Open Access Highly Accessed Research article

Copy number variations in endoglin locus: mapping of large deletions in Spanish families with hereditary hemorrhagic telangiectasia type 1

Ana Fontalba1, Jose L Fernández-Luna1, Roberto Zarrabeitia2, Lucia Recio-Poveda3, Virginia Albiñana3, Maria L Ojeda-Fernández3, Carmelo Bernabéu3, Luis A Alcaraz4 and Luisa M Botella3*

Author Affiliations

1 Molecular Genetics Unit, Hospital Valdecilla, and Instituto de Formación e Investigación Marqués de Valdecilla (IFIMAV), Santander, Spain

2 HHT Spanish Unit, Hospital Sierrallana and Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Torrelavega, Santander, Spain

3 Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

4 Bioarray S.L, Crevillente, Alicante, Spain

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BMC Medical Genetics 2013, 14:121  doi:10.1186/1471-2350-14-121

Published: 25 November 2013



The 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).


We 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.


All 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.


The 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.

Hereditary hemorrhagic telangiectasia (HHT); Endoglin deletions; Multiplex ligation PCR assisted assay (MLPA); Copy number variation (CNV) arrays; Alu repetitive sequences