Clinical information
Congenital disorders of glycosylation (CDG) are a genetically and clinically heterogeneous group that includes more than 100 pathologies caused by mutations in genes encoding enzymes involved in the glycosylation process. This process involves the addition of sugar blocks, called glycans, to proteins and lipids in cells throughout the body. Broadly speaking, CDG is currently classified into four categories: (I) N-glycosylation of proteins, (II) O-linked protein glycosylation, (III) Combined N- and O-linked glycosylation, and (IV) Defect in lipid and glycosylphosphatidylinositol (GPI) biosynthesis. Typically, they present with multisystemic manifestations, more frequently developmental delay, growth failure, hypotonia, neurological abnormalities, hepatopathy, and coagulopathy.
The genetic study of these pathologies provides crucial information for establishing a precise diagnosis and accurate classification. Additionally, it allows for genetic counselling, improves the prognosis and management of these patients, and contributes to research and the development of therapies.
Study indication
Confirmation of clinical or analytical suspicion of the pathology. This test is especially indicated in cases of diseases with different candidate genes or with a phenotype lacking a clear genetic basis.
Diagnostic utility
Identify genetic variants related to clinical suspicion of a hereditary bleeding disorder.
Method
Whole exome sequencing (WES) for the identification of pathogenic variants. WES study is based on the capture of fragmented DNA, derived from whole blood, through hybridization of specific probes. This test allows the sequencing of the entire human exome, comprising coding genomic regions (exons) for proteins and the flanking intronic regions of all genes. Subsequently, a virtual gene panel selected according to the pathology under study (see gene panel section) is used to limit and focus genetic analysis on those genes related to the patient's phenotype.
Especially in the study of complex phenotypes or in the case of a difficult assessment of identified variants, trio analysis (patient and two direct family members) is recommended. This strategy can simplify and strengthen the analyses, providing information on the heredity of the disease.
Finally, the candidate mutation(s) detected by NGS are verified by traditional Sanger sequencing to reach an unequivocal result. Design of specific primers to analyse the specific region where the variant is located will likely be necessary.
If no candidate mutation potentially causing the pathology is identified, additional studies may be considered and discussed with the requesting medical team.
Gene panel
The genetic study of CDG analyses 141 genes. The genes in the panel have been carefully selected based on scientific literature, mutation databases, and personal experience. It is important to highlight that this panel is periodically updated based on current knowledge, allowing for modification of the selection of candidate genes and reanalysis of results. However, at the request of the responsible physician, other genes that are not part of the virtual panel and may be related to specific clinical characteristics can be analysed. This is possible thanks to complete exome sequencing.
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Congenital disorders of glycosylation |
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ALDOB |
B4GAT1 |
EOGT |
MAGT1 |
PIGT |
SLC35C1 |
Limitations
This test does not detect:
- Complex structural variants such as complex inversions
- Genetic conversions
- Balance translocations
- Repetitive expansions of nucleotides
- Variants in deep intronic regions
This test may not reliably detect:
- Indels greater than 50 bp
- Deletions or duplications of single exons
- Variants within pseudogene regions/duplicated segments
Reference values
Not applicable
Diagnostic algorithm
Not applicable
Turnaround time
8 weeks
Specimen information
Sample: Whole blood
Tube: EDTA K3 tube 5-10 ml if it is a blood sample
Minimum necessary volume: 3 ml
Stability:
- At room temperature: 4 days
- In refrigeration: 10 days
Transport instructions: Preferably at room temperature
Reason for rejection: Coagulated sample and/or incorrectly identified
Other types of accepted samples:
- Purified DNA: minimum 300 ng (30 ng/μL). The recommended volume is a minimum of 60 μl
- Buccal mucosa: contact the laboratory to inquire about collection specifications
Administrative information
BST Code: LRD2829
Test Description: Whole Exome Study
Synonyms: Complete exome sequencing, WES, genetic-based disease molecular study.
Section: Congenital Coagulopathies
BST Rate: Check the updated rates by clicking here.
On the molecular study request form, the Other box must be checked, specifying that the whole exome study is requested, and filling in (attaching) the available phenotypic data.
References
- https://www.mayoclinic.org/es/departments-centers/clinical-genomics/overview/specialty-groups/cdg-clinic
- Francisco R, Brasil S, Poejo J, Jaeken J, Pascoal C, Videira PA, Dos Reis Ferreira V. Congenital disorders of glycosylation (CDG): state of the art in 2022. Orphanet J Rare Dis. 2023 Oct 19;18(1):329. doi: 10.1186/s13023-023-02879-z. PMID: 37858231; PMCID: PMC10585812.
- Protocolo Nextera Flex for Enrichment Reference Guide (1000000048041) de Illumina.
Base de dades de mutacions
- Human Gene Mutation Database: http://www.hgmd.cf.ac.uk
- Leiden Open Variation Database: https://databases.lovd.nl/shared/genes
- Genome Aggregation Database: https://gnomad.broadinstitute.org
- 1000 Genomes Database: https://www.internationalgenome.org