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

Autor:	Balachandar S; Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA., Graves TJ; Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA., Shimonty A; Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA., Kerr K; School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK., Kilner J; School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK., Xiao S; National Heart and Lung Institute, Imperial College London, London, UK.; Genomics England Respiratory Clinical Interpretation Partnership (GeCIP), London, UK., Slade R; National Heart and Lung Institute, Imperial College London, London, UK.; Genomics England Respiratory Clinical Interpretation Partnership (GeCIP), London, UK., Sroya M; Department of Surgery and Cancer, Imperial College London, London, UK., Alikian M; Genomics England Respiratory Clinical Interpretation Partnership (GeCIP), London, UK.; West London Genomic Medicine Centre, Imperial College Healthcare NHS Trust, London, UK., Curetean E; West London Genomic Medicine Centre, Imperial College Healthcare NHS Trust, London, UK., Thomas E; West London Genomic Medicine Centre, Imperial College Healthcare NHS Trust, London, UK.; Genomics England, London, UK., McConnell VPM; Regional Genetics Service, Belfast Health and Social Care Trust, Belfast, UK., McKee S; Regional Genetics Service, Belfast Health and Social Care Trust, Belfast, UK., Boardman-Pretty F; Genomics England, London, UK., Devereau A; Genomics England, London, UK., Fowler TA; Genomics England, London, UK.; William Harvey Research Institute, Queen Mary University of London, London, UK., Caulfield MJ; Genomics England, London, UK.; William Harvey Research Institute, Queen Mary University of London, London, UK., Alton EW; National Heart and Lung Institute, Imperial College London, London, UK.; Genomics England Respiratory Clinical Interpretation Partnership (GeCIP), London, UK., Ferguson T; West London Genomic Medicine Centre, Imperial College Healthcare NHS Trust, London, UK., Redhead J; West London Genomic Medicine Centre, Imperial College Healthcare NHS Trust, London, UK., McKnight AJ; School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.; Genomics England Respiratory Clinical Interpretation Partnership (GeCIP), London, UK., Thomas GA; Department of Surgery and Cancer, Imperial College London, London, UK., Aldred MA; Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.; Genomics England Respiratory Clinical Interpretation Partnership (GeCIP), London, UK., Shovlin CL; National Heart and Lung Institute, Imperial College London, London, UK.; Genomics England Respiratory Clinical Interpretation Partnership (GeCIP), London, UK.; West London Genomic Medicine Centre, Imperial College Healthcare NHS Trust, London, UK.
Jazyk:	angličtina
Zdroj:	American journal of medical genetics. Part A [Am J Med Genet A] 2022 Mar; Vol. 188 (3), pp. 959-964. Date of Electronic Publication: 2021 Dec 13.
DOI:	10.1002/ajmg.a.62584
Abstrakt:	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. (© 2021 Wiley Periodicals LLC.)
Databáze:	MEDLINE
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