Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations

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Title: Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations
Authors: Balachandar, S
Graves, TJ
Shimonty, A
Kerr, K
Kilner, J
Xiao, S
Slade, R
Sroya, M
Alikian, M
Curetean, E
Thomas, E
McConnell, VPM
McKee, S
Boardman-Pretty, F
Devereau, A
Fowler, TA
Caulfield, MJ
Alton, EW
Ferguson, T
Redhead, J
McKnight, AJ
Thomas, GA
Aldred, MA
Shovlin, CL
Item Type: Journal Article
Abstract: 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.
Issue Date: Mar-2022
Date of Acceptance: 2-Nov-2021
URI: http://hdl.handle.net/10044/1/93519
DOI: 10.1002/ajmg.a.62584
ISSN: 0148-7299
Publisher: Wiley
Start Page: 959
End Page: 964
Journal / Book Title: American Journal of Medical Genetics Part A
Volume: 188
Issue: 3
Copyright Statement: © 2021 Wiley Periodicals LLC. This is the accepted version of the following article: Balachandar, S., Graves, T. J., Shimonty, A., Kerr, K., Kilner, J., Xiao, S., Slade, R., Sroya, M., Alikian, M., Curetean, E., Thomas, E., McConnell, V. P. M., McKee, S., Boardman-Pretty, F., Devereau, A., Fowler, T. A., Caulfield, M. J., Alton, E. W., Ferguson, T., … Shovlin, C. L. (2021). Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations. American Journal of Medical Genetics Part A, 1– 6, which has been published in final form at https://doi.org/10.1002/ajmg.a.62584
Sponsor/Funder: Imperial College Healthcare NHS Trust
Funder's Grant Number: CLRN 09/10
Keywords: Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
arteriovenous malformations
bone morphogenetic protein 9
hereditary hemorrhagic telangiectasia
JUVENILE POLYPOSIS
MUTATIONS
GENE
arteriovenous malformations
bone morphogenetic protein 9
hereditary hemorrhagic telangiectasia
Genomics England Research Consortium
Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
arteriovenous malformations
bone morphogenetic protein 9
hereditary hemorrhagic telangiectasia
JUVENILE POLYPOSIS
MUTATIONS
GENE
0604 Genetics
1103 Clinical Sciences
Publication Status: Published
Embargo Date: 2022-12-12
Online Publication Date: 2021-12-13
Appears in Collections:Department of Surgery and Cancer
National Heart and Lung Institute
Faculty of Medicine