal ceroid lipofuscinosis X
BCKDHA Maple syrup urine disease X
BCKDHB Maple syrup urine disease X
BCKDK Branched-chain alpha-keto acid dehydrogenase kinase deficiency X
C19orf12 Neurodegeneration with brain iron accumulation 4 X
CA5A Hyperammonemia due to carbonic anhydrase VA deficiency X
CBS Homocystinuria due to cystathionine beta-synthase deficiency X
CLN3 Neuronal ceroid lipofuscinosis type 3 (CLN3) X
CLN5 Neuronal ceroid lipofuscinosis type 5 (CLN5) X
CLN6 Neuronal ceroid lipofuscinosis type 6 (CLN6) X
CLN8 Neuronal ceroid lipofuscinosis type 8 (CLN8) X
COASY Neurodegeneration with Brain Iron Accumulation 6 X
CP Ceruloplasmin deficiency X
CPS1 Carbamoyl phosphate synthetase I deficiency X
CTSD Neuronal ceroid lipofuscinosis type 10 (CLN10) X
CYP27A1 Cerebrotendinous xanthomatosis X
DBH Dopamine beta-hydroxylase deficiency X
DBT Maple syrup urine disease X
DCAF17 Woodhouse-Sakati syndrome X
DDC Aromatic L-amino acid decarboxylase deficiency X
DLD Dihydrolipoamide dehydrogenase (DLD) deficiency X
FAH Tyrosinemia type I X
FTL Neurodegeneration with Brain Iron Accumulation 3 (NBIA3), hereditary hyperferritinemia-cataract syndrome,  L-ferritin deficiency X
FUCA1 Fucosidosis X
GALC Krabbe disease X
GAMT Guanidinoacetate methyltransferase (GAMT) deficiency X
GATM Cerebral creatine deficiency due to arginine:glycine amidinotransferase (AGAT) deficiency X
GCH1 Dopa-responsive dystonia and GTP cyclohydrolase deficiency X X
GCSH Glycine encephalopathy X
GLA Fabry disease X
GLB1 GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB, also known as Morquio B) X
GLDC Glycine encephalopathy X
GM2A GM2-gangliosidosis, AB variant, also known as GM2 activator deficiency X
GNS Mucopolysaccharidosis type IIID (MPS IIID or  Sanfilippo D) X
GSS Glutathione synthetase deficiency X
HEXA Tay Sachs disease X
HEXB Sandhoff disease X
HGSNAT Mucopolysaccharidosis Type IIIC (MPS IIIC or Sanfilippo C) X
HMGCL 3-hydroxy-3-methylglutaryl (3HMG)-CoA lyase deficiency X
HPRT1 Lesch-Nyhan syndrome X
MAN2B1 Alpha-mannosidosis X
MANBA Beta-mannosidase X
MAOA Brunner syndrome X
MFSD8 Neuronal ceroid lipofuscinosis type 7 (CLN7) X
MMACHC Methylmalonic aciduria and homocystinuria, cblC type X
MTHFR Severe N (5,10)-methylenetetrahydrofolate reductase (MTHFR) deficiency X
MTR Cobalamin G (cblG) deficiency
NAGLU Mucopolysaccharidosis type IIIB (MPS IIIB or Sanfilippo B); Charcot-Marie-Tooth disease type 2V X X
NAGS N-acetylglutamate synthase deficiency X
NPC1 Niemann-Pick Disease Type C X
NPC2 Niemann-Pick Disease Type C X
OTC Ornithine transcarbamylase deficiency X
PAH Hyperphenylalaninemia X
PANK2 Pantothenate kinase-associated neurodegeneration (PKAN) X
PCCA Propionic acidemia X
PCCB Propionic acidemia X
PLA2G6 Neurodegeneration with Brain Iron Accumulation 2B, autosomal recessive Parkinson disease 14 X
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) X X
PPT1 Neuronal ceroid lipofuscinosis type 1 (CLN1) X
PRODH Hyperprolinemia type I X
PSAP Metachromatic leukodystrophy due to SAP-b deficiency, atypical Gaucher disease, atypical Krabbe disease X
PTS Tetrahydrobiopterin-deficient hyperphenylalaninemia due to 6-pyruvoyltetrahydropterin synthase deficiency X
QDPR Tetrahydrobiopterin-deficient hyperphenylalaninemia due to quinoid dihydropteridine reductase (DHPR) deficiency X
SGSH Mucopolysaccharidosis Type IIIA (MPS IIIA or Sanfilippo A) X
SLC6A8 Creatine transporter deficiency X
SLC7A7 Lysinuric protein intolerance X
SLC25A13 Citrin deficiency X
SLC25A15 Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome X
SLC52A1 Riboflavin transporter deficiency X
SLC52A2 Brown-Vialetto-Van Laere syndrome 2 X
SLC52A3 Brown-Vialetto-Van Laere syndrome 1 X
SPR Sepiapterin reductase deficiency X X
SUMF1 Multiple sulfatase deficiency X
TBX1 DiGeorge syndrome X
TH Tyrosine hydroxylase deficiency X
TPP1 Neuronal ceroid lipofuscinosis 2 (CLN2) X
WDR45 Neurodegeneration with Brain Iron Accumulation 5 (NBIA5), early infantile epileptic encephalopathy, Rett syndrome X

Individually, inherited metabolic disorders that can cause psychiatric symptoms are rare disorders, but when they are considered collectively, the prevalence can be quite common. However the exact prevalence of psychiatric presentations due to underlying inherited metabolic disorders is difficult to determine.

This panel is appropriate for patients who present with acute onset or chronic symptoms which may include:

  • Altered level of consciousness
  • Disorientation/confusion
  • Mood disorders/refractory depression
  • Delusions/Hallucinations
  • Unexplained diminished cognitive or executive functioning
  • Psychosis
  • Self-injurious behavior
  • Aggression/irritability
  • Anxiety disorders/OCD
  • Schizophrenia
  • Personality disorders
  • Dissociative disorder
  • Paranoia
  • Catatonia
  • Dementia
  • Attention deficit disorder
  • Physical symptoms could include: movement disorders, ataxia, eye abnormalities or hepatosplenomegaly

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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 and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

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
ABCD1 NM_000033.3
ADSL NM_000026.2
ALDH5A1 NM_001080.3
AMACR NM_014324.5
AMT NM_000481.3
AP1S1 NM_001283.3
ARG1 NM_000045.3
ARSA NM_000487.5
ASL NM_000048.3
ASS1 NM_000050.4
ATP13A2 NM_022089.3
ATP7B NM_000053.3
BCKDHA NM_000709.3
BCKDHB NM_183050.2
BCKDK NM_005881.3
C19orf12 NM_001031726.3
CA5A NM_001739.1
CBS NM_000071.2
CLN2 (TPP1) NM_000391.3
CLN3* NM_001042432.1
CLN5 NM_006493.2
CLN6 NM_017882.2
CLN8 NM_018941.3
COASY NM_025233.6
CP NM_000096.3
CPS1 NM_001875.4
CTSD NM_001909.4
CTSF NM_003793.3
CYP27A1 NM_000784.3
DBH NM_000787.3
DBT NM_001918.3
DCAF17 NM_025000.3
DDC* NM_000790.3
DLD NM_000108.4
DNAJC5 NM_025219.2
FAH NM_000137.2
FTL NM_000146.3
FUCA1 NM_000147.4
GALC* NM_000153.3
GAMT NM_000156.5
GATM NM_001482.2
GCH1 NM_000161.2
GCSH NM_004483.4
GLA* NM_000169.2
GLB1 NM_000404.2
GLDC NM_000170.2
GM2A NM_000405.4
GNS NM_002076.3
GRN NM_002087.3
GSS NM_000178.2
HEXA NM_000520.4
HEXB NM_000521.3
HGSNAT NM_152419.2
HMGCL NM_000191.2
HPRT1 NM_000194.2
MAN2B1 NM_000528.3
MANBA NM_005908.3
MAOA NM_000240.3
MFSD8 NM_152778.2
MMACHC NM_015506.2
MTHFR NM_005957.4
MTR NM_000254.2
NAGLU NM_000263.3
NAGS NM_153006.2
NPC1 NM_000271.4
NPC2 NM_006432.3
OTC* NM_000531.5
PAH NM_000277.1
PANK2 NM_153638.2
PCCA NM_000282.3
PCCB NM_000532.4
PLA2G6 NM_003560.2
POLG NM_002693.2
PPT1* NM_000310.3
PRODH NM_016335.4
PSAP NM_002778.3
PTS NM_000317.2
QDPR NM_000320.2
SGSH NM_000199.3
SLC25A13 NM_014251.2
SLC25A15 NM_014252.3
SLC52A1 NM_017986.3
SLC52A2 NM_024531.4
SLC52A3 NM_033409.3
SLC6A8 NM_005629.3
SLC7A7 NM_001126106.2
SPR NM_003124.4
SUMF1 NM_182760.3
TBX1 NM_080647.1
TH NM_199292.2
WDR45 NM_007075.3

CLN3: Analysis includes the intronic variant NM_001042432.1; c.461-13G>C.
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.
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.