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

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

Whole genome sequences discriminate hereditary hemorrhagic telangiectasia phenotypes by non-HHT deleterious DNA variation

“…Note that the major HHT genes are ACVRL1 (red) and ENG (green). 6-8 SMAD4 6,9 is less common, and GDF2 was more recently described as HHT causal, 44 whereas EPHB4 and RASA1 cause separate endothelial vasculopathies (CM-AVM2 and CM-AVM1) that overlap phenotypically with HHT. (B) Schematic of the cohort of 104 patients plotted on 4 separate axes for hemorrhage (H), anemia (A), thrombosis (T), and deep-seated infection (I).…”

A Formative Study of the Implementation of Whole Genome Sequencing in Northern Ireland

“…Indeed, several clinicians acknowledged that an individual’s diagnosis may lie beyond the top tiered variants, but that they simply did not have the time to explore these. One example of the benefit of collaboratively exploring lower tiered variants was reported by the respiratory Genomics England Clinical Interpretation Partnership, who found a tier 3 variant causative of hereditary haemorrhagic telangiectasia in a family who participated in the 100 KGP, through further functional multiomic analysis [ 43 ]. Further multiomic functional analyses of rare diseases, conducted collaboratively between clinicians and researchers, following recommendations for application of PS3/BS3 ACMG criteria, is vital to fully explore phenotypically plausible variants which may not always be feasible to explore in a clinical environment [ 44 ].…”

New Mutations and Pathogenesis of Pulmonary Hypertension: Progress and Puzzles in Disease Pathogenesis

“…This is further illustrated by several cases with heterozygous GDF2 variants and an HHT-like vascular anomaly syndrome, 44 and a family with typical HHT, including childhood-onset pulmonary arteriovenous malformations in the proband. 45…”

“…This is further illustrated by several cases with heterozygous GDF2 variants and an HHT-like vascular anomaly syndrome, 44 and a family with typical HHT, including childhood-onset pulmonary arteriovenous malformations in the proband. 45 The occurrence of more severe disease in homozygous cases compared with heterozygotes suggests that the inheritance pattern may be semidominant rather than true dominant where homozygous cases are not more severe. However, since PAH varies considerably in the age of onset and clinical course, it can be difficult to distinguish these two scenarios.…”