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  • Test code: 06170
  • 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 Comprehensive Lysosomal Storage Disorders Panel

Test description

The Invitae Comprehensive Lysosomal Storage Disease (LSD) panel analyzes up to 53 genes associated with lysosomal storage diseases. This panel may be appropriate for individuals with signs and symptoms of any lysosomal storage disease. Additionally, this panel may be appropriate for those in whom a LSD is suspected due to abnormal lysosomal enzyme study, abnormal tissue biopsy or abnormal newborn screen. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions.

Any individual with low enzymatic activity for any lysosomal enzyme must undergo variant analysis for disease confirmation. Most LSDs have known pseudodeficiency alleles, and these can cause false positive results on enzyme testing. Pseudodeficiency alleles result in 5%–20% of normal enzyme activity but do NOT cause clinical disease.

Please note that this panel does not include analysis for Gaucher disease.

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Primary panel (48 genes)

AGA ARSA ARSB ASAH1 CLN2 (TPP1) CLN3 CLN5 CLN6 CLN8 CTNS CTSA CTSD CTSK FUCA1 GAA GALC GALNS GLA GLB1 GM2A GNPTAB GNPTG GNS GUSB HEXA HEXB HGSNAT HYAL1 IDS IDUA KCTD7 LAMP2 LIPA MAN2B1 MANBA MCOLN1 MFSD8 NAGA NAGLU NEU1 NPC1 NPC2 PPT1 PSAP SGSH SLC17A5 SMPD1 SUMF1

Add-on Chitotriosidase Deficiency Gene (1 gene)

Chitotriosidase (chito) is an enzyme that can be elevated in some untreated lysosomal storage disorders such as Gaucher disease and Niemann-Pick types A, B, and C. The degree of elevation generally correlates with disease severity. Plasma chito levels are often utilized as a biomarker in the diagnosis and management of individuals with the aforementioned conditions. However, certain variants in the CHIT1 gene lead to absent or decreased chito levels (chito deficiency), limiting the utility of chito as an accurate biomarker unless genotype is available to aid in the interpretation of results. On its own, chito deficiency does not cause any human disease. Therefore, CHIT1 variants known to cause chito deficiency will only be reported if an individual is found to have a confirmed (two causative variants) or a suspected (two Variants of Uncertain Significance, one causative variant, or one causative variant plus one Variant of Uncertain Significance in an affected individual) genetic diagnosis of Niemann-Pick types A, B, or C. This gene can be added at no additional charge.

CHIT1

Add-on Preliminary Evidence Gene (1 gene)

Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test. Some clinicians may wish to include genes which do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.

ATP13A2

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 Disorders
AGA Aspartylglucosaminuria
ARSA Metachromatic leukodystrophy
ARSB Mucopolysaccharidosis type VI
ASAH1 Farber disease
CLN3 Neuronal ceroid lipofuscinosis 3 (CLN3)
CLN5 Neuronal ceroid lipofuscinosis 5 (CLN5)
CLN6 Neuronal ceroid lipofuscinosis 6 (CLN6)
CLN8 Neuronal ceroid lipofuscinosis 8 (CLN8)
CTNS cystinosis
CTSA Galactosialidosis
CTSD Neuronal ceroid lipofuscinosis 10 (CLN10)
CTSK Pycnodysostosis
FUCA1 Fucosidosis
GAA Pompe disease
GALC Krabbe disease
GALNS Mucopolysaccharidosis type IVa
GLA Fabry disease
GLB1 GM1 gangliosidosis, Mucopolysaccharidosis IVb
GM2A GM2-gangliosidosis, AB variant
GNPTAB Mucolipidosis type II alpha/beta, Mucolipidosis III alpha/beta
GNPTG Mucolipidosis III gamma
GNS Mucopolysaccharidosis type IIID
GUSB Mucopolysaccharidosis type VII
HEXA Tay-Sachs disease
HEXB Sandhoff disease
HGSNAT Mucopolysaccharidosis type IIIC
HYAL1 Mucopolysaccharidosis type IX
IDS Mucopolysaccharidosis type II
IDUA Mucopolysaccharidosis type I
KCTD7 Neuronal ceroid lipofuscinosis 14 (CLN14)
LAMP2 Danon disease
LIPA Lysosomal acid lipase deficiency
MAN2B1 alpha-mannosidosis
MANBA beta-mannosidosis
MCOLN1 Mucolipidosis type IV
MFSD8 Neuronal ceroid lipofuscinosis 7 (CLN7)
NAGA Schindler disease
NAGLU Mucopolysaccharidosis IIIB
NEU1 Mucolipidosis type I,  Sialidosis I
NPC1 Niemann-Pick type C
NPC2 Niemann-Pick type C
SGSH Mucopolysaccharidosis IIIA
PPT1 Neuronal ceroid lipofuscinosis 1 (CLN1)
PSAP Prosaposin deficiency, SapA deficiency (Krabbe variant), SapB deficiency (MLD variant), SapC deficiency (Gaucher variant)
SLC17A5 Infantile sialic acid storage disease, Salla disease
SMPD1 Niemann Pick types A and B
SUMF1 Multiple sulfatase deficiency
TPP1 Neuronal ceroid lipofuscinosis 2 (CLN2)

*Please note that this panel does not include analysis for Gaucher disease.

Opt in and preliminary evidence disorders tested:

Gene Disorders
ATP13A2 Neuronal ceroid lipofuscinosis 12 (CLN12; preliminary evidence), Kufor-Rakeb syndrome (KRS)
CTSF Neuronal ceroid lipofuscinosis 13 (CLN13)
DNAJC5 Neuronal ceroid lipofuscinosis 4 (CLN4)
GRN Neuronal ceroid lipofuscinosis 11 (CLN11), frontotemporal dementia

Lysosomal storage diseases (LSDs) comprise a constellation of monogenic disorders involving the disruption of normal lysosome function. Disease occurs due to loss of lysosomal enzyme activity or, less frequently, non-lysosomal proteins that are involved in transport across the lysosomal membrane, protein maturation or lysosomal biogenesis. These defects result in accumulation of undigested substrate within the lysosome and progressive tissue dysfunction.

The LSDs present with a broad and variable phenotypic spectrum. Disease manifestations depend on the specific accumulated substrate, the site of production and degradation of the substrate and amount of residual enzyme activity, but in general, LSDs are characterized by a progressive course with high morbidity and mortality. Affected individuals are typically normal at birth (although LSDs are a known cause of non-immune hydrops) and the age of postnatal symptom onset is highly variable. This variability can even occur within a single disease as LSDs are known to manifest with a continuum of severe though attenuated symptoms. LSDs are often multisystemic, and clinical features may include just one one or any combination of the following symptoms – coarse facial features, organomegaly, visual loss (especially cherry red spot observed on ophthalmologic exam), corneal clouding, hearing loss, white matter abnormalities, central nervous system dysfunction, developmental regression, skeletal dysplasia, contractures, short stature, hepatosplenomegaly, acroparaesthesias, interstitial lung disease, cytopenia, angiokeratomas, movement disorders, leukodystrophy, cardiomyopathy, psychiatric features such as psychosis and renal failure.

Treatment for most of the LSDs is supportive, but some specific LSDs have commercially available enzyme replacement therapies or substrate reduction therapies. These pharmaceuticals have not proven successful in treating central nervous system disease. Hematopoietic stem cell transplant has also been used successfully to treat some of the LSDs when performed before there is significant disease progression.

LSDs follow autosomal recessive inheritance, with the exception of MPS II, Danon disease and Fabry disease which are X-linked.

The overall combined prevalence of all lysosomal storage diseases is estimated at 1:5000 but as LSDs are being added to newborn screening programs there are indications that the prevalence could be much higher. Certain ethnicities have a much higher prevalence of specific LSDs, such as Gaucher disease in the Ashkenazi Jewish population. Overall, the sphingolipidoses and the mucopolysaccharidsoses are the most commonly observed LSDs.

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
AGA NM_000027.3
ARSA NM_000487.5
ARSB NM_000046.3
ASAH1 NM_177924.3
ATP13A2 NM_022089.3
CHIT1 NM_003465.2
CLN2 (TPP1) NM_000391.3
CLN3* NM_001042432.1
CLN5 NM_006493.2
CLN6 NM_017882.2
CLN8 NM_018941.3
CTNS NM_004937.2
CTSA NM_000308.3
CTSD NM_001909.4
CTSF NM_003793.3
CTSK NM_000396.3
DNAJC5 NM_025219.2
FUCA1 NM_000147.4
GAA* NM_000152.3
GALC* NM_000153.3
GALNS NM_000512.4
GLA* NM_000169.2
GLB1 NM_000404.2
GM2A NM_000405.4
GNPTAB NM_024312.4
GNPTG NM_032520.4
GNS NM_002076.3
GRN NM_002087.3
GUSB NM_000181.3
HEXA NM_000520.4
HEXB NM_000521.3
HGSNAT NM_152419.2
HYAL1 NM_153281.1
IDS* NM_000202.6
IDUA NM_000203.4
KCTD7 NM_153033.4
LAMP2 NM_002294.2
LIPA NM_000235.3
MAN2B1 NM_000528.3
MANBA NM_005908.3
MCOLN1 NM_020533.2
MFSD8 NM_152778.2
NAGA NM_000262.2
NAGLU NM_000263.3
NEU1 NM_000434.3
NPC1 NM_000271.4
NPC2 NM_006432.3
PPT1* NM_000310.3
PSAP NM_002778.3
SGSH NM_000199.3
SLC17A5 NM_012434.4
SMPD1 NM_000543.4
SUMF1 NM_182760.3

CLN3: Analysis includes the intronic variant NM_001042432.1; c.461-13G>C.
GAA: Analysis includes the promoter variant NM_000152.3:c.-32-13T>G as well as the common exon 18 deletion.
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).
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.