Hereditary hemorrhagic telangiectasia: Breakpoint characterization of a novel large deletion in ACVRL1 suggests the causing mechanism

Laura Boeri, Orietta Radi, Cecilia Canzonieri, Elisabetta Buscarini, Agnese Scatigno, Antonella Minelli, Federica Ornati, Fabio Pagella, Cesare Danesino, Carla Olivieri

Research output: Contribution to journalArticle

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia. Mutations in either ENG or ACVRL1 account for around 85% of cases, and 10% are large deletions and duplications. Here we present a large novel deletion in ACVRL1 gene and its molecular characterization in a 3 generation Italian family. We employed short tandem repeats (STRs) analysis, direct sequencing, multiplex ligation-dependant probe amplification (MLPA) analysis, and 'deletion-specific' PCR methods. STRs Analysis at ENG and ACVRL1 loci suggested a positive linkage for ACVRL1. Direct sequencing of this gene did not identify any mutations, while MLPA identified a large deletion. These results were confirmed and exactly characterized with a 'deletion-specific' PCR: the deletion size is 4,594 bp and breakpoints in exon 3 and intron 8 show the presence of short direct repeats of 7 bp [GCCCCAC]. We hypothesize, as causative molecular mechanism, the replication slippage model. Understanding the fine mechanisms associated with genomic rearrangements may indicate the nonrandomness of these events, highlighting hot spots regions. The complete concordance among MLPA, STRs analysis and 'deletion-specific PCR' supports the usefulness of MLPA in HHT molecular analysis.

Original languageEnglish
Pages (from-to)119-124
Number of pages6
JournalMolecular Syndromology
Volume4
Issue number3
DOIs
Publication statusPublished - Mar 2013

Keywords

  • ACVRL1
  • Large deletion
  • MLPA
  • Short direct repeats
  • Slippage

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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