Abstract
BackgroundThe hereditary hemorrhagic telangiectasia syndrome (HHT), also known as the Rendu–Osler-Weber syndrome is a multiorganic vascular disorder inherited as an autosomal dominant trait. Diagnostic clinical criteria include: epistaxis, telangiectases in mucocutaneous and gastrointestinal sites, arteriovenous malformations (AVMs) most commonly found in pulmonary, hepatic and cerebral circulations, and familial inheritance. HHT is transmitted in 90% of the cases as an autosomal dominant condition due to mutations in either endoglin (ENG), or activin receptor-like kinase 1 (ACVRL1/ALK1) genes (HHT type 1 and 2, respectively).MethodsWe have carried out a genetic analysis of four independent Spanish families with HHT clinical criteria, which has permitted the identification of new large deletions in ENG. These mutations were first detected using the MLPA technique and subsequently, the deletion breakpoints were mapped using a customized copy number variation (CNV) microarray. The array was designed to cover the ENG gene and surrounding areas.ResultsAll tested families carried large deletions ranging from 3-kb to 100-kb, involving the ENG gene promoter, several ENG exons, and the two downstream genes FGSH and CDK9. Interestingly, common breakpoints coincident with Alu repetitive sequences were found among these families.ConclusionsThe systematic hybridization of DNA from HHT families, with deletions or duplications, to custom designed microarrays, could allow the mapping of breakpoints, coincident with repetitive Alu sequences that might act as “hot spots” in the development of chromosomal anomalies.
Highlights
The hereditary hemorrhagic telangiectasia syndrome (HHT), known as Rendu–Osler-Weber syndrome [1,2,3] is a vascular disorder inherited as an autosomal dominant trait
HHT is transmitted as an autosomal dominant condition due to a single mutation in Endoglin (ENG; HHT1) [7], Activin Receptor-Like Kinase 1 (ACVRL1/ALK1; HHT2) [8], or MADH4/SMAD4 (JHPT, a combined syndrome of juvenile polyposis and HHT) [9]
Correlation between the presence of deletions in ENG and the clinical phenotype Table 1 shows the clinical symptoms and genetics of HHT patients belonging to 4 independent families
Summary
The hereditary hemorrhagic telangiectasia syndrome (HHT), known as the Rendu–Osler-Weber syndrome is a multiorganic vascular disorder inherited as an autosomal dominant trait. HHT is transmitted in 90% of the cases as an autosomal dominant condition due to mutations in either endoglin (ENG), or activin receptor-like kinase 1 (ACVRL1/ALK1) genes (HHT type 1 and 2, respectively). The hereditary hemorrhagic telangiectasia syndrome (HHT), known as Rendu–Osler-Weber syndrome [1,2,3] is a vascular disorder inherited as an autosomal dominant trait. The clinical symptoms characteristic of HHT are the so-called Curaçao criteria [2], which help in its diagnosis when at least 3 of the 4 criteria are present in a patient These include: epistaxis (nose bleeds), telangiectasia at mucocutaneous and gastrointestinal sites, arteriovenous malformations (AVMs) most commonly found in pulmonary, hepatic and cerebral circulations, and dominant familial inheritance [3,6]. There are at least two further unidentified genes that can cause HHT: HHT3 between 141.9 and 146.4 Mb on chromosome 5q [3,11] and HHT4 on chromosome 7p between D7S2252 and D7S510.130 [12]
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