Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a genetically heterogeneous disorder, involving mutations in two predominant genes known as Endoglin (ENG; HHT1) and activin receptor-like kinase 1 (ACVRL1/ALK1; HHT2), as well as in some less frequent genes, such as MADH4/SMAD4 (JP-HHT) or BMP9/GDF2 (HHT5). The diagnosis of HHT patients currently remains at the clinical level, according to the “Curaçao criteria,” whereas the molecular diagnosis is used to confirm or rule out suspected HHT cases, especially when a well characterized index case is present in the family or in an isolated population. Unfortunately, many suspected patients do not present a clear HHT diagnosis or do not show pathogenic mutations in HHT genes, prompting the need to investigate additional biomarkers of the disease. Here, several HHT biomarkers and novel methodological approaches developed during the last years will be reviewed. On one hand, products detected in plasma or serum samples: soluble proteins (vascular endothelial growth factor, transforming growth factor β1, soluble endoglin, angiopoietin-2) and microRNA variants (miR-27a, miR-205, miR-210). On the other hand, differential HHT gene expression fingerprinting, next generation sequencing of a panel of genes involved in HHT, and infrared spectroscopy combined with artificial neural network patterns will also be reviewed. All these biomarkers might help to improve and refine HHT diagnosis by distinguishing from the non-HHT population.
Highlights
Hereditary hemorrhagic telangiectasia (HHT; OMIM 187300), or Rendu–Osler–Weber syndrome, is an inherited autosomal dominant disease affecting 1 in 5,000 individuals as assessed in several human populations (Shovlin, 2010)
The disease is characterized by abnormal vascular structures, which lead to epistaxis, telangiectases, and anemia as well as visceral arteriovenous malformations (AVMs) in the lung, brain, and liver
The first genes identified as mutated in HHT patients, were Endoglin (ENG), located on chromosome 9q33-34, causing HHT1 (Fernández-Ruiz et al, 1993; McAllister et al, 1994) and ACVRL1/ALK1, that causes HHT2 (Johnson et al, 1995, 1996)
Summary
Luisa-María Botella 1,2*, Virginia Albiñana 1, Luisa Ojeda-Fernandez 1,2, Lucia Recio-Poveda 1 and Carmelo Bernabéu 1,2. Many suspected patients do not present a clear HHT diagnosis or do not show pathogenic mutations in HHT genes, prompting the need to investigate additional biomarkers of the disease. Differential HHT gene expression fingerprinting, generation sequencing of a panel of genes involved in HHT, and infrared spectroscopy combined with artificial neural network patterns will be reviewed. All these biomarkers might help to improve and refine HHT diagnosis by distinguishing from the non-HHT population
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