Hereditary hemorrhagic telangiectasia panel
Hereditary hemorrhagic telangiectasia (HHT) is a rare inherited disorder characterized by the presence of multiple arteriovenous malformations that lack intervening capillaries and result in direct connections between arteries and veins. The most common clinical manifestation is epistaxis (spontaneous and recurrent nosebleeds) with childhood onset.
Incidence 1:10,000 1, 2
Major clinical symptoms:
- Epistaxis (nosebleeds), spontaneous and recurrent.
- Mucocutaneous telangiectases
- Visceral arteriovenous malformation (AVM)
Less common clinical symptoms:
- Pulmonary AVMs resulting in transient ischemic attacks, embolic stroke, cerebral and other abscesses 3
- Cerebral AVMs 4
- Hepatic vascular abnormalities 5
- Pulmonary hypertension
- Presence of ≥3 of the following clinical features:
- Mucocutaneous telangiectases
- Visceral AVMs and/or
- A family history of HHT
- Identification of a heterozygous pathogenic variant in one of the following genes:
- Anemia treatment
- Prevention and treatment of epistaxis
- Management of AVM (early detection and occlusion)
- Liver transplantation in some cases
- Antiangiogenic drugs (thalidomide and anti-VEGF antibodies)
- von Willebrand disease and other bleeding diatheses, caused by pathogenic variants in VWF and GP1BA
- Ataxia-telangiectasia, caused by pathogenic variants in ATM
- Hereditary benign telangiectasia
- CRST (calcinosis, Raynaud phenomenon, sclerodactyly, telangiectasia) syndrome
- Capillary malformation-arteriovenous malformation (CM-AVM), caused by pathogenic variants in RASA1, GNAQ, CCM1 and other genes
To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for HHT using NGS Panel Genomic targeted towards this specific phenotype:
Step 1: Whole genome sequencing from a single filter card (drop of blood). The sequencing covers the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the HHT panel. Copy Number Variants analysis derived from NGS data is also included.
Step 2: If no pathogenic variant is identified after analysis of the HHT panel, we further recommend to continue the bioinformatics analysis of the data obtained by whole genome sequencing to cover genes that are either implicated in an overlapping phenotype or could be involved in a similar pathway but not strongly clinically implicated based on the current information in literature.
- Individuals with a family history of HHT and presentation of the most common symptoms such as night nosebleeds and mucocutaneous telangiectases.
- Individuals without a positive family history of HHT, but with symptoms resembling HHT.
- Individuals with a negative but suspected family history of HHT.
Sequencing, deletion/duplication of HHT-associated genes should be performed in all individuals suspected for HHT. In parallel, other genes reported to be related with HHT should also be analyzed for the presence of pathogenic variants, due to the overlap in many clinical features. Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of HHT, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.
Overview of genes included in the HHT panel
|Gene (OMIM)||Disease (OMIM)||Gene product||Gene location||Frequency of associated pathogenic variants|
|ACVRL1 (601284)||HHT2 (600376)||Activin A receptor 1||12q13.13||25%-57% for HTT 6, 7|
|ADAM17 (603639)||Inflammatory skin and bowel disease, neonatal, 1 (614328)||Tumor necrosis factor-alpha converting enzyme||2p25.1||Reported for HTT 10|
|ENG (131195)||HHT1 (187300)||Endoglin||9q34.11||39%-59% for HTT 6, 7|
|GDF2 (605120)||HHT5 (615506)||Growth/differentiation factor 2||10q11.22||Reported for HTT 9|
|PTPN14 (603155)||Choanal atresia and lymphedema (613611)||Protein-tyrosine phosphatase 14||1q32-q41||Few families with HTT 11|
|RASA1 (139150)||Capillary malformation-arteriovenous malformation (608354); Parkes Weber syndrome (608355); |
Basal cell carcinoma, somatic (605462)
|Ras p21 protein activator 1||5q14.3||One patient with HTT 12|
|SMAD4 (600993)||Juvenile polyposis/HHT syndrome (175050);Myhre syndrome (139210); Pancreatic cancer, somatic (260350); Polyposis, juvenile intestinal (174900)||SMA- and MAD-related protein 4||18q21.2||1%-2% for HTT 6-8 27% for juvenile polyposis 13 55/55 for Myhre Syndrome14|