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• W54525413 abstract "Hereditary hemorrhagic telangiectasia is an autosomal dominant disease caused by mutations in the ACVRL1 and ENG genes characterized by arterio-venous malformations and telangiectases. Over 700 mutations have been described in these two genes, and missense mutations are common. We describe 10 cases in which more than one potentially pathogenic mutation was identified. We report that 8 novel missense mutations, as well as previously reported pathogenic missense mutations, were seen in combination with a second mutation, which raises questions with regards to their respective pathogenicity. Our data and discussion indicate the challenges of classifying missense mutations as pathogenic or benign and the value of co-segregation studies, as well as suggest that there may be hereditary hemorrhagic telangiectasia gene mutations that have only mild phenotypic effects. We present evidence to suggest that four missense mutations (ENG p.G331S, ENG p.L8P, ENG p.P452L and ACVRL1 p.C344R) are pathogenic, two novel mutations (ACVRL1 p.A311T and ENG p.S576G) are neutral, and two previously reported disease-causing mutations are benign or have suspected benign variants (ACVRL1 p.A482V and ENG p.V504M). We conclude that for the purpose of establishing a causative hereditary hemorrhagic telangiectasia mutation in a family proband, all exons and intron/exon borders of both genes should be sequenced and deletion/duplication analysis should be performed unless a mutation that is well-proven to be pathogenic is identified. Hereditary hemorrhagic telangiectasia is an autosomal dominant disease caused by mutations in the ACVRL1 and ENG genes characterized by arterio-venous malformations and telangiectases. Over 700 mutations have been described in these two genes, and missense mutations are common. We describe 10 cases in which more than one potentially pathogenic mutation was identified. We report that 8 novel missense mutations, as well as previously reported pathogenic missense mutations, were seen in combination with a second mutation, which raises questions with regards to their respective pathogenicity. Our data and discussion indicate the challenges of classifying missense mutations as pathogenic or benign and the value of co-segregation studies, as well as suggest that there may be hereditary hemorrhagic telangiectasia gene mutations that have only mild phenotypic effects. We present evidence to suggest that four missense mutations (ENG p.G331S, ENG p.L8P, ENG p.P452L and ACVRL1 p.C344R) are pathogenic, two novel mutations (ACVRL1 p.A311T and ENG p.S576G) are neutral, and two previously reported disease-causing mutations are benign or have suspected benign variants (ACVRL1 p.A482V and ENG p.V504M). We conclude that for the purpose of establishing a causative hereditary hemorrhagic telangiectasia mutation in a family proband, all exons and intron/exon borders of both genes should be sequenced and deletion/duplication analysis should be performed unless a mutation that is well-proven to be pathogenic is identified. Telangiectases and arteriovenous malformations (AVMs) are the characteristic phenotypic manifestations of hereditary hemorrhagic telangiectasia (HHT), a heterogeneous autosomal dominant disorder. Recurring nosebleeds are the most common complication of telangiectases in patients with HHT, but can be mild and infrequent when they begin, typically in late childhood or early teens.1Assar A Friedman C White R The natural history of epistaxis in hereditary hemorrhagic telangiectases.Laryngoscope. 1991; 101: 977-980Crossref PubMed Scopus (180) Google Scholar AVMs that occur in the lungs, brain, or gastrointestinal tract are usually congenital lesions and can cause sudden, life-threatening complications secondary to either hemorrhage or the shunting of blood through these abnormal blood vessels. Oral and dermal telangiectasia, which can be seen by careful examination, often do not appear until the third or fourth decade of life. Although the penetrance approaches 100% by age 40, clinical expression is extremely variable and age-dependent, making HHT often a difficult diagnosis to make based on clinical examination alone.2Bayrak-Toydemir P Mao R Lewin S McDonald J Hereditary hemorrhagic telangiectasia: an overview of diagnostic and management in the molecular era for clinicians.Genetic in Medicine. 2004; 6: 175-191Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar Yet all patients with HHT should be screened for internal AVMs, which can usually be effectively removed or permanently occluded. To allow for early diagnosis and prevention of severe complications in HHT families, determination of the family's disease causing mutation is important. Five molecular subtypes of HHT have been described to date and cannot be distinguished on a clinical basis. Although AVMs in certain organs have been shown to be relatively more common in one molecular type versus another (i.e., pulmonary AVMs are more common in HHT1 and hepatic AVMs more common in HHT2), the gene involved cannot be reliable predicted based on clinical presentation.3Bayrak-Toydemir P McDonald J Markewitz B Lewin S Miller F Chou LS 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 (159) Google Scholar HHT1 is caused by mutations in the Endoglin gene (9q33-q34.1)4McAllister KA Grogg KM Johnson DW Gallione CJ Baldwin MA Jackson CE Helmbold EA Markel DS McKinnon WC Murrell J McCormick MK Pericak-Vance MA Heutink P Oostra BA Haitjema T Westerman CJJ Porteous ME Guttmacher AE Letarte M Marchuk DA Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1.Nat Genet. 1994; 8: 345-351Crossref PubMed Scopus (1230) Google Scholar and HHT2 by mutations in the ACVRL1 gene (12q11-q14).5Berg JN Gallione CJ Stenzel TT Johnson DW Allen WP Schwartz CE Jackson CE Porteous MEM 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 (206) Google Scholar Detectable mutations in these two genes account for approximately 85% of the HHT cases reported.6Bossler 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 (114) Google Scholar,7Prigoda N Savas S Abdalla S Piovesan B Rushlow D Vandezande K Zhang E Ozcelik H Gallie B Letarte M Hereditary hemorrhagic telangiectasia: mutation detection, test sensitivity and novel mutations.J Med Genet. 2006; 43: 722-728Crossref PubMed Scopus (89) Google Scholar Two HHT families have been published that show linkage to 5q31.3–32 (HHT3)8Cole 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 (248) Google Scholar and chromosome 7p14 (HHT4).9Bayrak-Toydemir P McDonald J Akarsu N Toydemir R 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. 2006; 140A: 2155-2162Crossref Scopus (178) Google Scholar Mutations in SMAD4 cause a combined syndrome of HHT and juvenile polyposis, but probably represent less than 3% of families diagnosed with HHT.10Gallione CJ Repetto GM Legius E Rustgi AK Schelley SL Tejpar S Mitchell G Drouin E Westermann CJ Marchuk DA A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4).Lancet. 2004; 363: 852-859Abstract Full Text Full Text PDF PubMed Scopus (541) Google Scholar It is unknown whether additional loci for HHT exist and there is little data regarding possible regulatory region mutations for the ACVRL1 and ENG genes. Clinical molecular genetic testing for SMAD4 has only recently become available and mutation analysis for HHT3 and HHT4 is not possible until specific genes are identified. Sequence analysis to look for mutations in the ENG and ACVRL1 has been clinically available since 2003. There are no common mutations in these two genes, the majority of mutations identified in family probands are novel, and de novo mutations are rare. Although a dominant-negative mechanism is not ruled out for all mutations, evidence suggests that haploinsufficiency is the main mechanism leading to HHT.2Bayrak-Toydemir P Mao R Lewin S McDonald J Hereditary hemorrhagic telangiectasia: an overview of diagnostic and management in the molecular era for clinicians.Genetic in Medicine. 2004; 6: 175-191Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar No affected individual has been reported to date with two deleterious mutations. In ENG, approximately 15% of sequence variants are nonsense, 38% are small deletions/duplications, 7% are large deletions/duplications, 12% are splice site mutations, and 27% are missense mutations. In ACVRL1 approximately 15% are nonsense, 14% are small deletions/duplications, 7% are large deletions/duplications, 2% are splice site mutations, and 62% are missense mutations.7Prigoda N Savas S Abdalla S Piovesan B Rushlow D Vandezande K Zhang E Ozcelik H Gallie B Letarte M Hereditary hemorrhagic telangiectasia: mutation detection, test sensitivity and novel mutations.J Med Genet. 2006; 43: 722-728Crossref PubMed Scopus (89) Google Scholar Thus, a significant percentage of the sequence variants/mutations identified in affected family probands are novel and missense.6Bossler 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 (114) Google Scholar,7Prigoda N Savas S Abdalla S Piovesan B Rushlow D Vandezande K Zhang E Ozcelik H Gallie B Letarte M Hereditary hemorrhagic telangiectasia: mutation detection, test sensitivity and novel mutations.J Med Genet. 2006; 43: 722-728Crossref PubMed Scopus (89) Google Scholar,11Gedge F McDonald J Phansalkar A Chou L Calderon F Mao R Lyon E Bayrak-Toydemir P Clinical and analytic sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations.J Mol Diagn. 2007; 9: 258-265Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Here we describe ten cases in which two possibly pathogenic mutations were detected in either ACVRL1 or ENG in families with HHT clinically confirmed according to published criteria.12Shovlin C Guttmacher A Buscarini E Faughnan M Hyland R Westermann C Kjeldsen A Plauchu H Diagnostic criteria for hereditary haemorrhagic telangiectasia.Am J Med Genet. 2000; 91: 66-67Crossref PubMed Scopus (1269) Google Scholar These cases demonstrate the challenge clinical labs face when interpreting the significance of missense mutations, including the limitations in the clinical laboratory setting of prediction programs, such as SIFT and PolyPhen. Our analysis suggests that previously published assumptions regarding the effect of some missense mutations are incorrect or uncertain. Since 2004 individuals from approximately 400 families have had molecular diagnostic testing for HHT at Associated Regional and University Pathologists Laboratories. Coding regions, exon-intron boundaries, and parts of the untranslated regions of both ENG and ACVRL1 genes were sequenced bidirectionally. Our general approach to the evaluation of the clinical significance of missense mutations has been previously reported13Bayrak-Toydemir P McDonald J Mao R Phansalkar A Gedge F Robles J Goldgar D Lyon E Likelihood ratios to assess genetic evidence for clinical significance of uncertain variants: hereditary hemorrhagic telangiectasia as a model.Exp Mol Path. 2008; 85: 45-49Crossref PubMed Scopus (20) Google Scholar and is in accordance with recently published American College of Medical Genetics guidelines.14Richards C Bale S Bellissimo D Das S Grody W Hegde M Lyon E Ward B ACMG recommendations for standards for interpretation and reporting of sequence variations: revisions 2007.Genet Med. 2008; 10: 294-300Abstract Full Text Full Text PDF PubMed Scopus (611) Google Scholar Coding regions and exon/intron boundaries of both genes were sequenced in 100 healthy individuals to help interpret novel sequence changes found in our laboratory. None of the mutations listed in this study were found in 100 healthy controls. A missense mutation is initially classified as of uncertain significance if it has not been previously reported in more than one HHT family in our laboratory, the published literature and/or the International HHT Mutation Database (hhtmutation.org). Multiplex ligation-dependent probe amplification analysis of both genes is performed using the MRC-Holland (Amsterdam, the Netherlands) kit according to manufacturer's instructions to rule out a large deletion or duplication. As is recommended by the American College of Medical Genetics, family co-segregation studies are offered at no charge to families in which novel missense mutations, or other mutations considered to be of uncertain clinical significance, are identified. Family co-segregation studies are accomplished using an Institutional Review Board approved protocol (#12259) at the University of Utah. Effort is made to include the most distant affected relative(s) possible to increase the power of the co-segregation study. Lastly, prediction programs, SIFT, and PolyPhen,15Ng PC Henikoff S Predicting the effects of amino acid substitutions on protein function.Annu Rev Genomics Hum Genet. 2006; 7: 61-80Crossref PubMed Scopus (718) Google Scholar,16Ramensky V Bork P Sunyaev S Human non-synonymous SNPs: server and survey.Nucleic Acids Res. 2002; 30: 3894-3900Crossref PubMed Scopus (1869) Google Scholar are consulted to aide in the assessment of the amino acid substitution effect. Exon Splice Enhancer (ESE 3.0) Finder was used to evaluate splice site alterations. Mutation results for ten cases and our interpretation of the clinical significance are shown in Table 1. Figure 1 shows mutation results with clinical findings in the ten cases and family members. Co-segregation information is detailed in the text below.Table 1Mutation Results for Ten Cases and Our Interpretation of the Clinical SignificanceCaseGeneNucleotide changeAmino acid changeEffectAs previously reportedReferencesCis/transSIFT result (P value)Polyphen result (PSIC score)Co-segregation (variant found in)Our interpretation1ENGc.991G>Ap.G331SSplice, missensePathogenic[19Letteboer 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 (76) Google Scholar]N/ANT (0.00)B (1.192)Affected fatherPathogenicACVRL1c.931G>Ap.A311T*The ESE Finder Program predicts that A311T changes a SF2/ASF binding site in the ACVRL1 gene. The SR protein SF2/ASF has been initially characterized as a splicing factor but has also been shown to mediate post-splicing activities such as mRNA export and translation. Since an unaffected individual carries A311T, this is not likely to be a common splicing mechanism for the ACVRL1 gene.MissenseN/A (novel)NovelN/AT (0.14)B (0.477)Unaffected motherBenign2ENGc.991G>Ap.G331SSplice, missensePathogenic[19Letteboer 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 (76) Google Scholar]N/ANT (0.00)B (1.192)Not performedPathogenicACVRL1c.1445C>Tp.A482VMissensePathogenic[19Letteboer 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 (76) Google Scholar20D'Abronzo FHSB Klibanski A Alexander JM Mutational analysis of activin/transforming growth factor-beta type I and type II receptor kinases in human pituitary tumors.J Clin Endocrinol Metab. 1999; 84: 1716-1721Crossref PubMed Google Scholar21Lesca 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 (95) Google Scholar22Schulte C Geisthoff U Lux A Kupka S Zenner HP Blin N Pfister M High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients.Hum Mutat. 2005; 25: 595Crossref PubMed Scopus (36) Google Scholar]N/ANT (0.00)B (0.853)Benign3ACVRL1c.259C>Gp.H87DMissenseN/A (novel)NovelN/AT (0.18)Prob D (2.170)Affected grandparentVUSENGc.1712G>Ap.R571HMissenseN/A (novel)NovelN/ANT (0.00)Poss D (1.852)Unaffected grandparent and sib with recurrent epistaxisVUS4ENGc.23T>Cp.L8PMissensePathogenic[21Lesca 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 (95) Google Scholar]CisT (0.07)B (0.225)Affected fatherPathogenicENGc.1712G>Ap.R571HMissenseN/A (novel)NovelCisNT (0.00)Poss D (1.852)Affected fatherVUS5ENGc.23T>Cp.L8PMissensePathogenic[21Lesca 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 (95) Google Scholar]CisT (0.07)B (0.225)Affected father and siblingPathogenicENGc.1712G>Ap.R571HMissenseN/A (novel)NovelCisNT (0.00)Poss D (1.852)Affected father and siblingVUS6ENGc.23T>Cp.L8PMissensePathogenic[21Lesca 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 (95) Google Scholar]TransT (0.07)B (0.225)Affected nephew, symptomatic motherPathogenicENGc.1510G>Ap.V504MMissensePathogenic[21Lesca 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 (95) Google Scholar23Brusgaard K Kjeldsen AD Poulsen L Moss H Vase P Rasmussen K Kruse TA Horder M Mutations in endoglin and in activin receptor-like kinase 1 among Danish patients with hereditary hemorrhagic telangiectasia.Clin Genet. 2004; 66: 556-561Crossref PubMed Scopus (40) Google Scholar]TransNT (0.00)B (1.154)Unaffected brotherSuspected benign7ENGc.726C>Ap.C242XNonsenseN/A (novel)NovelTransN/AN/AAffected pat unclePathogenicENGc.674C>Tp.P225LMissenseN/A (novel)NovelTransNT (0.03)Prob D (2.130)Mother with recurrent epistaxisPossible mild effect8ACVRL1c.1355C>Tp.P452LMissensePathogenic[6Bossler 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 (114) Google Scholar17Abdalla S Cymerman U Rushlow D Chen N Stoeber G Lemire E Letarte M Novel mutations and polymorphisms in genes causing hereditary hemorrhagic telangiectasia.Hum Mutat. 2005; 25: 320-321Crossref PubMed Scopus (45) Google Scholar]N/AT (0.17)Poss D (1.886)ProbandPathogenicENGc.1726A>Gp.S576GMissenseN/A (novel)NovelN/AT (0.4)Poss D (1.528)Unaffected fatherBenign9ACVRL1c.698C>Tp.S233LMissensePathogenic[24Argyriou L Twelkemeyer S Panchulidze I Wehner LE Teske U Engel W Nayernia K Novel mutations in the ENG and ACVRL1 genes causing hereditary hemorrhagic teleangiectasia.Int J Mol Med. 2006; 17: 655-659PubMed Google Scholar]N/ANT (0.00)Prob D (2.326)Not performedSuspected PathogenicENGc.593C>Tp.P198LMissenseN/A (novel)NovelN/ANT (0.03)Poss D (1.858)VUS10ACVRL1c.890A>Gp.H297RMissensePathogenic[18Fernandez A Sanz-Rodriguez F Zarrabeitia R Perez-Molino A Morales C Restrepo CM Ramirez JR Coto E Lenato GM Bernabeu C Botella L Mutation study of spanish patients with hereditary hemorrhagic telangiectasia and expression analysis of endoglin and ALK1.Human Mutation. 2006; 27: 295Crossref Scopus (41) Google Scholar]UnknownT (0.56)B (0.745)Unaffected 6th relativeVUSACVRL1c.1030T>Cp.C344RMissensePathogenic[6Bossler 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 (114) Google Scholar, 3Bayrak-Toydemir P McDonald J Markewitz B Lewin S Miller F Chou LS 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 (159) Google Scholar†This is the same family.]UnknownNT (0.00)Prob D (3.925)Affected mother, grandfatherPathogenicFor SIFT result: NT, not tolerated; T, tolerated.PSIC: position specific independent count provides a numeric prediction score, with a higher score indicating more confidence in the prediction. B, benign; Prob D, probably damaging; Poss D, possibly damaging.VUS, variant uncertain significance; N/A, not applicable.* The ESE Finder Program predicts that A311T changes a SF2/ASF binding site in the ACVRL1 gene. The SR protein SF2/ASF has been initially characterized as a splicing factor but has also been shown to mediate post-splicing activities such as mRNA export and translation. Since an unaffected individual carries A311T, this is not likely to be a common splicing mechanism for the ACVRL1 gene.† This is the same family. Open table in a new tab For SIFT result: NT, not tolerated; T, tolerated. PSIC: position specific independent count provides a numeric prediction score, with a higher score indicating more confidence in the prediction. B, benign; Prob D, probably damaging; Poss D, possibly damaging. VUS, variant uncertain significance; N/A, not applicable. The proband (II-1) was reported to have epistaxis, pulmonary AVM, and a first degree relative with HHT. The two mutations identified were p.G331S in ENG and p.A311T in ACVRL1. The ENG mutation had been reported twice previously as deleterious, and the ACVRL1 mutation is novel. The ENG mutation was present in the affected father, whereas the ACVRL1 mutation was found in the unaffected mother. This proband (II-1) was reported to have epistaxis, telangiectases, and a pulmonary AVM. Two mutations were detected that had previously been classified as deleterious, p.G331S in ENG and p.A482V in ACVRL1. No family members were available for segregation studies. The proband (III-1) was 11 years of age and reported to have longstanding epistaxis (approximately 3 to 4 times per week), one equivocal telangiectasia and a father affected with HHT who was unavailable for molecular study. A previously reported mutation in ENG (p.R571H) and a previously unreported mutation in ACVRL1 (p.H87D) were detected in the proband. Samples on additional family members were analyzed for co-segregation. Neither mutation was identified in the proband's unaffected mother. The ACVRL1 mutation was identified in the reportedly affected paternal grandmother. The ENG mutation was identified in the asymptomatic paternal grandfather and the proband's 8-year-old brother who, like the proband, was reported to have a history of nosebleeds 3 to 4 times per week since 1 year of age. The proband (II-1). is reported to have epistaxis, multiple oral and dermal telangiectases, pulmonary AVM, and a family history of HHT. Two mutations were identified in ENG; p.L8P, previously published as a deleterious mutation, and p.R571H, previously listed in the HHT international database in an affected individual. Study of parental samples revealed that both mutations were inherited from the proband's symptomatic father and are therefore on the same chromosome (cis). The proband (II-2), reported to have epistaxis, telangiectases, and pulmonary AVM and a family history of HHT, had the same two mutations in ENG as Case 4, p.L8P and p.R571H. A family co-segregation study identified both mutations in the proband's affected father and sibling, and identified neither mutation in the mother or the unaffected sibling. The families are not known to be related; however, haplotype analysis with seven STR markers showed that these two families share at least 4 Mb around the ENG locus (data not shown). The proband (II-1), reported to have characteristic telangiectases, pulmonary AVM, and a family history of HHT, was determined to have two mutations in ENG: p.L8P (also seen in cases 4 and 5) and p.V504M. Both had been previously published as deleterious mutations in affected individuals. Haplotype analysis using the 7 STR markers described above showed a different pattern, suggesting the p.L8P mutation in this patient is an independent event. The proband's symptomatic mother and nephew were shown to have the p.L8P mutation only. The reportedly unaffected brother was shown to have p.V504M. The proband (II-1), a 24-year-old woman, is reported to have epistaxis and telangiectases typical for HHT at her age. She and her affected paternal uncle (I-1) have the nonsense mutation p.C242X in ENG. Her clinically affected father was not available for testing but is presumed to have the ENG p.C242X mutation. In addition, the proband had a novel missense mutation p.P225L in ENG, which was also detected in her mother (I-3). Her mother reports longstanding spontaneous nosebleeds that have required no medical attention but occur often at a frequency of 1 to 3 per week. The mother has not been examined but has no other medical or family history suspicious for HHT. The proband (II-2), with epistaxis, oral and dermal telangiectasia, and a pulmonary AVM, was shown to have ACVRL1 p.P452L, previously reported twice in individuals with HHT6Bossler 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 (114) Google Scholar,17Abdalla S Cymerman U Rushlow D Chen N Stoeber G Lemire E Letarte M Novel mutations and polymorphisms in genes causing hereditary hemorrhagic telangiectasia.Hum Mutat. 2005; 25: 320-321Crossref PubMed Scopus (45) Google Scholar and ENG p. S576G, which was novel. The patient's affected mother and brother were deceased and unavailable for study, but her unaffected father was shown to have ENG p.S576G. The proband (II-1) is reported to have epistaxis, telangiectases, and a pulmonary AVM, as well as a family history of HHT. The following mutations were identified: p.S233L in ACVRL1 (previously published in affected individuals- see Figure 1) and p.P198L in ENG (novel). No family members were available for segregation studies. Targeted sequencing of exon 7 of ACVRL1 was performed on an 11 year-old (V-1) with daily epistaxis since p.C344R had previously been identified in his symptomatic mother, grandfather, aunt and also an affected sixth degree relative. In the process of sequencing this single exon, an additional mutation, p.H297R, was also detected in exon 7 of the 11-year-old. Although p.H297R is predicted to be tolerated or benign by SIFT and Polyphen, it has been previously reported in seven affected members of a family with HHT.18Fernandez A Sanz-Rodriguez F Zarrabeitia R Perez-Molino A Morales C Restrepo CM Ramirez JR Coto E Lenato GM Bernabeu C Botella L Mutation study of spanish patients with hereditary hemorrhagic telangiectasia and expression analysis of endoglin and ALK1.Human Mutation. 2006; 27: 295Crossref Scopus (41) Google Scholar We have not tested the 11-year-old's father to distinguish paternal vs. de novo origin of p.H297R in this 11-year-old. The father's history with regards to manifestations of HHT is not known. Our clinical laboratory has performed genetics testing for HHT on approximately 400 probands since early 2004. Approximately 35% of affected patients are determined to have at least one missense mutation in either the Endoglin or ACVRL1 gene.2Bayrak-Toydemir P Mao R Lewin S McDonald J Hereditary hemorrhagic telangiectasia: an overview of diagnostic and management in the molecular era for clinicians.Genetic in Medicine. 2004; 6: 175-191Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar We report here ten cases in which more than one possibly deleterious mutation was found. Functional studies could help classify these mutations, but the difficulties of these studies prevent them from being routinely used by a clinical laboratory. To help classify mutations as either pathogenic or benign, family co-segregation studies were performed when feasible, in addition to a review o" @default.
• W54525413 created "2016-06-24" @default.
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• W54525413 date "2009-11-01" @default.
• W54525413 modified "2023-10-18" @default.
• W54525413 title "Multiple Sequence Variants in Hereditary Hemorrhagic Telangiectasia Cases" @default.
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