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• W2050301036 abstract "Hereditary hemorrhagic telangiectasia is a vascular dysplasia with variable onset and expression. Through identification of a mutation in a proband, mutation testing can be offered to family members. Mutation carriers can receive medical surveillance and treatment before potentially fatal complications arise. In this study, we assessed the significance of clinical evaluations as part of hereditary hemorrhagic telangiectasia diagnostic testing to determine the clinical sensitivity of molecular testing and to report novel mutations. Based on reported clinical symptoms, we classified 142 consecutive cases as affected, suspected, or unlikely affected. We performed temperature gradient capillary electrophoresis and full gene sequencing of both ACVRL1 and ENG genes. We then compared the mutation detection rates between these groups, categorizing sequence variants as mutations, variants of uncertain significance (VUS), or known polymorphisms. Our mutation and VUS detection rate in affected individuals was 74% and 16% in the suspected/unlikely affected group. Sixty-one percent of the mutations and all VUS were novel. The mutation detection rate for temperature gradient capillary electrophoresis was 97%. Our results suggest that a careful clinical evaluation increases the mutation detection rate. We have confirmed the occurrence of de novo mutations in three patients. Our results also show that temperature gradient capillary electrophoresis is an efficient mutation screening method. Hereditary hemorrhagic telangiectasia is a vascular dysplasia with variable onset and expression. Through identification of a mutation in a proband, mutation testing can be offered to family members. Mutation carriers can receive medical surveillance and treatment before potentially fatal complications arise. In this study, we assessed the significance of clinical evaluations as part of hereditary hemorrhagic telangiectasia diagnostic testing to determine the clinical sensitivity of molecular testing and to report novel mutations. Based on reported clinical symptoms, we classified 142 consecutive cases as affected, suspected, or unlikely affected. We performed temperature gradient capillary electrophoresis and full gene sequencing of both ACVRL1 and ENG genes. We then compared the mutation detection rates between these groups, categorizing sequence variants as mutations, variants of uncertain significance (VUS), or known polymorphisms. Our mutation and VUS detection rate in affected individuals was 74% and 16% in the suspected/unlikely affected group. Sixty-one percent of the mutations and all VUS were novel. The mutation detection rate for temperature gradient capillary electrophoresis was 97%. Our results suggest that a careful clinical evaluation increases the mutation detection rate. We have confirmed the occurrence of de novo mutations in three patients. Our results also show that temperature gradient capillary electrophoresis is an efficient mutation screening method. Hereditary hemorrhagic telangiectasia (HHT) is characterized phenotypically by telangiectases and arteriovenous malformations. These lesions result in hemorrhage, particularly in the nose, gastrointestinal tract, and brain, and complications related to shunting, primarily in the lungs and liver. Complications from this disorder include intracranial hemorrhage secondary to cerebral arteriovenous malformations and embolic stroke and brain abscess secondary to pulmonary arteriovenous malformations. The frequency of HHT is reported to be ∼1 in 10,000, but it is thought to be underdiagnosed.1Shovlin CL Guttmacher AE Buscarini E Faughnan ME Hyland RH Westermann CJ Kjeldsen AD Plauchu H Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome).Am J Med Genet. 2000; 91: 66-67Crossref PubMed Scopus (1305) Google Scholar Two genes, endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1), have been reported to cause HHT in an autosomal dominant manner if mutated.2Bayrak-Toydemir P Markewitz B Lewin S Miller F Chou L Gedge F Tang W Coon H Mao R Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations.Am J Med Genet A. 2006; 140: 463-470Crossref PubMed Scopus (164) Google Scholar Molecular diagnosis allows for diagnostic confirmation in symptomatic individuals and significantly improves care for individuals at risk for HHT after identification of a causative mutation. Because the initial clinical presentation of the disorder can be a catastrophic pulmonary or central nervous system event,3Fulbright RK Chaloupka JC Putman CM Sze GK Merriam MM Lee GK Fayad PB Awad IA White Jr, RI MR of hereditary hemorrhagic telangiectasia: prevalence and spectrum of cerebrovascular malformations.Am J Neuroradiol. 1998; 19: 477-484PubMed Google Scholar4Morgan T McDonald J Anderson C Ismail M Miller F Mao R Madan A Barnes P Hudgins L Manning M Intracranial hemorrhage in infants and children with hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome).Pediatrics. 2002; 109: E12-E18Crossref PubMed Scopus (97) Google Scholar5Moussouttas M Fayad P Rosenblatt M Hashimoto M Pollak J Henderson K Ma TY White RI Pulmonary arteriovenous malformations: cerebral ischemia and neurologic manifestations.Neurology. 2000; 55: 959-964Crossref PubMed Scopus (227) Google Scholar presymptomatic diagnosis for relatives of individuals with HHT offers an opportunity to prevent serious or lethal complications. Individuals shown to be unaffected can be spared unnecessary and costly medical screening. Developing simple and reliable diagnostic approaches has been difficult because of the lack of common mutations.2Bayrak-Toydemir P Markewitz B Lewin S Miller F Chou L Gedge F Tang W Coon H Mao R Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations.Am J Med Genet A. 2006; 140: 463-470Crossref PubMed Scopus (164) Google Scholar Thus, sensitive mutation scanning approaches followed by targeted sequencing might be useful in the clinical setting. To detect mutations many scanning techniques have been developed, differing in sensitivity, specificity, throughput, and cost. In this study, we used temperature gradient capillary electrophoresis (TGCE), which has been described to be reliable in detecting heteroduplexes caused by sequence variants such as point mutations or small deletions and insertions6Chou LS Gedge F Lyon E Complete gene scanning by temperature gradient capillary electrophoresis using the cystic fibrosis transmembrane conductance regulator gene as a model.J Mol Diagn. 2005; 7: 111-120Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar followed by DNA sequencing. The mutation detection rate by sequencing of these two genes has been previously reported as 68 to 78%.7Bossler AD Richards J George C Godmilow L Ganguly A Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype.Hum Mutat. 2006; 27: 667-675Crossref PubMed Scopus (118) Google Scholar8Lesca G Plauchu H Coulet F Lefebvre S Plessis G Odent S Riviere S Leheup B Goizet C Carette MF Cordier JF Pinson S Soubrier F Calender A Giraud S Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France.Hum Mutat. 2004; 23: 289-299Crossref PubMed Scopus (98) Google Scholar9Prigoda NL Savas S Abdalla SA Piovesan B Rushlow D Vandezande K Zhang E Ozcelik H Gallie BL Letarte M Hereditary haemorrhagic telangiectasia: mutation detection, test sensitivity and novel mutations.J Med Genet. 2006; 43: 722-728Crossref PubMed Scopus (94) Google Scholar Deletions/duplications or a third10Cole SG Begbie ME Wallace GM Shovlin CL A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5.J Med Genet. 2005; 42: 577-582Crossref PubMed Scopus (257) Google Scholar/fourth11Bayrak-Toydemir P McDonald J Akarsu N Toydemir RM Calderon F Tuncali T Tang W Miller F Mao R A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7.Am J Med Genet A. 2006; 140: 2155-2162Crossref PubMed Scopus (186) Google Scholar locus may account for the rest of the cases. In addition, mutations in SMAD4 cause manifestations of HHT combined with juvenile polyposis.12Gallione CJ Richards JA Letteboer TG Rushlow D Prigoda NL Leedom TP Ganguly A Castells A Ploos van Amstel JK Westermann CJ Pyeritz RE Marchuk DA SMAD4 mutations found in unselected HHT patients.J Med Genet. 2006; 43: 793-797Crossref PubMed Scopus (190) Google Scholar In this study, we review 143 consecutive cases received for molecular analysis of HHT genes from January 2004 to April 2006. We present clinical background and molecular test results obtained by gene scanning and sequencing of ACVRL1 and ENG. We report novel sequence variations and address statistically the proportion of variants of uncertain significance (VUS) detected in affected individuals. In addition, we report three de novo mutations for this disease. Samples from 143 consecutive cases were submitted to Associated Regional and University Pathologists laboratories for clinical HHT testing and included in the study on institutional review board approval. Individuals were grouped into three categories based on the symptoms as described by the ordering physician. It is of note that the policy of our laboratory is to contact an ordering clinician for additional information when HHT mutation analysis is received for an individual who does not meet clinically published diagnostic criteria1Shovlin CL Guttmacher AE Buscarini E Faughnan ME Hyland RH Westermann CJ Kjeldsen AD Plauchu H Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome).Am J Med Genet. 2000; 91: 66-67Crossref PubMed Scopus (1305) Google Scholar based on the information provided on our requisition form. Group 1 consisted of 97 clinically affected individuals who were reported to have at least three of the following criteria: positive family history of HHT, recurring nosebleeds, dermal/oral telangiectases, liver shunts, pulmonary arteriovenous malformations, cerebral arteriovenous malformations, and gastrointestinal telangiectases/arteriovenous malformations.1Shovlin CL Guttmacher AE Buscarini E Faughnan ME Hyland RH Westermann CJ Kjeldsen AD Plauchu H Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome).Am J Med Genet. 2000; 91: 66-67Crossref PubMed Scopus (1305) Google Scholar Group 2 consisted of 29 individuals with a suspected diagnosis of HHT, who had two of the above-mentioned criteria. Group 3 consisted of 16 individuals that were considered unlikely to have HHT because they had only one of the above-mentioned criteria. One individual had insufficient clinical information and therefore was not included further in our study groups. This individual had no mutation or VUS. DNA was obtained from 1 ml of blood by MagnaPure Compact (Roche, Indianapolis, IN) extraction following the manufacturer's instructions. Sample analysis in the clinical laboratory involved polymerase chain reaction (PCR) and heteroduplex formation of all exons in ACVRL1 (GenBank accession no. AH005451) and ENG (GenBank accession no. AH006911) followed by TGCE scanning and targeted sequencing for 20 samples. If no mutation or VUS was found, the remaining exons were sequenced as well. In 123 cases, we did TGCE screening analysis and full gene sequencing simultaneously and compared the results. For potential splice-site variants, mRNA was isolated from whole blood. cDNA was prepared using random primers and amplified using locus-specific primers. Gel electrophoresis was performed to confirm the presence of two mRNA species and sequencing to confirm the alternate splicing. PCR was performed in 25-μl reactions using 0.4-μmol primers (forward and reverse), 1× High Fidelity PCR Master (Roche), and 100 ng of DNA. Primer sequences were as described by Bayrak-Toydemir and colleagues.2Bayrak-Toydemir P Markewitz B Lewin S Miller F Chou L Gedge F Tang W Coon H Mao R Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations.Am J Med Genet A. 2006; 140: 463-470Crossref PubMed Scopus (164) Google Scholar PCR and heteroduplex formation were performed in a PE 9700 (Applied Biosystems). PCR cycling conditions were 95°C for 5 minutes; 30 cycles of 94°C for 30 seconds, 58°C for 30 seconds, and 72°C for 30 seconds; 72°C for 7 minutes; and 4°C for 1 minute followed by heteroduplex formation according to manufacturer's recommendation (SpectruMedix Inc., State College, PA). After heteroduplex formation, 5 μl of sample was diluted with 1× PCR buffer (Applied Biosystems, Foster City, CA) to ensure unsaturated fluorescent intensity and suitable salt concentrations. Diluted samples were injected into a SpectruMedix instrument equipped with 24 capillaries (model SLE 2410; SpectruMedix Inc.) for TGCE. Other parameters included 3 kV (20 seconds) for sample injection, 50 to 60°C for temperature gradient, and 9 kV (50 minutes) for data collection. The ramp period was 21 minutes (from 50 to 60°C).6Chou LS Gedge F Lyon E Complete gene scanning by temperature gradient capillary electrophoresis using the cystic fibrosis transmembrane conductance regulator gene as a model.J Mol Diagn. 2005; 7: 111-120Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Data were analyzed using the Revelation 2.4 image analysis software (SpectruMedix Inc.). Peak patterns were used to score individual exons of a sample as wild type if there was only one sharp peak present. They were scored as heteroduplex if there were either more than one peak present or a peak with a shoulder. A peak pattern of four individual peaks indicated an insertion or deletion. PCR products were purified using ExoSAP-IT (USB, Cleveland, OH). Sequencing was performed using Big Dye Terminator chemistry and either the 3100 Genetic Analyzer or 3730 DNA Analyzer (Applied Biosystems). Sequencing Analysis v.5.0 (Applied Biosystems) and Sequencher (GeneCodes, Ann Arbor, MI) software were used for analysis and mutation detection. Throughout this article the term mutation is used to refer to sequence variations with convincing evidence to suggest that they are causative of HHT. Such evidence includes causation of a frameshift or premature stop codon, mRNA analysis to confirm splice-site variants, tracking of the sequence variation with the disorder in multiple, preferably distantly related family members, or a publication presenting information that is suggestive of the variation being causative of HHT.2Bayrak-Toydemir P Markewitz B Lewin S Miller F Chou L Gedge F Tang W Coon H Mao R Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations.Am J Med Genet A. 2006; 140: 463-470Crossref PubMed Scopus (164) Google Scholar,13Bayrak-Toydemir P Mao R Lewin S McDonald J Hereditary hemorrhagic telangiectasia: an overview of diagnosis and management in the molecular era for clinicians.Genet Med. 2004; 6: 175-191Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar We refer to VUS as sequence variants for which this type of evidence does not currently exist to determine whether they are benign or deleterious. Thus, when interpreting the significance of missense mutations, possible splice-site mutations, as well as in-frame small deletions and insertions, we advocate a more conservative approach for clinical laboratories than often used by research laboratories. Uncertain variants that are point mutations were analyzed using SIFT (Sorting Intolerant from Tolerant), available from http://blocks.fhcrc.org/sift/SIFT.html.14Ng PC Henikoff S Accounting for human polymorphisms predicted to affect protein function.Genome Res. 2002; 12: 436-446Crossref PubMed Scopus (571) Google Scholar SWISS-PROT 48.7 and TREMBL 31.7 were the databases searched with the median conservation of sequences set at 3.00 and sequences more than 90% identical removed. Amino acid changes with scores greater than 0.05 were considered tolerated. In 142 individuals tested for mutations in the ACVRL1 and ENG genes, 51 (36%) were determined to have mutations, 28 (20%) were determined to have VUS, and no mutation could be detected in 63 individuals (44%). The mutation frequency in all three groups is summarized in Table 1. In clinically affected individuals, we found a 51% (49 of 97) mutation detection rate and a 24% (23 of 97) VUS detection rate. As discussed below, most VUS are likely to be causative, and therefore combining both mutations and VUS gave an overall detection rate of 74% in clinically affected individuals. When suspected and unlikely affected individuals were combined, the mutation detection rate was 4% (2 of 45), and the VUS detection rate was 11% (5 of 45). No mutation or VUS was detected in 84% (38 of 45) of these cases.Table 1Mutation Detection Rates in Clinically Affected, Suspected, and Unlikely Affected IndividualsAffected individuals, n (%)Suspected individuals, n (%)Unlikely affected individuals, n (%)Total, n (%)Mutation49 (50.5)2 (6.9)051 (35.9)VUS23 (23.7)2 (6.9)3 (18.7)28 (19.7)Negative25 (25.8)25 (86.2)13 (81.3)63 (44.4)Total972916142 Open table in a new tab Of the 51 individuals with mutations, 25 (49%) had mutations in ACVRL1 and 26 (51%) in ENG. Of the 31 VUS, 13 (42%) occurred in ACVRL1 and 18 (58%) occurred in ENG. Two individuals had both a mutation and a VUS, and one individual had two VUS. Of the 14 mutations in the ACVRL1, 11 were missense, two were deletions, and one was a splice-site mutation (Table 2).15Trembath RC Thomson JR Machado RD Morgan NV Atkinson C Winship I Simonneau G Galie N Loyd JE Humbert M Nichols WC Morrell NW Berg J Manes A McGaughran J Pauciulo M Wheeler L Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia.N Engl J Med. 2001; 345: 325-334Crossref PubMed Scopus (587) Google Scholar16Letteboer TG Zewald RA Kamping EJ de Haas G Mager JJ Snijder RJ Lindhout D Hennekam FA Westermann CJ Ploos van Amstel JK Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients.Hum Genet. 2005; 116: 8-16Crossref PubMed Scopus (80) Google Scholar17Abdalla SA Pece-Barbara N Vera S Tapia E Paez E Bernabeu C Letarte M Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2.Hum Mol Genet. 2000; 9: 1227-1237Crossref PubMed Scopus (104) Google Scholar18Berg JN Gallione CJ Stenzel TT Johnson DW Allen WP Schwartz CE Jackson CE Porteous ME Marchuk DA The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2.Am J Hum Genet. 1997; 61: 60-67Abstract Full Text PDF PubMed Scopus (209) Google Scholar19Abdalla SA Geisthoff UW Bonneau D Plauchu H McDonald J Kennedy S Faughnan ME Letarte M Visceral manifestations in hereditary haemorrhagic telangiectasia type 2.J Med Genet. 2003; 40: 494-502Crossref PubMed Scopus (82) Google Scholar20Johnson DW Berg JN Baldwin MA Gallione CJ Marondel I Yoon SJ Stenzel TT Speer M Pericak-Vance MA Diamond A Guttmacher AE Jackson CE Attisano L Kucherlapati R Porteous ME Marchuk DA Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2.Nat Genet. 1996; 13: 189-195Crossref PubMed Scopus (871) Google Scholar21Cymerman U Vera S Pece-Barbara N Bourdeau A White Jr, RI Dunn J Letarte M Identification of hereditary hemorrhagic telangiectasia type 1 in newborns by protein expression and mutation analysis of endoglin.Pediatr Res. 2000; 47: 24-35Crossref PubMed Scopus (78) Google Scholar22Gallione CJ Klaus DJ Yeh EY Stenzel TT Xue Y Anthony KB McAllister KA Baldwin MA Berg JN Lux A Smith JD Vary CP Craigen WJ Westermann CJ Warner ML Miller YE Jackson CE Guttmacher AE Marchuk DA Mutation and expression analysis of the endoglin gene in hereditary hemorrhagic telangiectasia reveals null alleles.Hum Mutat. 1998; 11: 286-294Crossref PubMed Scopus (83) Google Scholar23Pece-Barbara N Cymerman U Vera S Marchuk DA Letarte M Expression analysis of four endoglin missense mutations suggests that haploinsufficiency is the predominant mechanism for hereditary hemorrhagic telangiectasia type 1.Hum Mol Genet. 1999; 8: 2171-2181Crossref PubMed Scopus (95) Google Scholar24Shovlin CL Hughes JM Scott J Seidman CE Seidman JG Characterization of endoglin and identification of novel mutations in hereditary hemorrhagic telangiectasia.Am J Hum Genet. 1997; 61: 68-79Abstract Full Text PDF PubMed Scopus (141) Google Scholar25Abdalla SA Cymerman U Rushlow D Chen N Stoeber GP Lemire EG Letarte M Novel mutations and polymorphisms in genes causing hereditary hemorrhagic telangiectasia.Hum Mutat. 2005; 25: 320-321Crossref PubMed Scopus (45) Google Scholar Among the 13 VUS in ACVRL1, 10 were missense variants, two were possible splice-site mutations, and one was an in-frame deletion (Table 3).Table 2List of the Mutations Found in This StudyGeneMutation typeNucleotide changeAmino acid changeNumber of cases and clinical statusReferenceACVRL1Deletionc.31_50del20‡De novo mutations.p.L11fsX361 Affected*This patient also had c.77 C>T (p.P26L) VUS in the ACVRL1.NovelACVRL1Splice sitec.525 + 1G>AUnknown1 AffectedNovelACVRL1Deletionc.759_761delCGAp.D254del2 Affected15Trembath RC Thomson JR Machado RD Morgan NV Atkinson C Winship I Simonneau G Galie N Loyd JE Humbert M Nichols WC Morrell NW Berg J Manes A McGaughran J Pauciulo M Wheeler L Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia.N Engl J Med. 2001; 345: 325-334Crossref PubMed Scopus (587) Google ScholarACVRL1Missensec.925G>Ap.G309S1 Affected16Letteboer TG Zewald RA Kamping EJ de Haas G Mager JJ Snijder RJ Lindhout D Hennekam FA Westermann CJ Ploos van Amstel JK Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients.Hum Genet. 2005; 116: 8-16Crossref PubMed Scopus (80) Google ScholarACVRL1Missensec.1030T>Cp.C344R1 Affected2Bayrak-Toydemir P Markewitz B Lewin S Miller F Chou L Gedge F Tang W Coon H Mao R Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations.Am J Med Genet A. 2006; 140: 463-470Crossref PubMed Scopus (164) Google ScholarACVRL1Missensec.1031G>Ap.C344Y2 Affected17Abdalla SA Pece-Barbara N Vera S Tapia E Paez E Bernabeu C Letarte M Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2.Hum Mol Genet. 2000; 9: 1227-1237Crossref PubMed Scopus (104) Google ScholarACVRL1Missensec.1048G>Cp.G350R1 Affected16Letteboer TG Zewald RA Kamping EJ de Haas G Mager JJ Snijder RJ Lindhout D Hennekam FA Westermann CJ Ploos van Amstel JK Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients.Hum Genet. 2005; 116: 8-16Crossref PubMed Scopus (80) Google ScholarACVRL1Missensec.1120C>Tp.R374W7 Affected and 1 suspected18Berg JN Gallione CJ Stenzel TT Johnson DW Allen WP Schwartz CE Jackson CE Porteous ME Marchuk DA The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2.Am J Hum Genet. 1997; 61: 60-67Abstract Full Text PDF PubMed Scopus (209) Google ScholarACVRL1Missensec.1121G>Ap.R374Q1 Affected19Abdalla SA Geisthoff UW Bonneau D Plauchu H McDonald J Kennedy S Faughnan ME Letarte M Visceral manifestations in hereditary haemorrhagic telangiectasia type 2.J Med Genet. 2003; 40: 494-502Crossref PubMed Scopus (82) Google ScholarACVRL1Missensec.1126A>Gp.M376V1 Affected8Lesca G Plauchu H Coulet F Lefebvre S Plessis G Odent S Riviere S Leheup B Goizet C Carette MF Cordier JF Pinson S Soubrier F Calender A Giraud S Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France.Hum Mutat. 2004; 23: 289-299Crossref PubMed Scopus (98) Google ScholarACVRL1Missensec.1232G>Ap.R411Q2 Affected20Johnson DW Berg JN Baldwin MA Gallione CJ Marondel I Yoon SJ Stenzel TT Speer M Pericak-Vance MA Diamond A Guttmacher AE Jackson CE Attisano L Kucherlapati R Porteous ME Marchuk DA Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2.Nat Genet. 1996; 13: 189-195Crossref PubMed Scopus (871) Google ScholarACVRL1Missensec.1232G>Cp.R411P1 Affected8Lesca G Plauchu H Coulet F Lefebvre S Plessis G Odent S Riviere S Leheup B Goizet C Carette MF Cordier JF Pinson S Soubrier F Calender A Giraud S Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France.Hum Mutat. 2004; 23: 289-299Crossref PubMed Scopus (98) Google ScholarACVRL1Missensec.1435C>Tp.R479X2 Affected8Lesca G Plauchu H Coulet F Lefebvre S Plessis G Odent S Riviere S Leheup B Goizet C Carette MF Cordier JF Pinson S Soubrier F Calender A Giraud S Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France.Hum Mutat. 2004; 23: 289-299Crossref PubMed Scopus (98) Google ScholarACVRL1Missensec.1436G>Ap.R479Q1 Affected2Bayrak-Toydemir P Markewitz B Lewin S Miller F Chou L Gedge F Tang W Coon H Mao R Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations.Am J Med Genet A. 2006; 140: 463-470Crossref PubMed Scopus (164) Google ScholarENGMissensec.1A>Gp.M1V1 Affected16Letteboer TG Zewald RA Kamping EJ de Haas G Mager JJ Snijder RJ Lindhout D Hennekam FA Westermann CJ Ploos van Amstel JK Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients.Hum Genet. 2005; 116: 8-16Crossref PubMed Scopus (80) Google ScholarENGInsertionc.34_35insGGCTGTTGCCCp.L12fsX181 Affected2Bayrak-Toydemir P Markewitz B Lewin S Miller F Chou L Gedge F Tang W Coon H Mao R Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations.Am J Med Genet A. 2006; 140: 463-470Crossref PubMed Scopus (164) Google ScholarENGInsertionc.41_42insTGGCCAGCTGC‡De novo mutations.p.S18fsX461 AffectedNovelENGSplice sitec.219G>Ap.T73T, skips exon 2, S23fs1 AffectedNovel§mRNA confirmation done.ENGMissensec.277C>Tp.R93X2 Affected and 1 suspected21Cymerman U Vera S Pece-Barbara N Bourdeau A White Jr, RI Dunn J Letarte M Identification of hereditary hemorrhagic telangiectasia type 1 in newborns by protein expression and mutation analysis of endoglin.Pediatr Res. 2000; 47: 24-35Crossref PubMed Scopus (78) Google ScholarENGSplice sitec.360 + 4_7 delAGTGUnknown1 AffectedNovel§mRNA confirmation done.ENGDeletionc.471_472delCTp.S158fsX1601 AffectedNovelENGSplice sitec.524-2A>Gp.N121fs2 Affected22Gallione CJ Klaus DJ Yeh EY Stenzel TT Xue Y Anthony KB McAllister KA Baldwin MA Berg JN Lux A Smith JD Vary CP Craigen WJ Westermann CJ Warner ML Miller YE Jackson CE Guttmacher AE Marchuk DA Mutation and expression analysis of the endoglin gene in hereditary hemorrhagic telangiectasia reveals null alleles.Hum Mutat. 1998; 11: 286-294Crossref PubMed Scopus (83) Google ScholarENGMissensec.662T>Cp.L221P1 Affected23Pece-Barbara N Cymerman U Vera S Marchuk DA Letarte M Expression analysis of four endoglin missense mutations suggests that haploinsufficiency is the predominant mechanism for hereditary hemorrhagic telangiectasia type 1.Hum Mol Genet. 1999; 8: 2171-2181Crossref PubMed Scopus (95) Google ScholarENGDeletionc.771delCp.P257fsX3581 AffectedNovelENGInsertionc.967insTp.V323fsX3331 Affected34ENGMissensec.991G>Ap.G331S1 Affected†This patient also had c.1445C>T (p.A482V) VUS in the ENG.16Letteboer TG Zewald RA Kamping EJ de Haas G Mager JJ Snijder RJ Lindhout D Hennekam FA Westermann CJ Ploos van Amstel JK Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients.Hum Genet. 2005; 116: 8-16Crossref PubMed Scopus (80) Google ScholarENGSplice sitec.992-1G->AUnknown1 AffectedNovelENGDeletionc.995delGp.G332fsX3581 Affected16Letteboer TG Zewald RA Kamping EJ de Haas G Mager JJ Snijder RJ Lindhout D Hennekam FA Westermann CJ Ploos van Amstel JK Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients.Hum Genet. 2005; 116: 8-16Crossref PubMed Scopus (80) Google ScholarENGMissensec.1121_1122AA>GC‡De novo mutations.p.K374S1 Affected16Letteboer TG Zewald RA Kamping EJ de Haas G Mager JJ Snijder RJ Lindhout D Hennekam FA Westermann CJ Ploos van Amstel JK Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients.Hum Genet. 2005; 116: 8-16Crossref PubMed Scopus (80) Google ScholarENGSplice sitec.1135 + 1G>Cp.G332fs1 Affected25Abdalla SA Cymerman U Rushlow D Chen N Stoeber GP Lemire EG Letarte M Novel mutations and polymorphisms in genes causing hereditary hemorrhagic telangiectasia.Hum Mutat. 2005; 25: 320-321Crossref PubMed Scopus (45) Google ScholarENGDeletionc.1267delAp.N423fsX4901 Affected22Gallione CJ Klaus DJ Yeh EY Stenzel TT Xue Y Anthony KB McAllister KA Baldwin MA Berg JN Lux A Smith JD Vary CP Craigen WJ Westermann CJ Warner ML Miller YE Jackson CE Guttmacher AE Marchuk DA Mutation and expression analysis of the endoglin gene in hereditary hemorrhagic telangiectasia reveals null alleles.Hum Mutat. 1998; 11: 286-294Crossref PubMed Scopus (83) Google ScholarENGInsertionc.1311 + 1_2insGUnknown1 AffectedNovelENGIndelc.1415_1417delAGAinsGTp.Q472fsX4901 Affected21Cymerman U Vera S Pece-Barbara N Bourdeau A White Jr, RI Dunn J Letarte M Identification of hereditary hemorrhagic telangiectasia type 1 in newborns by protein expression and mutation analysis of endoglin.Pediatr Res. 2000; 47: 24-35Crossref PubMed Scopus (78) Google ScholarENGInsertionc.1470_1471insAp.L490fsX5001 Affected21Cymerman U Vera S Pece-Barbara N Bourdeau A White Jr, RI Dunn J Letarte M Identification of hereditary hemorrhagic telangiectasia type 1 in newborns by protein expression" @default.
• W2050301036 created "2016-06-24" @default.
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• W2050301036 creator A5007295584 @default.
• W2050301036 creator A5019038863 @default.
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• W2050301036 creator A5052995165 @default.
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• W2050301036 date "2007-04-01" @default.
• W2050301036 modified "2023-10-18" @default.
• W2050301036 title "Clinical and Analytical Sensitivities in Hereditary Hemorrhagic Telangiectasia Testing and a Report of de Novo Mutations" @default.
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