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Congenital Disorders of Glycosylation Sequencing Panel with CNV Detection

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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TEST METHODS

Sequencing

Test Code Test Copy GenesCPT Code Copy CPT Codes
10625 ALG1 81479,81479 Add to Order
ALG11 81479,81479
ALG12 81479,81479
ALG13 81479,81479
ALG2 81479,81479
ALG3 81479,81479
ALG6 81479,81479
ALG8 81479,81479
ALG9 81479,81479
ATP6AP1 81479,81479
ATP6V0A2 81479,81479
B4GALT1 81479,81479
CCDC115 81479,81479
COG1 81479,81479
COG2 81479,81479
COG4 81479,81479
COG5 81479,81479
COG6 81479,81479
COG7 81479,81479
COG8 81479,81479
DDOST 81479,81479
DHDDS 81479,81479
DOLK 81479,81479
DPAGT1 81479,81479
DPM1 81479,81479
DPM2 81479,81479
DPM3 81479,81479
GMPPA 81479,81479
GNE 81479,81479
MAGT1 81479,81479
MAN1B1 81479,81479
MGAT2 81479,81479
MOGS 81479,81479
MPDU1 81479,81479
MPI 81405,81479
NGLY1 81479,81479
PGM1 81479,81479
PMM2 81479,81479
RFT1 81479,81479
SLC35A1 81479,81479
SLC35A2 81479,81479
SLC35C1 81479,81479
SLC39A8 81479,81479
SRD5A3 81479,81479
SSR4 81479,81479
STT3A 81479,81479
STT3B 81479,81479
TMEM165 81479,81479
TMEM199 81479,81479
TUSC3 81479,81479
Full Panel Price* $960.00
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
10625 Genes x (50) $960.00 81405, 81479(x99) Add to Order
Pricing Comment

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

Targeted Testing

For ordering sequencing of targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 26 days.

Clinical Sensitivity

Clinical sensitivity for this panel is difficult to estimate at this time, as this specific group of genes has not previously been tested in a large cohort to date. The majority of CDGs have only been reported in a handful of individuals; some exceptions include CDG caused by defects in the PMM2 gene, which has been reported in over 700 individuals to date and CDG due to pathogenic variants in the MPI, ALG6, SRD5A3, and COG6 genes (Sparks and Krasnewich. 2017. PubMed ID: 20301507).

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Clinical Features

Congenital disorders of glycosylation (CDGs) are a clinically heterogeneous group of inborn errors of metabolism that are characterized by defects in protein or lipid glycosylation, a form of post-translational modification. These disorders can be further differentiated into several categories depending upon what part of the glycosylation pathway has been disrupted: protein N-linked protein glycosylation defects, which are the most common; O-linked protein glycosylation defects; glycolipid and glycosylphosphatidylinositol (GPI) anchor defects; or multi-pathway defects (Brasil et al. 2018. PubMed ID: 29702557; Jaeken. 2017. PubMed ID: 28484880; Scott et al. 2014. PubMed ID: 24831587). Analysis via serum transferrin isoelectrofocusing is often considered the standard first screen test for N-linked protein glycosylation disorders; however, normal results with this test do not preclude the possibility of a CDG diagnosis (N-linked or otherwise), and therefore molecular testing is often advised if a CDG is part of the differential (Jaeken. 2017. PubMed ID: 28484880).

As detective glycosylation negatively impacts a wide variety of cellular processes, most of these diseases are multi-systemic and early onset in nature. However, varying degrees of severity and age at onset have been described, even in patients with defects in the same gene (Sparks and Krasnewich. 2015. PubMed ID: 20301289; Sparks and Krasnewich. 2017. PubMed ID: 20301507). The majority of N-linked CDGs present in infancy, and symptoms may include failure to thrive, developmental delay, liver dysfunction, seizures, hypotonia, hypoglycemia, protein-losing enteropathy, eye dysfunction (such as strabismus or retinitis pigmentosa), immunologic dysfunction, skin abnormalities, and/or skeletal abnormalities (Sparks and Krasnewich. 2017. PubMed ID: 20301507).

CDG type Ia (PMM2-CDG) due to pathogenic variants in PMM2 is the most common N-linked CDG described to date. The clinical spectrum of PMM2-CDG may range from a severe infantile-onset multi-system disease to an adult stable disability disorder (Sparks and Krasnewich. 2015. PubMed ID: 20301289).

O-linked CDGs, in contrast, typically present as muscular dystrophies with additional phenotypes such as hypotonia, brain malformations, intellectual disability, cardiac involvement, and/or ocular dysfunction (Martin. 2005. PubMed ID: 16584074).

GPI anchor defects are characterized by intellectual disability, hyperphosphatasia, and/or paroxysmal nocturnal hemoglobinuria (Witters et al. 2017. PubMed ID: 29112118). Lastly, defects that result in multi-pathway dysfunction, such as those that involve the dolichol phosphate mutase (DPM) complex that is essential for all three glycosylation pathways, often result in severe multi-system phenotypes. Clinical features may overlap with symptoms seen in both N- and O-linked glycosylation disorders (Witters et al. 2017. PubMed ID: 29112118).

At this time, treatment is available for MPI-CDG (oral mannose and/or liver transplantation) (Jaeken. 2017. PubMed ID: 28484880). Partial treatments exist for SLC35C1-CDG (oral fucose); DOLK-CDG (heart transplantation); PGM1-CDG, SLC35A2-CDG, and SLC39A8-CDG (galactose); and DPAGT1-CDG and ALG2-CDG (cholinesterase inhibitors) (Jaeken. 2017. PubMed ID: 28484880).

Genetics

The great majority of CDGs tested in this panel exhibit autosomal recessive inheritance, with a few exceptions: notably, ALG13, ATP6AP1, MAGT1, SLC35A2, and SSR4 exhibit X-linked inheritance (Sparks and Krasnewich. 2017. PubMed ID: 20301507; Evers et al. 2017. PubMed ID: 28688840). See individual gene test descriptions for additional information regarding gene function and pathogenic variant spectra.

Note that the most common pathogenic variant in PMM2, p.Arg141His, has a very high carrier rate in certain populations (up to ~0.8% in European continental populations, http://gnomad.broadinstitute.org/), yet homozygotes for this variant have not yet been documented. Homozygotes are therefore strongly suspected to be embryonically lethal (Matthijs et al. 1998. PubMed ID: 9497260; Thiel et al. 2006. PubMed ID: 16847317).

Testing Strategy

For this Next Generation Sequencing (NGS) test, sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments.

For Sanger sequencing, polymerase chain reaction (PCR) is used to amplify targeted regions. After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Copy number variants (CNVs) are also detected from NGS data. We utilize a CNV calling algorithm that compares mean read depth and distribution for each target in the test sample against multiple matched controls. Neighboring target read depth and distribution and zygosity of any variants within each target region are used to reinforce CNV calls. All CNVs are confirmed using another technology such as aCGH, MLPA, or PCR before they are reported.

This panel typically provides ≥98% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Individuals with clinical symptoms that are consistent with a suspected underlying congenital disorder of glycosylation (CDG) or individuals with diagnostic serum transferrin isoform results are candidates for this test.

Diseases

Name Inheritance OMIM ID
Alacrima, Achalasia, and Mental Retardation Syndrome AR 615510
Carbohydrate-Deficient Glycoprotein Syndrome Type II AR 212066
Congenital Disorder of Deglycosylation AR 615273
Congenital Disorder Of Glycosylation Type 1A AR 212065
Congenital Disorder Of Glycosylation Type 1B AR 602579
Congenital Disorder Of Glycosylation Type 1C AR 603147
Congenital Disorder Of Glycosylation Type 1D AR 601110
Congenital Disorder Of Glycosylation Type 1E AR 608799
Congenital Disorder Of Glycosylation Type 1F AR 609180
Congenital Disorder Of Glycosylation Type 1G AR 607143
Congenital Disorder Of Glycosylation Type 1H AR 608104
Congenital Disorder Of Glycosylation Type 1I AR 607906
Congenital Disorder Of Glycosylation Type 1J AR 608093
Congenital Disorder Of Glycosylation Type 1K AR 608540
Congenital Disorder Of Glycosylation Type 1L AR 608776
Congenital Disorder Of Glycosylation Type 1M AR 610768
Congenital Disorder Of Glycosylation Type 1O AR 612937
Congenital Disorder Of Glycosylation Type 1P AR 613661
Congenital Disorder Of Glycosylation Type 1Q AR 612379
Congenital Disorder Of Glycosylation Type 2C AR 266265
Congenital Disorder Of Glycosylation Type 2D AR 607091
Congenital Disorder Of Glycosylation Type 2E AR 608779
Congenital Disorder Of Glycosylation Type 2F AR 603585
Congenital Disorder Of Glycosylation Type 2G AR 611209
Congenital Disorder Of Glycosylation Type 2I AR 613612
Congenital Disorder Of Glycosylation Type IIb AR 606056
Congenital Disorder Of Glycosylation Type IIh AR 611182
Congenital Disorder Of Glycosylation Type IIj AR 613489
Congenital Disorder of Glycosylation Type IIk AR 614727
Congenital Disorder of Glycosylation Type IIl AR 614576
Congenital Disorder of Glycosylation Type IIm XL 300896
Congenital Disorder of Glycosylation Type IIn AR 616721
Congenital Disorder of Glycosylation Type IIo AR 616828
Congenital Disorder of Glycosylation Type IIp AR 616829
Congenital Disorder of Glycosylation Type IIq AR 617395
Congenital Disorder Of Glycosylation Type In AR 612015
Congenital Disorder of Glycosylation Type Ir AR 614507
Congenital Disorder of Glycosylation Type It AR 614921
Congenital Disorder of Glycosylation Type Iu AR 615042
Congenital Disorder of Glycosylation Type Iw AR 615596
Congenital Disorder of Glycosylation Type Ix AR 615597
Congenital Disorder of Glycosylation Type Iy XL 300934
Cutis Laxa, Autosomal Recessive, Type IIA AR 219200
Epileptic Encephalopathy, Early Infantile, 36 XL 300884
GNE Myopathy AR 605820
Immunodeficiency and Hepatopathy with Cutis Laxa XL 300972
Immunodeficiency, X-Linked, With Magnesium Defect, Epstein-Barr Virus Infection, And Neoplasia XL 300853
Mental Retardation, Autosomal Recessive 15 AR 614202
Mental Retardation, Autosomal Recessive 7 AR 611093
Retinitis Pigmentosa 59 AR 613861
Sialuria AD 269921
Wrinkly Skin Syndrome AR 278250

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Congenital Disorders of Glycosylation, Type Ib (CDG Ib) via MPI Gene Sequencing with CNV Detection
Congenital Disorders of Glycosylation, Type Ic (CDG Ic) via ALG6 Gene Sequencing with CNV Detection
Congenital Disorders of Glycosylation, Type Id (CDG Id) via ALG3 Gene Sequencing with CNV Detection
Congenital Disorders of Glycosylation, Type Ie (CDG Ie) via DPM1 Gene Sequencing with CNV Detection
Congenital Disorders of Glycosylation, Type If (CDG If) via MPDU1 Gene Sequencing with CNV Detection
Congenital Disorders of Glycosylation, Type Ig (CDG Ig) via ALG12 Gene Sequencing with CNV Detection
Congenital Disorders of Glycosylation, Type Ih (CDG Ih) via the ALG8 Gene
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Congenital Disorders of Glycosylation, Type IIj via COG4 Gene Sequencing with CNV Detection
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CONTACTS

Genetic Counselors
Geneticist
Citations
  • Brasil et al. 2018. PubMed ID: 29702557
  • Evers et al. 2017. PubMed ID: 28688840
  • Jaeken and Péanne. 2017. PubMed ID: 28484880
  • Martin. 2005. PubMed ID: 16584074
  • Matthijs et al. 1998. PubMed ID: 9497260
  • Scott et al. 2014. PubMed ID: 24831587
  • Sparks and Krasnewich. 2015. PubMed ID: 20301289
  • Sparks and Krasnewich. 2017. PubMed ID: 20301507
  • Thiel et al. 2006. PubMed ID: 16847317
  • Witters et al. 2017. PubMed ID: 29112118
Order Kits
TEST METHODS

Exome Sequencing with CNV Detection

Test Procedure

For the PGxome we use Next Generation Sequencing (NGS) technologies to cover the coding regions of targeted genes plus ~10 bases of non-coding DNA flanking each exon. As required, genomic DNA is extracted from patient specimens. Patient DNA corresponding to these regions is captured using Agilent Clinical Research Exome hybridization probes. Captured DNA is sequenced on the NovaSeq 6000 using 2x150 bp paired-end reads (Illumina, San Diego, CA, USA). The following quality control metrics are generally achieved: >97% of target bases are covered at >20x, and mean coverage of target bases >120x. Data analysis and interpretation is performed by the internally developed software Titanium-Exome. In brief, the output data from the NovaSeq 6000 is converted to fastqs by Illumina Bcl2Fastq, and mapped by BWA. Variant calls are made by the GATK Haplotype caller and annotated using in house software and SnpEff. Variants are filtered and annotated using VarSeq (www.goldenhelix.com).

For Sanger sequencing, polymerase chain reaction (PCR) is used to amplify targeted regions. After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Copy number variants (CNVs) are also detected from NGS data. We utilize a CNV calling algorithm that compares mean read depth and distribution for each target in the test sample against multiple matched controls. Neighboring target read depth and distribution and zygosity of any variants within each target region are used to reinforce CNV calls. All CNVs are confirmed using another technology such as aCGH, MLPA, or PCR before they are reported.

Analytical Validity

Copy Number Variant Analysis: The PGxome test detects most larger deletions and duplications including intragenic CNVs and large cytogenetic events; however aberrations in a small percentage of regions may not be accurately detected due to sequence paralogy (e.g., pseudogenes, segmental duplications), sequence properties, deletion/duplication size (e.g., 1-3 exons vs. 4 or more exons), and inadequate coverage. In general, sensitivity for single, double, or triple exon CNVs is ~70% and for CNVs of four exon size or larger is >95%, but may vary from gene-to-gene based on exon size, depth of coverage, and characteristics of the region.

Analytical Limitations

Interpretation of the test results is limited by the information that is currently available. Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.

When sequencing does not reveal any heterozygous differences from the reference sequence, we cannot be certain that we were able to detect both patient alleles.

For technical reasons, the PGxome test is not 100% sensitive. Some exons cannot be efficiently captured, and some genes cannot be accurately sequenced because of the presence of multiple copies in the genome. Therefore, a small fraction of sequence variants will not be detected.

We sequence coding exons for most given transcripts, plus ~10 bp of flanking non-coding DNA for each exon. Unless specifically indicated, test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions, uncharacterized alternative exons, chromosomal rearrangements, repeat expansions, epigenetic effects, and mitochondrial genome variants.

In most cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants due to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient's nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during amplification.

Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes if taken from whole blood). Test reports contain no information about the DNA sequence in other cell-types.

We cannot be certain that the reference sequences are correct.

Balanced translocations or inversions are only rarely detected.

Certain types of sex chromosome aneuploidy may not be detected.  

In nearly all cases, our ability to determine the exact copy number change within a targeted region is limited.

Our ability to detect CNVs due to somatic mosaicism is limited.

We have confidence in our ability to track a specimen once it has been received by PreventionGenetics. However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.

A negative finding does not rule out a genetic diagnosis.

Genetic counseling to help to explain test results to the patients and to discuss reproductive options is recommended.

Order Kits

Ordering Options


myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
REQUISITION FORM
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

SPECIMEN TYPES
WHOLE BLOOD

(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.

DNA

(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.

CELL CULTURE

(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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