Imperial College London
Alternate

ProfessorEricAlton

Faculty of Medicine, National Heart & Lung Institute

Chair in Gene Therapy
 
 
 
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Contact

 

+44 (0)20 7594 7929e.alton

 
 
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Assistant

 

Miss Samia Soussi +44 (0)20 7594 7980

 
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Location

 

Emmanuel Kaye BuildingRoyal Brompton Campus

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Summary

 

Publications

Citation

BibTex format

@article{Balachandar:2022:10.1002/ajmg.a.62584,
author = {Balachandar, S and Graves, TJ and Shimonty, A and Kerr, K and Kilner, J and Xiao, S and Slade, R and Sroya, M and Alikian, M and Curetean, E and Thomas, E and McConnell, VPM and McKee, S and Boardman-Pretty, F and Devereau, A and Fowler, TA and Caulfield, MJ and Alton, EW and Ferguson, T and Redhead, J and McKnight, AJ and Thomas, GA and Aldred, MA and Shovlin, CL},
doi = {10.1002/ajmg.a.62584},
journal = {American Journal of Medical Genetics Part A},
pages = {959--964},
title = {Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations},
url = {http://dx.doi.org/10.1002/ajmg.a.62584},
volume = {188},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant multisystemic vascular dysplasia, characterized by arteriovenous malformations (AVMs), mucocutaneous telangiectasia and nosebleeds. HHT is caused by a heterozygous null allele in ACVRL1, ENG, or SMAD4, which encode proteins mediating bone morphogenetic protein (BMP) signaling. Several missense and stop-gain variants identified in GDF2 (encoding BMP9) have been reported to cause a vascular anomaly syndrome similar to HHT, however none of these patients met diagnostic criteria for HHT. HHT families from UK NHS Genomic Medicine Centres were recruited to the Genomics England 100,000 Genomes Project. Whole genome sequencing and tiering protocols identified a novel, heterozygous GDF2 sequence variant in all three affected members of one HHT family who had previously screened negative for ACVRL1, ENG, and SMAD4. All three had nosebleeds and typical HHT telangiectasia, and the proband also had severe pulmonary AVMs from childhood. In vitro studies showed the mutant construct expressed the proprotein but lacked active mature BMP9 dimer, suggesting the mutation disrupts correct cleavage of the protein. Plasma BMP9 levels in the patients were significantly lower than controls. In conclusion, we propose that this heterozygous GDF2 variant is a rare cause of HHT associated with pulmonary AVMs.
AU  - Balachandar,S
AU  - Graves,TJ
AU  - Shimonty,A
AU  - Kerr,K
AU  - Kilner,J
AU  - Xiao,S
AU  - Slade,R
AU  - Sroya,M
AU  - Alikian,M
AU  - Curetean,E
AU  - Thomas,E
AU  - McConnell,VPM
AU  - McKee,S
AU  - Boardman-Pretty,F
AU  - Devereau,A
AU  - Fowler,TA
AU  - Caulfield,MJ
AU  - Alton,EW
AU  - Ferguson,T
AU  - Redhead,J
AU  - McKnight,AJ
AU  - Thomas,GA
AU  - Aldred,MA
AU  - Shovlin,CL
DO  - 10.1002/ajmg.a.62584
EP  - 964
PY  - 2022///
SN  - 0148-7299
SP  - 959
TI  - Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations
T2  - American Journal of Medical Genetics Part A
UR  - http://dx.doi.org/10.1002/ajmg.a.62584
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000729742700001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.62584
UR  - http://hdl.handle.net/10044/1/93519
VL  - 188
ER  -
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