title: Copy number variations in endoglin locus: mapping of large deletions in Spanish families with hereditary hemorrhagic telangiectasia type 1.
abstract: BACKGROUND
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain. cibluisa@cib.csic.es.
authors.forename: Ana
authors.initials: A
authors.lastname: Fontalba
authors.forename: Jose L
authors.initials: JL
authors.lastname: Fernández-Luna
authors.forename: Roberto
authors.initials: R
authors.lastname: Zarrabeitia
authors.forename: Lucia
authors.initials: L
authors.lastname: Recio-Poveda
authors.forename: Virginia
authors.initials: V
authors.lastname: Albiñana
authors.forename: Maria L
authors.initials: ML
authors.lastname: Ojeda-Fernández
authors.forename: Carmelo
authors.initials: C
authors.lastname: Bernabéu
authors.forename: Luis A
authors.initials: LA
authors.lastname: Alcaraz
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Botella
mesh_terms: D015703:Antigens, CD / Q000235:genetics*; D002874:Chromosome Mapping; D042863:Cyclin-Dependent Kinase 9 / Q000235:genetics; D056915:DNA Copy Number Variations; D000071063:Endoglin; D005091:Exons; D017353:Gene Deletion; D056726:Genetic Association Studies; D056426:Genetic Loci; D005838:Genotype; D006801:Humans; D060885:Multiplex Polymerase Chain Reaction; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics*; D013030:Spain; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics* / Q000473:pathology; D044465:White People / Q000235:genetics*
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D042863:Cyclin-Dependent Kinase 9