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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.
Genes tested
Primary panel
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
CHIT1
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.
Add-on Preliminary Evidence Gene
ATP13A2
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.
Add-on adult-onset neuronal ceroid lipofuscinoses genes
CTSF DNAJC5 GRN
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()
Order test
Primary panel (48 genes)
Customized gene selection (0 included, 0 excluded)
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)
Customized gene selection (0 included, 0 excluded)
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)
Customized gene selection (0 included, 0 excluded)
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)
Customized gene selection (0 included, 0 excluded)
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
Clinical information
Disorders tested
| 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 |
Clinical description
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.
Inheritance
LSDs follow autosomal recessive inheritance, with the exception of MPS II, Danon disease and Fabry disease which are X-linked.
Prevalence/Incidence
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.
References
- Grace, ME, et al. Type 1 Gaucher disease: null and hypomorphic novel chitotriosidase mutations-implications for diagnosis and therapeutic monitoring. Hum. Mutat. 2007; 28(9):866-73. PMID: 17464953
- van, Dussen, L, et al. Value of plasma chitotriosidase to assess non-neuronopathic Gaucher disease severity and progression in the era of enzyme replacement therapy. J. Inherit. Metab. Dis. 2014; 37(6):991-1001. PMID: 24831585
- Giugliani, R, et al. Current molecular genetics strategies for the diagnosis of lysosomal storage disorders. Expert Rev. Mol. Diagn. 2016; 16(1):113-23. PMID: 26567866
- Stone, DL, Sidransky, E. Hydrops fetalis: lysosomal storage disorders in extremis. Adv Pediatr. 1999; 46:409-40. PMID: 10645471
- Kingma, SD, et al. Epidemiology and diagnosis of lysosomal storage disorders; challenges of screening. Best Pract. Res. Clin. Endocrinol. Metab. 2015; 29(2):145-57. PMID: 25987169
- Filocamo, M, Morrone, A. Lysosomal storage disorders: molecular basis and laboratory testing. Hum. Genomics. 2011; 5(3):156-69. PMID: 21504867
- Isman, F, et al. Plasma chitotriosidase in lysosomal storage diseases. Clin Chim Acta. 2008 Jan;387(1-2):165-7. Epub 2007 Jul 28. PMID: 17869233
- Kadali, S. et al. Clinical evaluation of chitotriosidase enzyme activity in Gaucher and Niemann Pick A/B diseases: A retrospective study from India. Clin Chim Acta. 2016 Jun 1;457:8-11. PMID: 26975750
Assay
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.
Resources
References
- Filocamo, M, Morrone, A. Lysosomal storage disorders: molecular basis and laboratory testing. Hum. Genomics. 2011; 5(3):156-69. PMID: 21504867
- Giugliani, R, et al. Current molecular genetics strategies for the diagnosis of lysosomal storage disorders. Expert Rev. Mol. Diagn. 2016; 16(1):113-23. PMID: 26567866
- Grace, ME, et al. Type 1 Gaucher disease: null and hypomorphic novel chitotriosidase mutations-implications for diagnosis and therapeutic monitoring. Hum. Mutat. 2007; 28(9):866-73. PMID: 17464953
- Isman, F, et al. Plasma chitotriosidase in lysosomal storage diseases. Clin Chim Acta. 2008 Jan;387(1-2):165-7. Epub 2007 Jul 28. PMID: 17869233
- Kadali, S. et al. Clinical evaluation of chitotriosidase enzyme activity in Gaucher and Niemann Pick A/B diseases: A retrospective study from India. Clin Chim Acta. 2016 Jun 1;457:8-11. PMID: 26975750
- Kingma, SD, et al. Epidemiology and diagnosis of lysosomal storage disorders; challenges of screening. Best Pract. Res. Clin. Endocrinol. Metab. 2015; 29(2):145-57. PMID: 25987169
- Stone, DL, Sidransky, E. Hydrops fetalis: lysosomal storage disorders in extremis. Adv Pediatr. 1999; 46:409-40. PMID: 10645471
- van, Dussen, L, et al. Value of plasma chitotriosidase to assess non-neuronopathic Gaucher disease severity and progression in the era of enzyme replacement therapy. J. Inherit. Metab. Dis. 2014; 37(6):991-1001. PMID: 24831585
