Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia characterized by telangiectases and arteriovenous malformations (AVMs) in particular locations described in consensus clinical diagnostic criteria published in 2000. Two genes in the transforming growth factor-beta (TGF-β) signaling pathway, ENG and ACVRL1, were discovered almost two decades ago, and mutations in these genes have been reported to cause up to 85% of HHT. In our experience, approximately 96% of individuals with HHT have a mutation in these two genes, when published (Curaçao) diagnostic criteria for HHT are strictly applied. More recently, two additional genes in the same pathway, SMAD4 and GDF2, have been identified in a much smaller number of patients with a similar or overlapping phenotype to HHT. Yet families still exist with compelling evidence of a hereditary telangiectasia disorder, but no identifiable mutation in a known gene. Recent availability of whole exome and genome testing has created new opportunities to facilitate gene discovery, identify genetic modifiers to explain clinical variability, and potentially define an increased spectrum of hereditary telangiectasia disorders. An expanded approach to molecular diagnostics for inherited telangiectasia disorders that incorporates a multi-gene next generation sequencing (NGS) HHT panel is proposed.

Keywords: HHT; Rendu-Osler-Weber; arteriovenous malformation; genetics; molecular diagnostics; telangiectasia.

FIGURE 1

Hereditary hemorrhagic telangiectasia is a genetically heterogeneous disorder caused by mutations in several genes in the TGF-β/BMP signaling pathway. BMP9 binds to specific type I (R-I; namely ALK1) and type II (R-II) cell surface receptors that exhibit serine/threonine kinase activity, as well as to the auxiliary receptor endoglin. Upon ligand binding, the R-II transphosphorylates ALK1 (R-I), which then propagates the signal by phosphorylating receptor-regulated Smads (R-Smads) Smad1/5/8. Once phosphorylated, R-Smads form heteromeric complexes with Smad4 and translocate into the nucleus where they regulate transcriptional activity of target genes, including Id1. Endoglin, ALK1, BMP9, and Smad4 proteins are encoded by ENG, ACVRL1, GDF2, and SMAD4, whose pathogenic mutations give rise to HHT and JP/HHT, respectively. This figure was adapted from (Fernández-L et al., 2006).

FIGURE 2

Proposed molecular testing algorithm for HHT based on the suspected clinical diagnosis. The testing algorithm for classic HHT is shown on the left. An algorithm for patients suspected to have HHT or an HHT-like phenotype (right) depicts the use of a five gene HHT next generation sequencing panel and aCGH. The dashed line indicates a streamlined future diagnostic algorithm for HHT patients as NGS costs and turn-around times are reduced.