Hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia
[12 genes]

– Rendu-Osler-Weber syndrome –

Includes:

  • The two priority genes encompassing most mutations that have been identified in connection with HHT: the ENG (defines HHT type 1, more related to pulmonary arteriovenous fistulas) and ACVRL1 (defines HHT type 2, with higher frequency of liver involvement) genes.
  • Other priority genes are SMAD4 and BMPR1A, which determine an HHT affectation associated with juvenile colonic polyposis syndrome.
  • Other secondary genes are SMAD1, GDF2 (BMP9), BMP10, BMPR2, RASA1, EPHB4, ELMO2, and TEK (TIE2).
Informed consent
ENGACVRL1SMAD4BMPR1ASMAD1GDF2 (BMP9)BMP10BMPR2RASA1EPHB4
ELMO2TEK (TIE2)
Hereditary hemorrhagic telangiectasia panel

Includes:

  • The two priority genes encompassing most mutations that have been identified in connection with HHT: the ENG (defines HHT type 1, more related to pulmonary arteriovenous fistulas) and ACVRL1 (defines HHT type 2, with higher frequency of liver involvement) genes.
  • Other priority genes are SMAD4 and BMPR1A, which determine an HHT affectation associated with juvenile colonic polyposis syndrome.
  • Other secondary genes are SMAD1, GDF2 (BMP9), BMP10, BMPR2, RASA1, EPHB4, ELMO2, and TEK (TIE2).
Informed consent
ENGACVRL1SMAD4BMPR1A
SMAD1GDF2 (BMP9)BMP10BMPR2
RASA1EPHB4ELMO2TEK (TIE2)
Nota genes
NOTES ON GENES
-> Priority genes: Genes where there is sufficient evidence (clinical and functional) to consider them as associated with the disease; they are included in clinical practice guidelines. -> Secondary genes: Genes related to the disease but with a lower level of evidence
or constituting sporadic cases. -> * Candidate genes: Without sufficient evidence in humans but potentially associated with the disease.
  • Patients meeting any of the four Curaçao criteria that define the disease: 1) spontaneous recurrent epistaxis, 2) cutaneous or mucosal telangiectasias, 3) visceral AVMs, or 4) first-degree relatives with those characteristics.
  • It is especially useful in patients with probable (two Curaçao criteria present) or unlikely (less than two criteria present) diagnosis, as well as in patients with an atypical presentation of the disease, which could suggest a mutation in genes other than ENG or ACVRL1.
  • Genetic testing can help to confirm or rule out the clinical diagnosis in these individuals.
  • In addition, knowing the molecular diagnosis of the disease may provide information about prognosis, appropriate type of monitoring, and management of the disease.
  • Identifying the causal mutation is also useful for familial genetic screening, allowing for the early detection of affected patients, which can help selecting the appropriate clinical study and follow-up.
  • Finally, identifying the causal mutation allows for preimplantation genetic diagnosis, i.e. detecting said mutation in embryos prior to their implantation in order to prevent disease in the progeny.
  • International guidelines for the diagnosis and management of Hereditary Hemorrhagic Telangiectasia. J Med Genet 2011;48:73-87.
  • McDonald J, et al. Hereditary Hemorrhagic Telangiectasia: genetics and molecular diagnostics in a new era. Front Genet 2015;6:1-8.
  • Hernandez F, et al. Mutations in RASA1 and GDF2 identified in patients with clinical features of Hereditary Hemorrhagic Telangiectasia. Hum Genome Var. 2015;2:15040.

The performance of this panel is optimal for genetic confirmation of HHT and increases with the number of clinical criteria for the disease met by the patient. The probability of detecting a mutation in the ENG or ACVRL1 genes is estimated to be over 85% in patients who meet the four Curaçao criteria. However, other secondary genes need to be considered in those patients who do not meet all of these criteria or in those with an atypical presentation, e.g. without epistaxis.

The current test panel includes all these priority genes, as well as secondary genes. Among those considered priority genes, with the highest level of evidence for HHT, are ENG and ACVRL1. Also included as priority genes are SMAD4 and BMPR1A. Secondary genes include, among others, RASA1 and EPHB4, which are causative for capillary malformation-arteriovenous malformation syndromes 1 and 2 (CM-AVM1 and CM-AVM2), respectively, and whose mutations have been described to cause a clinical picture overlapping with and clinically indistinguishable from HHT. Mutations in these genes are detected through next generation sequencing (NGS), which is the currently recommended technique and which can also detect previously undescribed mutations. The results of the genetic testing are reported along with information from cases with the identified mutation described in the literature, which contribute to its clinical interpretation. Therefore, both the clinical setting and the familial cosegregation study provide essential information to support the pathological role of the detected mutation.

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