Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by a unique pattern of telangiectasia and arteriovenous malformations (AVMs). Mutations in one of two genes (ENG and ACVRL1) cause approximately 85% of cases. Genetic testing impacts clinical management because genotype/phenotype correlations exist, and early preventive screening for internal AVMs is recommended in affected individuals prior to the age at which a diagnosis can typically be made based on clinical criteria. We report 383 consecutive cases in which sequencing and large deletion/duplication analysis were performed simultaneously for endoglin (ENG) and activin-like receptor kinase 1 (ACVRL1). We report the first case of mosaicism in an affected individual and 61 novel mutations. We discuss the potential benefits of a diagnostic testing approach for HHT whereby ENG and ACVRL1 are analyzed simultaneously by sequencing and a method which detects large deletion/duplications, rather than by a sequential or reflex testing protocol. We report a case in which a deletion would probably have been missed if large deletion/duplication analysis was performed only if a suspected pathogenic mutation was not first identified by sequencing.

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...…”

“…[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 ...…”

“…The Smad dimer then enters the nucleus where it acts as a transcription factor, regulating the transcription of angiogenesis genes such as VEGF. Reduced presence of endoglin, a coreceptor for ALK family of receptors, has been shown to decrease the activity of the ALK1 pathway, as well as the ALK5 pathway that counterbalances ALK1 activity by promoting cell c.24A > T Missense p.Lys8Ans [16] c.31_50del20 Deletion p.Leu11Glyfs*20 [17] c.37delC Deletion p.Leu13Cysfs*2 [18] c.50dupT Duplication p.Leu17Phefs*21 [19] c.50_53delTGGT Deletion p.Leu*17 [20] c.61 + 1G > A Missense p.? [14] c.61 + 10G > A 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.? [37] c.626-5_634del14 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.?…”