Genetic testing for hereditary hemorrhagic telangiectasia
Article Category: Technical Report
Published Online: Sep 19, 2018
Page range: 32 - 34
DOI: https://doi.org/10.2478/ebtj-2018-0031
Keywords
© 2018 Yeltay Rakhmanov, Paolo Enrico Maltese, Stefano Paolacci, Carla Marinelli, Raul Ettore Mattassi, Bruno Amato, Tommaso Beccari, Munis Dundar, Matteo Bertelli, published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.
(Other synonyms: Telangiectasia, hereditary hemorrhagic, type 1; telangiectasia, hereditary hemorrhagic of Rendu, Osler and Weber; telangiectasia, hereditary hemorrhagic, type 2; juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome)
Hereditary haemorrhagic telangiectasia (HHT) can be subdivided in hereditary hemorrhagic telangiectasia, type 1 (OMIM disease 187300), and type 2 (OMIM disease 600376), juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (OMIM disease 175050). All these conditions are characterized by recurrent epistaxis, cutaneous telangiectasia, and visceral arteriovenous malformations (AVMs) that affect the lungs, gastrointestinal tract, liver, brain and other internal organs (1).
The population prevalence rate varies according to different authors. Porteus et al. (2) documented a minimum prevalence of 1 in 40000. Bideau et al. (3) reported a higher prevalence of HHT cases (1/2300) in an isolated French valley. HHT has autosomal dominant inheritance with incomplete penetrance, and sporadic cases due to
HHT appears with nosebleeds, and telangiectases on the lips, hands and oral mucosa. Telangiectases in the nasal and gastrointestinal mucosa, and brain arteriovenous malformations generally present with bleeding (6).
Clinical diagnosis of HHT is established when three out of four Curaçao’s diagnostic criteria are met. These criteria are: 1) recurrent spontaneous mild to severe epistaxis; 2) multiple mucocutaneous telangiectases; 3) AVMs or telangiectases in internal organs, such as lungs, brain, liver, intestines, stomach and spinal cord; 4) more than one affected family member (7).
The differential diagnosis should consider von Willebrand disease, ataxia-telangiectasia, calcinosis, Raynaud phenomenon, sclerodactyly, telangiectasia syndrome, capillary malformation-arteriovenous malformation and hereditary benign telangiectasia.
Identification of a heterozygous pathogenic variant in
All these genes are involved in the transforming growth factor beta/bone morphogenetic protein (TGF-beta/BMP) pathway.
Pathogenic variants may include missense, nonsense, splicing, small insertions, small deletions, small indels, gross deletions, duplications.
To determine the gene defect responsible for the disease;
To confirm clinical diagnosis;
To assess the recurrence risk and perform genetic counselling for at-risk/affected individuals.
The test is listed in the Orphanet database and is offered by 24 accredited medical genetic laboratories in the EU, and in the GTR database, offered by 18 accredited medical genetic laboratories in the US.
Guidelines for clinical use of the test are described in Genetics Home Reference (
A multi-gene next generation sequencing panel is used for the detection of nucleotide variations in coding exons and flanking introns of the above genes. Potentially causative variants and region with low coverage are Sanger-sequenced. Sanger sequencing is also used for family segregation studies.
Multiplex Ligation Probe Amplification (MLPA) is used to detect insertions and deletions in
To perform molecular diagnosis, a single sample of biological material is normally sufficient. This may be 1 ml peripheral blood in a sterile tube with 0.5 ml K3EDTA or 1 ml saliva in a sterile tube with 0.5 ml ethanol 95%. Sampling rarely has to be repeated.
Gene-disease associations and the interpretation of genetic variants are rapidly developing fields. It is therefore possible that the genes mentioned in this note may change as new scientific data is acquired. It is also possible that genetic variants today defined as of “unknown or uncertain significance” may acquire clinical importance.
Identification of pathogenic variants in the above genes confirms the clinical diagnosis and is an indication for family studies.
A pathogenic variant is known to be causative for a given genetic disorder based on previous reports, or predicted to be causative based on loss of protein function or expected significant damage to proteins or protein/protein interactions. In this way it is possible to obtain a molecular diagnosis in new/other subjects, establish the risk of recurrence in family members and plan preventive and/or therapeutic measures.
Detection of a variant of unknown or uncertain significance (
The absence of variations in the genomic regions investigated does not exclude a clinical diagnosis but suggests the possibility of:
lterations that cannot be identified by sequencing, such as large rearrangements that cause loss (deletion) or gain (duplication) of extended gene fragments;
sequence variations in gene regions not investigated by this test, such as regulatory regions (5’ and 3’ UTR) and deep intronic regions;
variations in other genes not investigated by the present test.
Unexpected results may emerge from the test, for example information regarding consanguinity, absence of family correlation or other genetically-based diseases.
In autosomal dominant transmission, the probability that an affected carrier transmit the variant to his/her children is 50% in any pregnancy, irrespective of the sex of the child conceived.
The test is limited by current scientific knowledge regarding the gene and disease.
NGS Analytical sensitivity >99.99%, with a minimum coverage of 10X; Analytical specificity 99.99%.
SANGER Analytical sensitivity >99.99%; Analytical specificity 99.99%.
MLPA Analytical sensitivity >99.99%; Analytical specificity 99.99%.
Clinical sensitivity: it is reported that the mutation detection rate for
Clinical specificity: Data not available
The genetic test is appropriate when:
the patient meets the diagnostic criteria for HHT;
the sensitivity of the test is greater than or equal to that of tests described in the literature.
| Clinical management | Utility |
|---|---|
| Confirmation of clinical diagnosis | Yes |
| Differential diagnosis | Yes |
| Couple risk assessment | Yes |
| Availability of clinical trials can be checked on-line at | |