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Genome sequencing reveals a deep intronic splicing ACVRL1 mutation hotspot in Hereditary Haemorrhagic Telangiectasia
  1. Whitney L. Wooderchak-Donahue1,2,
  2. Jamie McDonald2,3,
  3. Andrew Farrell4,
  4. Gulsen Akay1,5,
  5. Matt Velinder4,
  6. Peter Johnson1,
  7. Chad VanSant-Webb1,
  8. Rebecca Margraf1,
  9. Eric Briggs1,
  10. Kevin J Whitehead3,6,
  11. Jennifer Thomson7,
  12. Angela E Lin8,
  13. Reed E Pyeritz9,
  14. Gabor Marth4,
  15. Pinar Bayrak-Toydemir1,2
  1. 1ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, Salt Lake City, USA
  2. 2Department of Pathology, University of Utah, Salt Lake City, Utah, USA
  3. 3HHT Center, Department of Radiology, University of Utah, Salt Lake City, Utah, USA
  4. 4USTAR Center for Genetic Discovery, University of Utah, Salt Lake City, Utah, USA
  5. 5Department of Pediatric Genetics, Zeynep Kamil Maternity and Children’s Training and Research Hospital, Istanbul, Turkey
  6. 6Division of Cardiovascular Medicine, Department of Medicine, University of Utah, Salt Lake City, Utah, USA
  7. 7Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, UK
  8. 8Medical Genetics, Department of Pediatrics, Mass General Hospital for Children, Boston, Massachusetts, USA
  9. 9Department of Internal Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  1. Correspondence to Dr Pinar Bayrak-Toydemir, Molecular Genetics Department, ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT 84108, USA; pinar.bayrak-toydemir{at}


Introduction Hereditary haemorrhagic telangiectasia (HHT) is a genetically heterogeneous disorder caused by mutations in the genes ENG, ACVRL1, and SMAD4. Yet the genetic cause remains unknown for some families even after exhaustive exome analysis. We hypothesised that non-coding regions of the known HHT genes may harbour variants that disrupt splicing in these cases.

Methods DNA from 35 individuals with clinical findings of HHT and 2 healthy controls from 13 families underwent whole genome sequencing. Additionally, 87 unrelated cases suspected to have HHT were evaluated using a custom designed next-generation sequencing panel to capture the coding and non-coding regions of ENG, ACVRL1 and SMAD4. Individuals from both groups had tested negative previously for a mutation in the coding region of known HHT genes. Samples were sequenced on a HiSeq2500 instrument and data were analysed to identify novel and rare variants.

Results Eight cases had a novel non-coding ACVRL1 variant that disrupted splicing. One family had an ACVRL1intron 9:chromosome 3 translocation, the first reported case of a translocation causing HHT. The other seven cases had a variant located within a ~300 bp CT-rich ‘hotspot’ region of ACVRL1intron 9 that disrupted splicing.

Conclusions Despite the difficulty of interpreting deep intronic variants, our study highlights the importance of non-coding regions in the disease mechanism of HHT, particularly the CT-rich hotspot region of ACVRL1intron 9. The addition of this region to HHT molecular diagnostic testing algorithms will improve clinical sensitivity.

  • genetics
  • molecular genetics
  • clinical genetics

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  • WL.W-D and JMD contributed equally.

  • Contributors WWD planned, conducted all experiments, analysed the data and drafted the manuscript. JM and PBT planned experiments, obtained all samples, interpreted data and drafted the manuscript. AF, MV, RM and GM performed the bioinformatics analysis, assisted in the interpretation of results and reviewed the manuscript. GA, PJ, CVW and EB assisted with experiments, data analysis and reviewed the manuscript. KW, JT, AEL and REP saw the patients, obtained samples and reviewed the manuscript.

  • Funding This study was funded by Cure HHT, the Chan Soon-Shiong Family Foundation (Heritage 1K Utah Genome Project) and the ARUP Institute for Clinical and Experimental Pathology. Dr Gulsen Akay was supported by the Scientific and Technological Research Council of Turkey (TUBİTAK), with 2219 Postdoctoral Research Fellowship.

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval This study was approved by the University of Utah Institutional Review Board (IRB #7275, 35637 and 20480).

  • Provenance and peer review Not commissioned; externally peer reviewed.