National mutation study among Danish patients with hereditary haemorrhagic telangiectasia

Abstract

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominantly inherited vascular disease characterized by the presence of mucocutaneous telangiectasia and visceral arteriovenous malformations (AVM). The clinical diagnosis of HHT is based on the Curaçao criteria. About 85% of HHT patients carry mutations in the ENG, ACVRL1 or SMAD4 genes. Here, we report on the genetic heterogeneity in the Danish national HHT population and address the prevalence of pulmonary arteriovenous malformations (PAVM). Probands of 107 apparently unrelated families received genetic testing, including sequencing and multiplex ligation-dependent probe amplification (MLPA) analyses of ENG, ACVRL1 and SMAD4. These 107 families included 320 patients confirmed to have HHT either clinically or genetically. In 89% of the probands (n=95), a mutation was identified. We detected 64 unique mutations of which 27 (41%) were novel. Large deletions were identified in ENG and ACVRL1. The prevalence of PAVM was 52.3% in patients with an ENG mutation and 12.9% in the ACVRL1 mutation carriers. We diagnosed 80% of the patients clinically, fulfilling the Curaçao criteria, and those remaining were diagnosed by genetic testing. It is discussed when to assign pathogenicity to missense and splice site mutations. The adding of an extra criterion to the Curaçao criteria is suggested.

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...…”

“…[37] c.526-3C > G Splice Site p.? [30] c.526-1G > A Missense p.? [14] c.526G > T Missense p.Asp176Tyr [37] c.526delG Deletion p.Asp176Thrfs*82 [19] c.536A > C Missense p.Asp179Ala [51] c.540_541insA Insertion p.Asp181Argfs*44 [29] c.563delC Deletion p.Ser188* [19] c.567delG Deletion p.Leu190Serfs*68 [47] c.573delC Deletion p.Phe192Serfs*66 [26] c.590C > T Missense p.Thr197Ile [24] c.593T > A Missense p.Val198Glu [52] c.598C > G Missense p.Arg200Gly [43] c.601C > T Missense p.Gln201* [45] c.601C > A Missense p.Gln201Lys [30] c.602A > G Missense p.Gln201Arg [53] c.602A > C Missense p.Gln201Pro [19] c.611T > G Missense p.Leu204Trp [19] c.614T > G Missense p.Val205Gly [43] c.617A > G Missense p.Glu206Gly [20] c.617_625delAGTGTGTGG Deletion p.Glu206_Val208del [54] c.620delG Deletion p.Cys207Leufs*51 [14] c.623_624dupTG Duplication p.Gly209Trpfs*50 [39] c.626-9_629del13 Deletion p.?…”

“…[39] c.626-3C > G Splice Site p.? [55] c.632G > A Missense p.Gly211Asp [51] c.639T > G Missense p.Tyr213* [14] c.641delG Deletion p.Gly214Alafs*44 [45] c.643G > A Missense p.Glu215Lys [31] c.647T > G Missense p.Val216Gly [19] c.649T > G Missense p.Trp217Gly [45] c.650G > A Missense p.Trp217* [20] c.651G > A Missense p.Trp217* [24] c.653_654delGGinsCC Delins p.Arg218Pro [52] c.656G > A Missense p.Gly219Asp [24] c.661T > G Missense p.Trp221Gly [14] c.662G > A Missense p.Trp221* [19] c.663G > A Missense p.Trp221* [47] c.664_668delCACGG Deletion p.His222* [31] Continued c.667G > C Missense p.Gly223Arg [31] c.670G > A Missense p.Glu224Lys [25] c.673A > T Missense p.Ser225Cys [16] c.673_674delAG Deletion p.Ser225Cysfs*11 [47] c.676G > C Missense p.Val226Leu [30] c.677T > A Missense p.Val226Glu [45] c.682delG Deletion p.Val228Serfs*30 [31] c.683T > A Missense p.Val228Asp [19] c.686A > T Missense p.Lys229Met [55] c.686A > G Missense p.Lys229Arg [31] c.696_698delCTC Deletion p.Ser233del [56] c.698C > T Missense p.Ser233Leu [37] c.698C > A Missense p.Ser233* [57] c.704delA Deletion p.Asp235Valfs*23 [31] c.709C > T Missense p.Gln237* [25] c.716G > A Missense p.Trp239* [46] c.743_744delCA Deletion p.Thr248Serfs*143 [29] c.760_762delGAC Deletion p.Asp254del [18] c.759_761delCGA Deletion p.Asp254del [31] c.772 + 3_772 + 4dupAA Duplication p.? [43] c.772 + 5G > A Missense p.?…”

“…[31] c.773-2A > C Splice Site p.? [19] c.778A > C Missense p.Ile260Leu [24] c.793A > C Missense p.Thr265Pro [37] c.811_823del13bp Deletion p.Thr271Serfs*26 [35] c.818T > C Missense p.Leu273Pro [48] c.821_824dupGGCT Duplication p.Ile276Alafs*117 [40] c.822G > A Missense p.Trp274* [45] c.827T > C Missense p.Ile276Thr [48] c.835_837dupTAC Duplication p.Tyr279dup [14] c.838C > G Missense p.His280Asp [25] c.839A > G Missense p.His280Arg [45] c.842delA Deletion p.Glu281Glyfs*20 [26] c.851C > T Missense p.Ser284Phe [48] c.853dupC Duplication p.Leu285Profs*107 [20] c.853C > T Missense p.Leu285Phe [31] c.854T > C Missense p.Leu285Pro [58] c.858C > G Missense p.Tyr286* [25] c.858C > A Missense p.Tyr286* [35] c.863_909del47 Deletion p.Phe288Cysfs*88 [14] c.864dupT Duplication p.Leu289Serfs*103 [38] Continued c.866T > C Missense p.Leu289Pro [24] c.870delG Deletion p.Arg219Aspfs*10 [14] c.874delC Deletion p.Gln292Argfs*9 [30] c.874C > T Missense p.Gln292* [19] c.875A > C Missense p.Gln292Pro [26] c.881T > G Missense p.Leu294Arg [45] c.905T > G Missense p.Leu302Arg [26] c.913T > C Missense p.Ser305Pro [48] c.913delT Deletion p.Ser305Profs*49 [59] c.914C > T Missense p.Ser305Phe [17] c.916G > C Missense p.Ala306Pro [31] c.917C > A Missense p.Ala306Glu [30] c.921_927dupATGCGGC Duplication p.Leu310Metfs*84 [47] c.924C > A Missense p.Cys308* [38] c.925G > T Missense p.Gly309Cys ...…”

Hereditary haemorrhagic telangiectasia

“…ENG mutations tend to be slightly more common than ACVRL1 in northern Europe and North America, while the reverse is true in the Mediterranean, although reports vary (1,12,13) . A juvenile polyposis/HHT overlap syndrome (JPHT) accounts for approximately 2% of HHT; this is due to mutations in the MADH4 gene on chromosome 18, which codes for the SMAD4 protein (12,14) . Two further gene loci have been identified recently, the HHT 3 gene on chromosome 5 and HHT4 on chromosome 7 (15) .…”