Abstract
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.
Highlights
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder that affects 1 in 5,000–10,000 individuals. It is characterized by skin and nasal telangiectases along with arteriovenous malformations (AVMs) in the brain, lungs and liver.[1]
When preselected for meeting at least 3 of 4 Curacao criteria, ~ 87% of HHT cases are associated with identifiable mutations in ENG, ACVRL1 and SMAD4
Ambry Genetics from 2008 to 2014, where HHT was either indicated or suspected, the detection rate for causative mutations identified in ENG, ACVRL1 and SMAD4 was ~ 47%
Summary
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder that affects 1 in 5,000–10,000 individuals. Ambry Genetics from 2008 to 2014, where HHT was either indicated or suspected, the detection rate for causative mutations identified in ENG, ACVRL1 and SMAD4 was ~ 47%. These data suggest that HHT may result from mutations in genes that have yet to be discovered or that phenotypes between vascular disorders have significant overlap, making it difficult for the clinician to make an accurate diagnosis. The complex genetic heterogeneity and the overlapping phenotypes between patients with classic HHT and those harboring RASA1 and GDF2 mutations may make it difficult for clinicians to accurately identify the molecular lesion underlying the clinical presentation. Paired-end conditions as described in the manufacturer’s standard workflow (Illumina)
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