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Your search keyword '"Endoglin genetics"' showing total 3 results
Start Over Descriptor "Endoglin genetics" Journal american journal of medical genetics part a
3 results on '"Endoglin genetics"'

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

Author

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, and Shovlin CL

Subjects
Activin Receptors, Type II genetics, Arteriovenous Fistula, Child, Endoglin genetics, Endoglin metabolism, Epistaxis, Growth Differentiation Factor 2 genetics, Humans, Mutation, Pulmonary Artery abnormalities, Pulmonary Veins abnormalities, Arteriovenous Malformations diagnosis, Arteriovenous Malformations genetics, Telangiectasia, Hereditary Hemorrhagic diagnosis, Telangiectasia, Hereditary Hemorrhagic genetics, Telangiectasia, Hereditary Hemorrhagic pathology
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., (© 2021 Wiley Periodicals LLC.)

Published
2022
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2. Clinical manifestations of patients with GDF2 mutations associated with hereditary hemorrhagic telangiectasia type 5.

Author

Farhan A, Yuan F, Partan E, and Weiss CR

Subjects
Activin Receptors, Type II genetics, Child, Endoglin genetics, Heterozygote, Humans, Growth Differentiation Factor 2 genetics, Mutation, Missense, Telangiectasia, Hereditary Hemorrhagic diagnosis, Telangiectasia, Hereditary Hemorrhagic genetics, Telangiectasia, Hereditary Hemorrhagic pathology
Abstract

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant fibrovascular dysplasia caused by mutations in ENG, ACVRL1, and SMAD4. Increasingly, there has been an appreciation for vascular conditions with phenotypic overlap to HHT but which have distinct clinical manifestations and arise from novel or uncharacterized gene variants. This study reported on a cohort of four unrelated probands who were diagnosed with a rare form of GDF2-related HHT5, for which only five prior cases have been described. Two patients harbored heterozygous missense variants not previously annotated as pathogenic (p.Val403Ile; p.Glu355Gln). Clinically, these patients had features resembling HHT1, including cerebrovascular involvement of their disease (first report documenting cerebral involvement of HHT5), but with earlier onset of epistaxis and a unique anatomic distribution of dermal capillary lesions that involved the upper forelimbs, trunk, and head. The other two patients harbored interstitial deletions larger than five megabases between 10q11.22 and 10q11.23 that included GDF2. To our knowledge, this is the first report detailing large genomic deletions leading to HHT5. These patients also demonstrated mucocutaneous capillary dysplasias, including intranasal vascular lesions complicated by childhood-onset epistasis, with a number of extravascular findings related to their 10q11.21q11.23 deletion. In conclusion, patients with GDF2-related HHT may present with a number of unique characteristics that differ from classically reported features of HHT., (© 2021 Wiley Periodicals LLC.)

Published
2022
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3. Clinical and molecular characterization of patients with hereditary hemorrhagic telangiectasia: Experience from an HHT Center of Excellence.

Author

Latif MA, Sobreira NLD, Guthrie KS, Motaghi M, Robinson GM, Shafaat O, Gong AJ, and Weiss CR

Subjects
Adult, Arteriovenous Fistula complications, Arteriovenous Fistula pathology, Female, Genetic Predisposition to Disease, Growth Differentiation Factor 2 genetics, Humans, Male, Mutation genetics, Pulmonary Artery pathology, Pulmonary Veins pathology, Retrospective Studies, Telangiectasia, Hereditary Hemorrhagic pathology, p120 GTPase Activating Protein genetics, Activin Receptors, Type II genetics, Arteriovenous Fistula genetics, Endoglin genetics, Pulmonary Artery abnormalities, Pulmonary Veins abnormalities, Smad4 Protein genetics, Telangiectasia, Hereditary Hemorrhagic genetics
Abstract

In this retrospective single-center study, we evaluated whether/how pathogenic/likely pathogenic variants of three hereditary hemorrhagic telangiectasia (HHT)-associated genes (ENG, ACVRL1, and SMAD4) are associated with specific clinical presentations of HHT. We also characterized the morphological features of pulmonary arteriovenous malformations (AVMs) in patients with these variants. Pathogenic or likely pathogenic variants were detected in 64 patients. Using nonparametric statistical tests, we compared the type and prevalence of specific HHT diagnostic features associated with these three variants. Pathogenic variants in these genes resulted in gene-specific HHT clinical presentations. Epistaxis was present in 93%, 94%, and 100% of patients with ENG, ACVRL1, and SMAD4 variants, respectively (p = 0.79). Pulmonary AVMs were more common in patients with the ENG variant (p = 0.034) compared with other subgroups. ACVRL1 variant was associated with the lowest frequency of pulmonary AVMs (p = 0.034) but the highest frequency of hepatic AVMs (p = 0.015). Patients with the ACVRL1 variant did not have significantly more pancreatic AVMs compared with the other groups (p = 0.72). ENG, ACVRL1, and SMAD4 pathogenic or likely pathogenic variants are associated with gene-specific HHT presentations, which is consistent with results from other HHT centers., (© 2021 Wiley Periodicals LLC.)

Published
2021
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