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Hum Genome Var. 2015 Nov 5;2:15040. doi: 10.1038/hgv.2015.40. eCollection 2015.

Mutations in RASA1 and GDF2 identified in patients with clinical features of hereditary hemorrhagic telangiectasia.

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Department of Research and Development, Ambry Genetics , Aliso Viejo, CA, USA.
Department of Bioinformatics, Ambry Genetics , Aliso Viejo, CA, USA.
Department of Clinical Genetics, Ambry Genetics , Aliso Viejo, CA, USA.
Division of Pulmonary/Critical Care, Georgia Regents University , Augusta, GA, USA.


Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder caused by mutations in ENG, ACVRL1 and SMAD4, which function in regulating the transforming growth factor beta and bone morphogenetic protein signaling pathways. Symptoms of HHT can be present in individuals who test negative for mutations in these three genes indicating other genes may be involved. In this study, we tested for mutations in two genes, RASA1 and GDF2, which were recently reported to be involved in vascular disorders. To determine whether RASA1 and GDF2 have phenotypic overlap with HHT and should be included in diagnostic testing, we developed a next-generation sequencing assay to detect mutations in 93 unrelated individuals who previously tested negative for mutations in ENG, ACVRL1 and SMAD4, but were clinically suspected to have HHT. Pathogenic mutations in RASA1 were identified in two samples (2.15%) and a variant of unknown significance in GDF2 was detected in one sample. All three individuals experienced epistaxis with dermal lesions described in medical records as telangiectases. These results indicate that the inclusion of RASA1 and GDF2 screening in individuals suspected to have HHT will increase the detection rate and aid clinicians in making an accurate diagnosis.

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