Lysosomal Disorders and Mucopolysaccharidosis Panel

  • bpg-method PLUS
  • bpg-method SEQ
  • bpg-method DEL/DUP

Test code: ME1501

The Blueprint Genetics Lysosomal Disorders and Mucopolysaccharidosis Panel is a 99 gene test for genetic diagnostics of patients with clinical suspicion of glycoprotein storage disorders, lipid storage disorders, lysosomal storage diseases (LSDs), mucolipidoses or mucopolysaccharidoses.

Lysosomal storage diseases (LSDs) comprise about 50 unique monogenic autosomal or X-linked diseases. This panel provides effective differential diagnosis and is also part of Comprehensive Metabolism Panel.

About Lysosomal Disorders and Mucopolysaccharidosis

About fifty different lysosomal storage diseases (LSDs) have been identified, including different types of disorders caused by genetic mutations that result in deficiency or reduced activity of native intracellular enzymes that catabolize biological macromolecules. Usually lysosomal storage disorders are caused by lysosomal dysfunction as a consequence of deficiency of a single enzyme required for the metabolism of lipids, glycoproteins or mucopolysaccharides. These enzyme defects result in accumulation of specific macromolecular compounds within lysosomes in various tissues and organs, causing progressive damage that can become life-threatening in some diseases. Although each LSD is individually rare, as a group they have an incidence of about 1/7,000-8,000 live births, varying between different populations. LSDs may be variably expressed as infantile, juvenile, or adult forms. In adult-onset diseases, the pathogenesis is usually slower than in the infantile or juvenile forms, and may include peripheral and CNS symptoms, whereas infantile and juvenile forms often involve progressive central nervous system involvement in addition to peripheral symptoms. In ultimate expression, LSDs show substantial heterogeneity in disease manifestation. Symptomatic pathology may be a function of mutation type and residual enzyme levels and specific mutations or types of mutations may be connected to discrete disease effects even if genotype-phenotype correlations are not strong. Most of LSDs are autosomal recessively inherited such as Niemann-Pick disease, type C, however a few are X-linked recessively inherited, such as Fabry disease and Hunter syndrome (MPS2). Other examples of LSDs covered by this panel are Gaucher’s disease (the most common LSD), Tay-Sachs disease, Type II Pompe Disease, Salla disease, Krabbe disease and Hurler disease. Enzyme-replacement therapy (ERT) is now commercially available for six LSDs, typically used lifelong with traditional management practices for each.

Availability

Results in 3-4 weeks. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more: http://blueprintgenetics.com/faqs/#prenatal

Genes in the Lysosomal Disorders and Mucopolysaccharidosis Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
ABCC8 Hyperinsulinemic hypoglycemia, Diabetes, permanent neonatal, Hypoglycemia, leucine-induced, Diabetes mellitus, transient neonatal AD/AR 122 613
ACY1 Aminoacylase 1 deficiency AR 5 14
ADAMTSL2 Geleophysic dysplasia AR 8 27
ADSL Adenylosuccinase deficiency AR 24 56
AGA Aspartylglucosaminuria AR 40 36
ALDH5A1 Succinic semialdehyde dehydrogenase deficiency AR 10 69
ALDH7A1 Epilepsy, pyridoxine-dependent AR 43 112
AMT Glycine encephalopathy AR 26 95
ANTXR2 Hyalinosis, infantile systemic, Fibromatosis, juveline hyaline AR 16 43
ARG1 Hyperargininemia AR 16 54
ARSA Metachromatic leukodystrophy AR 92 215
ARSB Mucopolysaccharidosis (Maroteaux-Lamy) AR 22 196
ASAH1 Spinal muscular atrophy with progressive myoclonic epilepsy, Farber lipogranulomatosis AR 11 56
ASPA Aspartoacylase deficiency (Canavan disease) AR 37 102
ATP13A2 Parkinson disease (Kufor-Rakeb syndrome) AR 17 37
BTD Biotinidase deficiency AR 183 235
CLN3 Ceroid lipofuscinosis, neuronal AR 85 70
CLN5 Ceroid lipofuscinosis, neuronal AR 47 43
CLN6 Ceroid lipofuscinosis, neuronal AR 25 81
CLN8 Ceroid lipofuscinosis, neuronal AR 34 41
COL2A1 Avascular necrosis of femoral head, Rhegmatogenous retinal detachment, Epiphyseal dysplasia, with myopia and deafness, Czech dysplasia, Achondrogenesis type 2, Platyspondylic dysplasia Torrance type, Hypochondrogenesis, Spondyloepiphyseal dysplasia congenital (SEDC), Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type, Kniest dysplasia, Spondyloperipheral dysplasia, Mild SED with premature onset arthrosis, SED with metatarsal shortening, Stickler syndrome type 1 AD 138 541
COL11A2 Weissenbacher-Zweymuller syndrome, Deafness, Otospondylomegaepiphyseal dysplasia, Fibrochondrogenesis, Stickler syndrome type 3 (non-ocular) AD/AR 23 54
CTNS Cystinosis AR 49 142
CTSA Galactosialidosis AR 17 36
CTSC Periodontitis, juvenile, Haim-Munk syndrome, Papillon-Lefevre syndrome AR 16 91
CTSD Ceroid lipofuscinosis, neuronal AR 13 14
CTSK Pycnodysostosis AR 24 54
DHCR7 Smith-Lemli-Opitz syndrome AR 64 214
DPYD 5-fluorouracil toxicity AD/AR 52 88
DYM Dyggve-Melchior-Clausen dysplasia, Smith-McCort dysplasia AR 20 34
ETFA Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 8 27
ETFB Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 6 14
ETFDH Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 37 169
FH Hereditary leiomyomatosis and renal cell cancer AD/AR 142 174
FOLR1 Cerebral folate deficiency AR 8 27
FUCA1 Fucosidosis AR 17 31
GAA Glycogen storage disease AR 136 528
GALC Krabbe disease AR 66 233
GALNS Mucopolysaccharidosis (Morquio syndrome) AR 41 333
GAMT Guanidinoacetate methyltransferase deficiency AR 16 55
GBA* Gaucher disease AR 76 459
GCDH Glutaric aciduria AR 64 205
GLA Fabry disease XL 188 910
GLB1 GM1-gangliosidosis, Mucopolysaccharidosis (Morquio syndrome) AR 60 212
GLDC Glycine encephalopathy AR 95 423
GNE Inclusion body myopathy, Nonaka myopathy, Sialuria AD/AR 50 200
GNPTAB Mucolipidosis AR 151 175
GNPTG Mucolipidosis AR 26 42
GNS Mucopolysaccharidosis (Sanfilippo syndrome) AR 6 25
GPC3 Simpson-Golabi-Behmel syndrome XL 26 72
GUSB* Mucopolysaccharidosis AR 24 61
HEXA Tay-Sachs disease, GM2-gangliosidosis, Hexosaminidase A deficiency AR 108 183
HEXB Sandhoff disease AR 33 111
HGSNAT Mucopolysaccharidosis (Sanfilippo syndrome), Retinitis pigmentosa AR 24 68
HPD Hawksinuria, Tyrosinemia AD/AR 4 9
HRAS Costello syndrome, Congenital myopathy with excess of muscle spindles AD 39 27
HYAL1 Mucopolysaccharidosis AR 2 3
IDS* Mucopolysaccharidosis XL 73 627
IDUA Mucopolysaccharidosis AR 49 252
L2HGDH L-2-hydroxyglutaric aciduria AR 11 75
LAMA2 Muscular dystrophy, congenital merosin-deficient AR 90 256
LDB3 Dilated cardiomyopathy (DCM), Myopathy, myofibrillar AD 9 12
LIPA Wolman disease, Cholesterol ester storage disease AR 12 78
MAN1B1 Mental retardation AR 6 21
MANBA Mannosidosis, lysosomal AR 12 18
MCOLN1 Mucolipidosis AR 45 35
MFSD8 Ceroid lipofuscinosis, neuronal AR 19 43
MOCS1 Molybdenum cofactor deficiency AR 7 32
MOCS2 Molybdenum cofactor deficiency AR 9 12
MYOT Myopathy, myofibrillar AD 8 16
NAGLU Mucopolysaccharidosis (Sanfilippo syndrome) AR 28 166
NEU1 Sialidosis AR 22 59
NPC1 Niemann-Pick disease AR 107 447
NPC2 Niemann-pick disease AR 16 27
PEX1 Heimler syndrome AR 77 130
PEX3 Zellweger syndrome, Peroxisome biogenesis disorder AR 5 9
PEX5 Adrenoleukodystrophy, neonatal, Rhizomelic chondrodysplasia punctata, Zellweger syndrome, Peroxisome biogenesis disorder AR 7 14
PEX6 Heimler syndrome AR 25 105
PEX10 Adrenoleukodystrophy, neonatal, Zellweger syndrome, Peroxisome biogenesis disorder, Ataxia AR 18 29
PEX12 Zellweger syndrome, Peroxisome biogenesis disorder AR 19 37
PEX13 Adrenoleukodystrophy, neonatal, Zellweger syndrome, Peroxisome biogenesis disorder AR 5 10
PEX16 Zellweger syndrome, Peroxisome biogenesis disorder AR 8 12
PEX26 Adrenoleukodystrophy, neonatal, Zellweger syndrome, Peroxisome biogenesis disorder AR 11 24
PGK1 Phosphoglycerate kinase 1 deficiency XL 15 26
PHYH Refsum disease AR 10 36
PPT1 Ceroid lipofuscinosis, neuronal AR 84 77
PRODH* Hyperprolinemia AR 41 10
PSAP Krabbe disease, atypical, Metachromatic leukodystrophy due to saposin-b deficiency, Combined saposin deficiency, Gaucher disease, atypical, due to saposin C deficiency AR 16 24
QDPR Hyperphenylalaninemia, BH4-deficient AR 9 61
RAI1 Smith-Magenis syndrome AD 26 108
SGSH Mucopolysaccharidosis (Sanfilippo syndrome) AR 29 145
SLC17A5 Sialuria, Finnish (Salla disease), Infantile sialic acid storage disorder AR 42 35
SLC25A15* Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome AR 21 36
SLC46A1 Folate malabsorption AR 17 20
SMPD1 Niemann-Pick disease AR 81 238
SUMF1 Multiple sulfatase deficiency AR 21 52
SUOX Sulfocysteinuria AR 6 28
TCF4 Corneal dystrophy, Fuchs endothelial, Pitt-Hopkins syndrome AD 67 136
TPP1 Spinocerebellar ataxia, Neuronal ceroid lipofuscinosis type 2 AR 52 110

*Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.

Gene Genomic location HG19 HGVS RefSeq RS-number
AMT Chr3:49459938 c.-55C>T NM_000481.3 rs386833677
GAA Chr17:78078341 c.-32-13T>G NM_000152.3 rs386834236
GAA Chr17:78078351 c.-32-3C>A NM_000152.3
GAA Chr17:78082266 c.1076-22T>G NM_000152.3 rs762260678
GLA ChrX:100654735 c.640-801G>A NM_000169.2 rs199473684
GNPTG Chr16:1412562 c.610-16_609+28del NM_032520.4 rs193302853
MOCS1 Chr6:39874534 c.*365_*366delAG NM_005943.5 rs397518419
PPT1 Chr1:40539203 c.*526_*529delATCA NM_000310.3 rs386833624

The strengths of this test include:

  • Blueprint Genetics is one of the few laboratories worldwide with CAP and ISO-15189 accreditation for NGS panels and CLIA certification
  • Superior sequencing quality
  • Careful selection of genes based on current literature, our experience and the most current mutation databases
  • Transparent and easy access to quality and performance data at the patient level that are accessible via our Nucleus portal
  • Transparent and reproducible analytical validation for each panel (see Test performance section; for complete details, see our Analytic Validation)
  • Sequencing and high resolution del/dup analysis available in one test
  • Inclusion of non-coding disease causing variants where clinically indicated (please see individual Panel descriptions)
  • Interpretation of variants following ACMG variant classification guidelines
  • Comprehensive clinical statement co-written by a PhD geneticist and a clinician specialist

 

This test does not detect the following:

  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Variants in regulatory or non-coding regions of the gene unless otherwise indicated (please see Non-coding disease causing variants covered by the panel). This mean for instance intronic variants locating deeper than 15 nucleotides from the exon-intron boundary.

 

This test may not reliably detect the following:

  • Low level mosaicism
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments
  • Disorders caused by long repetitive sequences (e.g. trinucleotide repeat expansions)

 

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

Blueprint Genetics offers a comprehensive Lysosomal Disorders and Mucopolysaccharidosis Panel that covers classical genes associated with glycoprotein storage disorders, lipid storage disorders, lysosomal storage diseases (LSDs), mucolipidoses and mucopolysaccharidoses. The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile.

The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

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ICD & CPT codes

CPT codes

SEQ 81479
DEL/DUP 81479


ICD codes

Commonly used ICD-10 codes when ordering the Lysosomal Disorders and Mucopolysaccharidosis Panel

ICD-10 Disease
E75.00 Lipid storage disorders
E76.0 Mucopolysaccharidoses
E77.9 Glycoprotein storage disorders
E76.3 Mucolipidoses

Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.

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