Exome Complete: Hereditary Hemorrhagic Telangiectasia and Other Vascular Diseases

Clinical information

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease, is a genetic disorder that causes an alteration in blood vessels leading to excessive bleeding. Specifically, it affects the development of blood vessels resulting in abnormal connections known as arteriovenous malformations, which form between arteries and veins. The most affected organs include the lips, nose, tongue, and fingertips. However, they can also develop in the lungs, brain, and liver. The most prominent manifestation of this condition is often the presence of spontaneous and unexplained nosebleeds, sometimes occurring daily.

The genetic study of these pathologies provides crucial information for establishing an accurate diagnosis and 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 particularly indicated in cases of diseases with different candidate genes or with a phenotype lacking a clear genetic basis.

Diagnostic utility

Identifying genetic variants associated with the 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 total blood, through hybridization of specific probes. This test allows for the sequencing of the entire human exome, which comprises the protein-coding genomic regions (exons) and the flanking intronic regions of all genes. Subsequently, a virtual gene panel selected based on the study pathology (see gene panel section) is used to limit and focus the genetic analysis on those genes related to the patient's phenotype.

Especially in the study of complex phenotypes or in cases of difficult evaluation 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 inheritance of the disease.

Finally, the candidate mutation(s) detected by NGS are confirmed by traditional Sanger sequencing to obtain an unequivocal result. It will likely be necessary to design specific primers to analyse the specific region where the variant is located.

If no candidate mutation likely to be causative (or potentially causative) of the pathology is identified, it will be reported and discussed with the requesting medical team regarding the possibility of conducting complementary studies.

Gene panel

The genetic study of HHT and other similar vasculopathies analyses 16 genes. The genes in the panel have been carefully selected from scientific literature, mutation databases, and personal experience. It is worth noting 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 not included in the virtual panel that may be related to specific clinical characteristics can be analysed. This is possible thanks to the complete exome sequencing.

Limitations

This test does not detect:

• Structural variants such as complex inversions
• Genetic conversions
• Balanced translocations
• Repetitive nucleotide expansions
• Variants in deep intronic regions

This test may not reliably detect:

• Indels larger than 50 bp
• Single exon deletions or duplications
• Variants within pseudogene/duplicated segment regions

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 essential volume: 3 ml

Stability:

• At room temperature: 4 days
• In refrigeration: 10 days

Transport instructions: Preferably at room temperature

Reasons 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 consult sample collection specifications

Administrative information

BST Code: LRD2829

Test Description: Whole Exome Study

Synonyms: Whole exome sequencing, WES, molecular study of genetically based diseases.

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 you want to study the whole exome, and fill in (attach) the available phenotypic data.

References

• Centers for Disease Control and Prevention website. Blood disorders: facts about hereditary hemorrhagic telangiectasia (HHT). www.cdc.gov/ncbddd/hht/. Updated April 28, 2023. Accessed May 1, 2023.
• Cappell MS, Lebwohl O. Hereditary hemorrhagic telangiectasia. In: Lebwohl MG, Heymann WR, Coulson IH, Murrell DF, eds. Treatment of Skin Disease. 6th ed. Philadelphia, PA: Elsevier; 2022:chap 102.
• 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