LSDP - Clinical: Lysosomal Storage Disease Panel by Next-Generation Sequencing

Test Catalog

Test Name

Test ID: LSDP    
Lysosomal Storage Disease Panel by Next-Generation Sequencing

Useful For Suggests clinical disorders or settings where the test may be helpful

Follow up for abnormal biochemical results and confirmation of suspected lysosomal storage disease (LSD)

 

Identifying mutations within genes known to be associated with lysosomal storage disease, allowing for predictive testing of at-risk family members

Genetics Test Information Provides information that may help with selection of the correct test or proper submission of the test request

This test includes next-generation sequencing and supplemental Sanger sequencing to evaluate the genes on this panel.

 

Targeted testing for familial variants (also called site-specific or known mutation testing) is available for all genes on this panel under FMTT / Familial Mutation, Targeted Testing. Call Mayo Medical Laboratories at 800-533-1710 to obtain more information about this testing option.

Testing Algorithm Delineates situation(s) when tests are added to the initial order. This includes reflex and additional tests.

See clinical information for recommended first-tier biochemical testing.

 

If skin biopsy is received, fibroblast culture will be added and charged separately.

 

For prenatal specimens only: If amniotic fluid (nonconfluent cultured cells) is received, amniotic fluid culture/genetic test will be added and charged separately. If chorionic villus specimen (nonconfluent cultured cells) is received, fibroblast culture for genetic test will be added and charged separately. For any prenatal specimen that is received, maternal cell contamination studies will be added.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Lysosomal storage diseases (LSDs) encompass a group of over 40 inherited biochemical diseases in which genetic mutations cause defective lysosomal functioning. Lysosomes perform catabolic functions for cells, which is accomplished through activity of various proteins such as lysosomal enzymes, transport proteins, and other proteins. Functional deficits in these proteins cause an accumulation of substrates in cells leading to progressive organ dysfunction.

 

This leads to variable clinical features that can affect the cardiovascular, neurological, ocular, and skeletal systems, among others. Clinical features are dependent on the amount and location of the substrate accumulation, but may include the following: characteristic facial features (coarse features), hepatomegaly, deafness, vision loss, abnormal skeletal findings, hydrops fetalis, ataxia, hypotonia, developmental delay/regression, and intellectual disability. Age of onset is variable, with symptoms presenting from the prenatal period to adulthood, but generally LSDs are progressive and cause significant morbidity and mortality with a decreased lifespan. Enzyme replacement therapy and oral substrate inhibitors are therapeutic options for some LSDs.

 

LSDs are inherited in an autosomal recessive manner with the exception of Hunter, Fabry, and Danon diseases, which are X-linked. There are some founder mutations associated with particular LSDs in the Ashkenazi Jewish and Finnish populations, leading to an increased carrier frequency for some. Overall, the prevalence of LSDs is estimated at 1/7000 to 1/8000.

 

Neuronal ceroid lipofuscinoses (NCLs) are a subset of lysosomal storage diseases that involve defective cellular processing of lipids. NCLs are clinically characterized by epilepsy, intellectual and motor decline, and blindness. Electron microscopy typically shows a characteristic accumulation of granular osmophilic deposits (GROD), curvilinear profiles (CVB), or fingerprint profiles (FP). Enzymatic testing may show deficiency in palmitoyl-protein thioesterase 1 (PPT1), tripeptidyl-peptidase 1 (TPP1), or cathepsin D (CTSD). Currently there are at least 14 genetically distinct forms.

 

Age of onset and clinical features can be variable, from congenital to adult onset. NCL is typically inherited in an autosomal recessive manner, although one adult onset form (ANCL; DNAJC5 gene) has been shown to be autosomal dominant.

 

First-tier biochemical testing is available for the 2 most common types of enzyme deficiency resulting in NCL: TPPTL / Tripeptidyl Peptidase 1 (TPP1) and Palmitoyl-Protein Thioesterase 1 (PPT1), Leukocytes; and TPPTF / Tripeptidyl Peptidase 1 (TPP1) and Palmitoyl-Protein Thioesterase 1 (PPT1), Fibroblasts.

 

This panel includes sequencing of 43 genes related to various LSDs, as well as 15 genes specific to neuronal ceroid lipofuscinosis, for a total of 58 genes.

 

See gene table below for genes and conditions that are included on the panel. Recommended first-tier biochemical testing is also provided.

Note: Testing for the 15 neuronal ceroid lipofuscinosis genes is also available separately (NCLP / Neuronal Ceroid Lipofuscinosis [NCL, Batten Disease] Panel by Next-Generation Sequencing).

 

Gene

Disease Name

OMIM ID

Inheritance

ACP2

Lysosomal acid phosphatase deficiency (ACPHD)

200950

AR

AGA

Aspartylglucosaminuria (AGU)

208400

AR

*Finnish Founder mutation

ARSA

Metachromatic leukodystrophy

250100

AR

ARSB

Mucopolysaccharidosis Type VI maroteaux-lamy

253200

AR

ARSH

Multiple sulfatase deficiency

300586

AR

ASAH1

Farber lipogranulomatosis

228000

AR

CHIT1

Chitotriosidase deficiency (with Gaucher 1)

600031, 614122

AR

CTNS

Cystinosis

219800

AR

CTSA

Galactosialidosis

256540

AR

FUCA1

Fucosidosis

230000

AR

GAA

Pompe disease-glycogen storage disease type II

232300

AR

GALC

Krabbe disease

245200

AR

GALNS

Mucopolysaccharidosis Type IVA Morquio A

612222

AR

GBA

Gaucher Disease

230800, 230900, 231000

AR

GFAP

Alexander disease

203450

AR

GLA

Fabry disease

301500

X linked

GLB1

Mucopolysaccharidosis type IVB-MorquioB

253010

AR

GM2A

GM2-gangliosidosis, AB variant

272750

AR

GNPTAB

Mucolipidosis II, and III

252500, 252600

AR

GNPTG

Mucolipidosis III gamma

232605

AR

GNS

Mucopolysaccharidosis type IIID Sanfilippo D

252940

AR

GUSB

Mucopolysaccharidosis type VII Sly

253220

AR

HEXA

Tay-Sachs disease

272800

AR

HEXB

Sandhoff disease

268800

AR

HGSNAT

Mucopolysaccharidosis type IIIC (Sanfilippo)

252930

AR

HYAL1

Mucopolysaccharidosis type IX: Hyaluroindase deficiency

601492

AR

IDS

Mucopolysaccharidosis type II Hunter disease

309900

X linked

IDUA

Mucopolysaccharidosis type I (Hurler/Scheie)

607014

AR

LAMP2

Glycogen Storage Disease Type IIB-Danon Disease

300257

AR

LIPA

Lysosomal acid lipase deficiency/Wolman disease

278000

AR

MAN2B1

Alpha-mannosidase deficiency

248500

AR

MANBA

Beta-mannosidosis

248510

AR

MCOLN1

Mucolipidosis type IV

252650

AR

NAGA

Schindler disease

609241

AR

NAGLU

Mucopolysaccharidosis Type IIIB

252920

AR

NEU1

Sialidosis

256550

AR

NPC1

Niemann-Pick type C1 and C2

257220

AR

NPC2

Niemann-Pick type C1 and C3

607625

AR

PSAP

Prosaposin Deficiency (Variants of other disorders as well)

611721, 610539, 611722, 249900

AR

SGSH

Mucopolysaccharidosis Type IIIA Sanfilippo

252900

AR

SLC17A5

Sialic acid storage disease

269920

AR

SMPD1

Niemann-Pick type A/B

257200, 607616

AR

SUMF1

Multiple Sulfatase Deficiency

272200

AR

AR=autosomal recessive

AD=autosomal dominant

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

All detected alterations are evaluated according to American College of Medical Genetics and Genomics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

 

Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and predictions made by these tools may change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Clinical Correlations: Some individuals who have involvement of 1 or more of the genes on the panel may have a mutation that is not identified by the methods performed (eg, promoter mutations, deep intronic mutations, large genomic deletions). The absence of a mutation, therefore, does not eliminate the possibility of a lysosomal storage disease (LSD).

 

For predictive testing of asymptomatic individuals, it is important to first document the presence of a gene mutation in an affected family member.

 

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

 

Technical Limitations: In some cases, DNA variants of undetermined significance may be identified. Due to the limitations of next-generation sequencing, we can detect 90% of insertions and deletions up to 28 bases and 38 bases, respectively. If a diagnosis of 1 of the syndromes on this panel is still suspected, consider full gene sequencing using traditional Sanger methods.

 

Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.

 

A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories at 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

 

Evaluation Tools: Multiple in-silico evaluation tools were used to assist in the interpretation of these results. These tools are updated regularly; therefore, changes to these algorithms may result in different predictions for a given alteration. Additionally, the predictability of these tools for the determination of pathogenicity is currently not validated.

 

Unless reported or predicted to cause disease, alterations found deep in the intron or alterations that do not result in an amino acid substitution are not reported. These and common polymorphisms identified for this patient are available upon request.

 

Reclassification of Variants-Policy: All detected alterations are evaluated according to American College of Medical Genetics and Genomics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. At this time, it is not standard practice for the laboratory to systematically review likely deleterious alterations or variants of uncertain significance that are detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time.

Clinical Reference Provides recommendations for further in-depth reading of a clinical nature

1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008;10(4):294-300

2. Wang RY, Bodamer OA, Watson MS, et al: ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Diseases: Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals. Genet Med 2011;13(5):457-484

3. Parenti G, Andria G, Ballabio A: Lysosomal storage diseases: from pathophysiology to therapy. Annu Rev Med 2015;66:471-486

4. Filocamo, M. Morrone A: Lysosomal storage disorders: Molecular basis and laboratory testing. Human Genomics 2011;5:156-169

5. Coutinho MF, Alves S: From rare to common and back again: 60 years of lysosomal dysfunction. Mol Genet Metab 2015

Special Instructions and Forms Describes specimen collection and preparation information, test algorithms, and other information pertinent to test. Also includes pertinent information and consent forms to be used when requesting a particular test