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Invitae Congenital Disorders of Glycosylation Panel
Test description
The Invitae Congenital Disorders of Glycosylation Panel analyzes up to 103 genes that are associated with congenital disorders of glycosylation (CDGs). This test is useful for the diagnosis of patients in whom a congenital disorder of glycosylation is suspected due to clinical symptoms or biochemical findings, such as abnormal transferrin isoelectric focusing.
This panel covers:
- disorders of N-linked glycosylation, including type I and type II
- conserved oligomeric golgi (COG) complex defects
- disorder of deglycosylation (NGLY1)
Genes tested
Primary panel
ALG1 ALG11 ALG12 ALG13 ALG2 ALG3 ALG6 ALG8 ALG9 ATP6V0A2 B3GLCT CHST14 COG1 COG2 COG4 COG5 COG6 COG7 COG8 DHDDS DOLK DPAGT1 DPM1 DPM2 DPM3 G6PC3 GFPT1 GMPPA GMPPB MAGT1 MAN1B1 MGAT2 MOGS MPDU1 MPI NGLY1 PGM1 PGM3 PMM2 RFT1 SEC23B SLC35A1 SLC35A2 SLC35C1 SRD5A3 SSR4 ST3GAL5 TMEM165 TRIP11 TUSC3
Add-on Preliminary-evidence Genes for Congenital Disorders of Glycosylation
ALG14 B4GALT1 DDOST NUS1 PIGM RPN2 SEC23A SLC35A3 ST3GAL3 STT3A STT3B
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 Disorders of O-mannosylation Genes
B3GALNT2 B4GAT1 FKRP FKTN GNE ISPD LARGE1 POMGNT1 POMGNT2 POMK POMT1 POMT2 RXYLT1
Disorders of o-mannosylation have defects in o-mannosyl glycan synthesis, mainly of alpha-dystroglycan. These disorders may have overlapping phenotypes with CDGs, including muscular phenotypes, brain malformations, and eye abnormalities. These genes can be included at no additional charge.
Add-on Glycosylation Genes Not Involved in N-glycosylation
B3GALT6 B3GAT3 B4GALNT1 B4GALT7 C1GALT1C1 CHST3 CHST6 CHSY1 DSE EOGT EXT1 EXT2 GALNT3 LFNG PAPSS2 PIGA PIGL PIGM PIGN PIGO PIGQ PIGT PIGV PIGW POFUT1 POGLUT1 SLC26A2 SLC35D1 XYLT1
Disorders of glycosamine synthesis, glycosphingolipids and o-linked glycosylation may have overlapping phenotypes with CDGs, including delayed motor and speech development, musculoskeletal disorders, skin disorders and immune system defects. These genes can be included at no additional charge.
Order test
Primary panel (50 genes)
Customized gene selection (0 included, 0 excluded)
ALG1 ALG11 ALG12 ALG13 ALG2 ALG3 ALG6 ALG8 ALG9 ATP6V0A2 B3GLCT CHST14 COG1 COG2 COG4 COG5 COG6 COG7 COG8 DHDDS DOLK DPAGT1 DPM1 DPM2 DPM3 G6PC3 GFPT1 GMPPA GMPPB MAGT1 MAN1B1 MGAT2 MOGS MPDU1 MPI NGLY1 PGM1 PGM3 PMM2 RFT1 SEC23B SLC35A1 SLC35A2 SLC35C1 SRD5A3 SSR4 ST3GAL5 TMEM165 TRIP11 TUSC3
Add-on Preliminary-evidence Genes for Congenital Disorders of Glycosylation (11 genes)
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.
ALG14 B4GALT1 DDOST NUS1 PIGM RPN2 SEC23A SLC35A3 ST3GAL3 STT3A STT3B
Add-on Disorders of O-mannosylation Genes (13 genes)
Customized gene selection (0 included, 0 excluded)
Disorders of o-mannosylation have defects in o-mannosyl glycan synthesis, mainly of alpha-dystroglycan. These disorders may have overlapping phenotypes with CDGs, including muscular phenotypes, brain malformations, and eye abnormalities. These genes can be included at no additional charge.
B3GALNT2 B4GAT1 FKRP FKTN GNE ISPD LARGE1 POMGNT1 POMGNT2 POMK POMT1 POMT2 RXYLT1
Add-on Glycosylation Genes Not Involved in N-glycosylation (29 genes)
Customized gene selection (0 included, 0 excluded)
Disorders of glycosamine synthesis, glycosphingolipids and o-linked glycosylation may have overlapping phenotypes with CDGs, including delayed motor and speech development, musculoskeletal disorders, skin disorders and immune system defects. These genes can be included at no additional charge.
B3GALT6 B3GAT3 B4GALNT1 B4GALT7 C1GALT1C1 CHST3 CHST6 CHSY1 DSE EOGT EXT1 EXT2 GALNT3 LFNG PAPSS2 PIGA PIGL PIGM PIGN PIGO PIGQ PIGT PIGV PIGW POFUT1 POGLUT1 SLC26A2 SLC35D1 XYLT1
Clinical information
Disorders tested
| Gene | Disorder name | Previous disorder name |
|---|---|---|
| Primary panel | ||
| ALG1 | ALG1-CDG | CDG-Ik |
| ALG2 | ALG2-associated myasthenic syndrome | CDG-Ii |
| ALG3 | ALG3-CDG | CDG-Id |
| ALG6 | ALG6-CDG | CDG-Ic |
| ALG8 | ALG8-CDG | CDG-Ih |
| ALG9 | ALG9-CDG | CDG-IL |
| ALG11 | ALG11-CDG | CDG-Ip |
| ALG12 | ALG12-CDG | CDG-Ig |
| ALG13 | ALG13-CDG | CDG-Is |
| ATPV0A2 | ATP6V0A2-associated cutis laxa | NA |
| B3GLCT | B3GLCT-CDG | Peters Plus syndrome |
| CHST14 | CHST14-CDG | Musculocontractural type Ehlers-Danlos syndrome |
| COG1 | COG1-CDG | CDG-IIg |
| COG2 | COG2-CDG | NA |
| COG4 | COG4-CDG | CDG-IIj |
| COG5 | COG5-CDG | CDG-IIi |
| COG6 | COG6-CDG | CDG-IIL |
| COG7 | COG7-CDG | CDG-IIe |
| COG8 | COG8-CDG | CDG-IIh |
| DOLK | DOLK-CDG | CDG-Im |
| DHDDS | DHDDS-CDG | NA |
| DPAGT1 | DPAGT1-CDG | CDG-Ij |
| DPM1 | DPM1-CDG | CDG-Ie |
| DPM2 | DPM2-CDG | CDG-Iu |
| DPM3 | DPM3-CDG | CDG-Io |
| G6PC3 | Congenital neutropenia | NA |
| GFPT1 | Congenital myasthenic syndrome | NA |
| GMPPA | GMPPA-CDG | NA |
| GMPPB | Congenital muscular dystrophy, congenital myasthenic syndrome, and dystroglycanopathy | NA |
| MAGT1 | MAGT1-CDG; X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia (XMEN) syndrome | NA |
| MAN1B1 | MAN1B1-CDG | NA |
| MGAT2 | MGAT2-CDG | CDG-IIa |
| MOGS | MOGS-CDG | CDG-IIb |
| MPDU1 | MPDU1-CDG | CDG-If |
| MPI | MPI-CDG | CDG-Ib |
| NGLY1 | NGLY1-CDG | CDG-Iv |
| PGM1 | PGM1-CDG | CDG-It |
| PGM3 | PGM3-CDG | Hyper-IgE syndrome |
| PMM2 | PMM2-CDG | CDG-Ia |
| RFT1 | RFT1-CDG | CDG-In |
| SEC23B | SEC23B-CDG | Congenital Dyserythropoietic Anemia |
| SLC35A1 | SLC35A1-CDG | CDG-IIf |
| SLC35A2 | SLC35A2-CDG | CDG-IIm |
| SLC35C1 | SLC35C1-CDG | CDG-IIc |
| SSR4 | SSR4-CDG | NA |
| SRD5A3 | SRD5A3-CDG | CDG-Iq |
| TMEM165 | TMEM165-CDG | CDG-IIk |
| TRIP11 | TRIP11-CDG | Achondrogenesis type 1A |
| TUSC3 | TUSC3-CDG | NA |
| Preliminary-evidence genes | ||
| ALG14 | ALG14-CDG | Myasthenic syndrome |
| B4GALT1 | B4GALT1-CDG | CDG-IId |
| DDOST | DDOST-CDG | CDG-Ir |
| NUS1 | NUS1-CDG | NA |
| RPN2 | RPN2-CDG | NA |
| SEC23A | SEC23A-CDG | Cranio-lenticulo-sutural dysplasia |
| SLC35A3 | SLC35A3-CDG | NA |
| ST3GAL3 | ST3GAL3-CDG | NA |
| STT3A | STT3A-CDG | CDG-Iw |
| STT3B | STT3B-CDG | CDG-Ix |
Clinical description
The congenital disorders of glycosylation (CDGs) are a group of rare disorders that result from a defect in one of the enzymes or transporters involved in the glycosylation of proteins and lipids. Because glycosylation pathways are shared among many proteins and lipids, these disorders often affect multiple organ systems in the body.
Patients with these disorders can have a wide range of symptoms, including developmental delay and intellectual disability, hypotonia, neurological findings (intractable seizures, brain MRI abnormalities such as atrophy and hypoplasia, stroke-like episodes, neuropathy), dysmorphic features (facial, inverted nipples, abnormal fat pads), coagulopathy, and eye abnormalities (optic atrophy, strabismus, retinitis pigmentosa). Some patients may also have features such as gastrointestinal issues, cardiomyopathy, and skeletal dysplasia. Almost any organ system can be affected. Variable expressivity has been observed in many of these disorders, even within families. The vast majority of patients identified to date have presented within the first year of life.
Most patients with defects in either type I or type II N-linked glycosylation will have abnormal patterns on transferrin isoelectric focusing. Patients with some types of O-linked glycosylation may have an abnormal pattern in ApoC-III isoelectric focusing.These assays are not able to determine the individual CDG, however, and some patients with confirmed CDGs have been reported with normal isoelectric focusing studies. Molecular studies are therefore needed to confirm a diagnosis.
Clinical sensitivity
The clinical sensitivity for this test is unknown. CDGs are clinically and genetically heterogeneous, and the percentage of patients with a CDG and pathogenic variants in one of the genes offered in this panel has not been determined.
Inheritance
Most CDGs exhibit an autosomal recessive inheritance pattern; however, a small number of CDGs, such as ALG13-CDG (CDG-Is), MGAT1-CDG, SLC35A2-CDG (CDG-IIm), and SSR4-CDG, are inherited in an X-linked manner.
Prevalence/Incidence
At this time, the prevalence of most individual congenital disorders of glycosylation and the combined prevalence are unknown due to the rarity of these disorders. A prevalence of 1 in 20,000 has been estimated for PMM2-CDG (CDG-Ia), the most common CDG (PMID:11701646).
Considerations for testing
This test may be considered for individuals with:
- early-onset multisystem disease
- patients with abnormal patterns on transferrin or ApoC-III isoelectric focusing
References
- Jaeken, J, Matthijs, G. Congenital disorders of glycosylation. Annu Rev Genomics Hum Genet. 2001; 2:129-51. PMID: 11701646
- Foulquier, F. COG defects, birth and rise!. Biochim. Biophys. Acta. 2009; 1792(9):896-902. PMID: 19028570
- Xia, B, et al. Serum N-glycan and O-glycan analysis by mass spectrometry for diagnosis of congenital disorders of glycosylation. Anal. Biochem. 2013; 442(2):178-85. PMID: 23928051
- Freeze, HH, et al. Neurological aspects of human glycosylation disorders. Annu. Rev. Neurosci. 2015; 38:105-25. PMID: 25840006
- Haeuptle, MA, Hennet, T. Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides. Hum. Mutat. 2009; 30(12):1628-41. PMID: 19862844
- Freeze, HH, et al. Solving glycosylation disorders: fundamental approaches reveal complicated pathways. Am. J. Hum. Genet. 2014; 94(2):161-75. PMID: 24507773
- Scott, K, et al. Congenital disorders of glycosylation: new defects and still counting. J. Inherit. Metab. Dis. 2014; 37(4):609-17. PMID: 24831587
- Sparks, SE, Krasnewich, DM. Congenital Disorders of N-linked Glycosylation Pathway Overview. 2005 Aug 15. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301507
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 |
|---|---|---|---|
| ALG1 | NM_019109.4 | ||
| ALG11 | NM_001004127.2 | ||
| ALG12 | NM_024105.3 | ||
| ALG13 | NM_001099922.2 | ||
| ALG14 | NM_144988.3 | ||
| ALG2 | NM_033087.3 | ||
| ALG3 | NM_005787.5 | ||
| ALG6 | NM_013339.3 | ||
| ALG8 | NM_024079.4 | ||
| ALG9 | NM_024740.2 | ||
| ATP6V0A2 | NM_012463.3 | ||
| B3GALNT2 | NM_152490.4 | ||
| B3GALT6 | NM_080605.3 | ||
| B3GAT3 | NM_012200.3 | ||
| B3GLCT | NM_194318.3 | ||
| B4GALNT1 | NM_001478.4 | ||
| B4GALT1 | NM_001497.3 | ||
| B4GALT7 | NM_007255.2 | ||
| B4GAT1 | NM_006876.2 | ||
| C1GALT1C1 | NM_001011551.2 | ||
| CHST14 | NM_130468.3 | ||
| CHST3 | NM_004273.4 | ||
| CHST6 | NM_021615.4 | ||
| CHSY1 | NM_014918.4 | ||
| COG1 | NM_018714.2 | ||
| COG2 | NM_007357.2 | ||
| COG4 | NM_015386.2 | ||
| COG5 | NM_006348.3 | ||
| COG6 | NM_020751.2 | ||
| COG7 | NM_153603.3 | ||
| COG8 | NM_032382.4 | ||
| DDOST | NM_005216.4 | ||
| DHDDS | NM_024887.3 | ||
| DOLK | NM_014908.3 | ||
| DPAGT1 | NM_001382.3 | ||
| DPM1 | NM_003859.1 | ||
| DPM2 | NM_003863.3 | ||
| DPM3 | NM_153741.1 | ||
| DSE | NM_013352.3 | ||
| EOGT | NM_173654.2 | ||
| EXT1 | NM_000127.2 | ||
| EXT2 | NM_207122.1 | ||
| FKRP | NM_024301.4 | ||
| FKTN* | NM_001079802.1 | ||
| G6PC3 | NM_138387.3 | ||
| GALNT3 | NM_004482.3 | ||
| GFPT1 | NM_001244710.1 | ||
| GMPPA | NM_205847.2 | ||
| GMPPB | NM_013334.3 | ||
| GNE | NM_001128227.2 | ||
| ISPD | NM_001101426.3 | ||
| LARGE1 | NM_004737.4 | ||
| LFNG | NM_001040167.1 | ||
| MAGT1 | NM_032121.5 | ||
| MAN1B1 | NM_016219.4 | ||
| MGAT2 | NM_002408.3 | ||
| MOGS | NM_006302.2 | ||
| MPDU1 | NM_004870.3 | ||
| MPI | NM_002435.2 | ||
| NGLY1 | NM_018297.3 | ||
| NUS1 | NM_138459.3 | ||
| PAPSS2 | NM_001015880.1 | ||
| PGM1 | NM_002633.2 | ||
| PGM3 | NM_001199917.1 | ||
| PIGA | NM_002641.3 | ||
| PIGL | NM_004278.3 | ||
| PIGM | NM_145167.2 | ||
| PIGN | NM_176787.4 | ||
| PIGO | NM_032634.3 | ||
| PIGQ | NM_004204.3 | ||
| PIGT | NM_015937.5 | ||
| PIGV | NM_017837.3 | ||
| PIGW | NM_178517.3 | ||
| PMM2 | NM_000303.2 | ||
| POFUT1 | NM_015352.1 | ||
| POGLUT1 | NM_152305.2 | ||
| POMGNT1 | NM_017739.3 | ||
| POMGNT2 | NM_032806.5 | ||
| POMK | NM_032237.4 | ||
| POMT1 | NM_007171.3 | ||
| POMT2 | NM_013382.5 | ||
| RFT1 | NM_052859.3 | ||
| RPN2 | NM_002951.4 | ||
| RXYLT1 | NM_014254.2 | ||
| SEC23A | NM_006364.3 | ||
| SEC23B | NM_006363.4 | ||
| SLC26A2* | NM_000112.3 | ||
| SLC35A1 | NM_006416.4 | ||
| SLC35A2 | NM_001042498.2 | ||
| SLC35A3 | NM_012243.2 | ||
| SLC35C1 | NM_018389.4 | ||
| SLC35D1 | NM_015139.2 | ||
| SRD5A3 | NM_024592.4 | ||
| SSR4 | NM_001204526.1 | ||
| ST3GAL3 | NM_006279.3 | ||
| ST3GAL5 | NM_003896.3 | ||
| STT3A | NM_001278503.1 | ||
| STT3B | NM_178862.2 | ||
| TMEM165 | NM_018475.4 | ||
| TRIP11 | NM_004239.4 | ||
| TUSC3 | NM_006765.3 | ||
| XYLT1 | NM_022166.3 |
FKTN: Analysis includes the intronic variant NM_001079802.1:c.647+2084G>T (also known as NM_001079802.1:c.648-1243G>T) and the ~3 kb retrotransposon insertion in the 3' UTR at position NM_001079802.1:c.*4392_*4393.
SLC26A2: Analysis includes the intronic variant NM_000112.3:c.-26+2T>C.
Resources
References
- Foulquier, F. COG defects, birth and rise!. Biochim. Biophys. Acta. 2009; 1792(9):896-902. PMID: 19028570
- Freeze, HH, et al. Neurological aspects of human glycosylation disorders. Annu. Rev. Neurosci. 2015; 38:105-25. PMID: 25840006
- Freeze, HH, et al. Solving glycosylation disorders: fundamental approaches reveal complicated pathways. Am. J. Hum. Genet. 2014; 94(2):161-75. PMID: 24507773
- Haeuptle, MA, Hennet, T. Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides. Hum. Mutat. 2009; 30(12):1628-41. PMID: 19862844
- Jaeken, J, Matthijs, G. Congenital disorders of glycosylation. Annu Rev Genomics Hum Genet. 2001; 2:129-51. PMID: 11701646
- Scott, K, et al. Congenital disorders of glycosylation: new defects and still counting. J. Inherit. Metab. Dis. 2014; 37(4):609-17. PMID: 24831587
- Sparks, SE, Krasnewich, DM. Congenital Disorders of N-linked Glycosylation Pathway Overview. 2005 Aug 15. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301507
- Xia, B, et al. Serum N-glycan and O-glycan analysis by mass spectrometry for diagnosis of congenital disorders of glycosylation. Anal. Biochem. 2013; 442(2):178-85. PMID: 23928051
