Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia inherited as an autosomal dominant trait. Care delivery is impeded by requirements for laborious, repeated phenotyping, and gaps in knowledge regarding the relationships between causal DNA variants in ENG, ACVRL1, SMAD4 and GDF2, and clinical manifestations. To address, we analysed DNA samples from 183 previously uncharacterised, unrelated HHT and suspected HHT cases using the ThromboGenomics high-throughput sequencing platform. We identified 168 heterozygous variants, 127 unique. Applying modified ACMG Guidelines, 106 were classified as pathogenic/likely pathogenic, 21 as non-pathogenic (variants of uncertain significance/benign). Unlike the protein products of ACVRL1 and SMAD4, the extracellular ENG amino acids are not strongly conserved. Our inferences of the functional consequences of causal variants in ENG were therefore informed by the crystal structure of endoglin. We then compared the accuracy of predictions of the causal gene blinded to the genetic data using two approaches: subjective clinical predictions and statistical predictions based on eight Human Phenotype Ontology (HPO) terms. Both approaches had some predictive power but they were insufficiently accurate to be used clinically in isolation from genetic testing. The distributions of red cell indices from larger HHT and control populations differed by causal gene but not sufficiently for clinical use in isolation of genetic data. We conclude that parallel sequencing of the four known HHT genes, MDT review of variant calls sequencing results in the context of detailed clinical information, and statistical and structural modelling are all required to provide a framework to better prognosticate and treat HHT.

Prognostic role and clinicopathological features of SMAD4 gene mutation in colorectal cancer: a systematic review and meta-analysis

“…The product of this gene forms homomeric complexes and heteromeric complexes with other activated Smad proteins in the context of activating by TGF-β receptors, then accumulate in the nucleus and regulate the transcription of target genes [ 4 ]. Mutations or deletions in the SMAD4 gene have been shown to result in pancreatic cancer [ 5 ], juvenile polyposis syndrome [ 6 ], and hereditary hemorrhagic telangiectasia [ 7 ]. In the past 2 decades, many studies had shown that SMAD4 mutation can not cause tumorigenesis by itself, but it can promote tumor progression caused by other genes [ 8 ].…”

COVID-19 genomic susceptibility: Definition of ACE2 variants relevant to human infection with SARS-CoV-2 in the context of ACMG/AMP Guidance

“…Study strengths include highlighting the landscape of genetic variation relevant to SARS-CoV-2, and questioning how strictly putative COVID-19 risk and protective alleles should be defined, particularly if they may become part of public health policies, as for underlying health conditions [25,26]. The pattern from Mendelian disorders was of over-exuberant pathogenicity calls in early research reports, with pathogenicity classifications of many variants later downgraded as assignments became increasingly stringent [14,28]. As a result, high proportion of coding variants in known disease-causing genes are currently clinically non-actionable due to classification as a VUS.…”

High definition analyses of single cohort, whole genome sequencing data provides a direct route to defining sub-phenotypes and personalising medicine

“…As described for the wider cohort,[7,16,20,53,54] all individuals reviewed in the clinical service were assessed using standardised methods including a detailed clinical history specifically focusing on aspects of the HHT phenotypes, and any disproportionate or unexpected symptomatic manifestations. Standardised hematological and biochemical assessments were performed using the hospital service laboratories as described.…”

“…[2-4] Estimated to affect approximately 1.5 million individuals worldwide,[5,6] HHT usually results from a heterozygous loss-of-function allele in ENG, ACVRL1 or SMAD4 , and is inherited as an autosomal dominant trait. [7] Haploinsufficiency at one of these loci predisposes to the development of abnormal vascular structures, especially arteriovenous malformations (AVMs) characterised by turbulent flow and defective vascular walls predisposing to hemorrhage. [8] Affected individuals experience spontaneous, recurrent nosebleeds due to abnormal nasal vasculature, and exhibit small visible telangiectatic vessels that tend to develop on the lips, oral cavity, and finger pads.…”