Distribution ofENG andACVRL1 (ALK1) mutations in French HHT patients

Abstract

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease characterized by arteriovenous malformations and resulting from mutations in two major genes: ENG and ACVRL1. The aim of the present study was to estimate the prevalence of the mutations of ENG and ACVRL1 in HHT, based on the largest series of patients reported so far, recruited through a national network. We previously reported the first mutation screening of both genes, in French HHT patients, using heteroduplex analysis. This previous study, bringing 60 novel mutations, provided a significant improvement to the knowledge of molecular pathology in HHT. However, 32% (n=48) of the patients with a confirmed clinical diagnosis remained without mutation. In these patients, we performed an extensive molecular analysis that included the sequencing of the whole coding sequence, the search for large rearrangements, and screening of the potential 5' regulatory regions. Additionally, due to the lack of large pedigrees suitable for linkage analysis, and since SMAD4 germline mutations have been reported in families with combined HHT and juvenile polyposis, we screened this gene and five other genes involved in the TGF-beta/BMP pathway in the patients without mutation of ENG or ACVRL1. Only a novel SMAD1 non-conservative substitution was found in one patient, changing a poorly conserved methionine to an isoleucin. Twenty-three mutations were found in ACVRL1 and 8 in ENG (including a duplication of exons 4 to 8 and deletions of exons 1 to 3 and 9 to 14). Our results, combined with our previous data, increase the mutation rate to 88% (n=119/136) in French patients with a confirmed clinical diagnosis. Our results also emphasize the higher prevalence of large insertions/deletions in ENG and the predominance of ACVRL1 over ENG mutations.

Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: Data from the French-Italian HHT network

“…According to our recent molecular studies, an overrepresentation of patients with an ACVRL1 mutation in our French/North Italian population is very likely and explains why, contrary to other studies cited in Table 7, our cohort has a large excess of HHT2 patients. 33,34 Epistaxis, telangiectases and GI bleeding in HHT1 and 2…”

“…1 According to our recent molecular studies, an overrepresentation of patients with an ACVRL1 mutation in this population is very likely. 33,34 Not taking into account the genotype of the patients may be misleading for future medical studies.…”

“…The detailed description of our mutation analysis has been previously reported. 23,33,34 For the purpose of the present study, mutations were divided into two groups according to their potential effect at the protein level: 1) Truncating mutations, including nonsense mutations, small size deletions, insertions/duplications leading to a frameshift, and large deletions/duplications that usually lead to a complete lack of the protein; and in-frame Genotype-phenotype correlation in HHT mutations included missense mutations and small deletions, duplications and insertions that conserved the reading frame. Splice-site mutations were not considered due to their low occurrence and to their unknown functional consequence.…”

Novel ACLV1 Mutation Identified in Late Onset Hereditary Hemorrhagic Telangiectasia

“…[21] c.65delA Deletion p.Asp22Alafs*3 [14] c.69delT Deletion p.Val24* [14] c.74_78delAGCCGins176bp Delins p.? [19] c.81dupT Duplication p.Arg28Serfs*10 [22] c.86delG Deletion p.Gly29Alafs*4 [23] c.88C > T Missense p.Pro30Ser [24] c.95T > G Missense p.Val32Gly [25] c.100dupT Duplication p.Cys34Leufs*4 [19] c.100_115del16 Deletion p.Cys34Hisfs*15 [26] c.101G > A Missense p.Cys34Tyr [24] c.102C > A Missense p.Cys34* [25] c.106T > C Missense p.Cys36Arg [14] c.107G > A Missense p.Cys36Tyr [27] c.115_118dupCCAC Duplication p.His40Profs*130 [28] c.121T > C Missense p.Cys41Arg [28] c.128_132delGGCCT Deletion p.Gly43Aspfs*124 [29] c.129delG Deletion p.Pro44Leufs*10 [14] c.136_137delTGinsCT Delins p.Cys46Leu [29] c.138C > A Missense p.Cys46* [19] c.139_140insCG Insertion p.Arg47Profs*8 [30] c.139dupC Duplication p.Arg47Profs*122 [24] Continued c.140G > C Missense p.Arg47Pro [27] c.142G > A Missense p.Gly48Arg [31] c.143G > A Missense p.Gly48Glu [32] c.143_147delGGGCCinsAGCCT Delins p.Gly48_Ala49delinsGluPro [33] c.145dupG Duplication p.Ala49Glyfs*120 [34] c.145delG Deletion p.Ala49Profs*5 [35] c.147delC Deletion p.Trp50Glyfs*4 [36] c.148T > G Missense p.Trp50Gly [37] c.149G > A Missense p.Trp50* [29] c.150G > T Missense p.Trp50Cys [38] c.150G > A Missense p.Trp50* [39] c.152G > A Missense p.Cys51Tyr [34] c.154A > G Missense p.Thr52Ala [24] c.155delC Deletion p.Thr52Lysfs*2 [30] c.164_169delTGGTGC Del...…”

Evaluation of previously nonscreened hereditary hemorrhagic telangiectasia patients shows frequent liver involvement and early cardiac consequences

“…The methodology for the mutation analysis of the ENG and ACVRL1 genes has been described previously. 14,15 …”