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Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant form of vascular dysplasia. Genetic diagnosis is made by identifying loss‐of‐function variants in genes, such as ENG and ACVRL1. However, the causal mechanisms of various variants of unknown significance remains unclear. In this study, we analyzed 12 Japanese patients from 11 families who were clinically diagnosed with HHT. Sequencing analysis identified 11 distinct variants in ACVRL1 and ENG. Three of the 11 were truncating variants, leading to a definitive diagnosis, whereas the remaining eight were splice‐site and missense variants that required functional analyses. In silico splicing analyses demonstrated that three variants, c.526‐3C > G and c.598C > G in ACVRL1, and c.690‐1G > A in ENG, caused aberrant splicing, as confirmed by a minigene assay. The five remaining missense variants were p.Arg67Gln, p.Ile256Asn, p.Leu285Pro, and p.Pro424Leu in ACVRL and p.Pro165His in ENG. Nanoluciferase‐based bioluminescence analyses demonstrated that these ACVRL1 variants impaired cell membrane trafficking, resulting in the loss of bone morphogenetic protein 9 (BMP9) signal transduction. In contrast, the ENG mutation impaired BMP9 signaling despite normal cell membrane expression. The updated functional analysis methods performed in this study will facilitate effective genetic testing and appropriate medical care for patients with HHT. [ABSTRACT FROM AUTHOR]

Hereditary hemorrhagic telangiectasia ( HHT, Osler-Weber-Rendu disease) is an autosomal dominant inherited disease defined by the presence of epistaxis and mucocutaneous telangiectasias and arteriovenous malformations ( AVMs) in internal organs. In most families (∼85%), HHT is caused by mutations in the ENG ( HHT1) or the ACVRL1 ( HHT2) genes. Here, we report the results of genetic testing of 113 Norwegian families with suspected or definite HHT. Variants in ENG and ACVRL1 were found in 105 families (42 ENG, 63 ACVRL1), including six novel variants of uncertain pathogenic significance. Mutation types were similar to previous reports with more missense variants in ACVRL1 and more nonsense, frameshift and splice-site mutations in ENG. Thirty-two variants were novel in this study. The preponderance of ACVRL1 mutations was due to founder mutations, specifically, c. 830C>A (p. Thr277Lys), which was found in 24 families from the same geographical area of Norway. We discuss the importance of founder mutations and present a thorough evaluation of missense and splice-site variants. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

McDonald J, Damjanovich K, Millson A, Wooderchak W, Chibuk JM, Stevenson DA, Gedge F, Bayrak-Toydemir P. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. 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. [ABSTRACT FROM AUTHOR]

Wooderchak W, Gedge F, McDonald M, Krautscheid P, Wang X, Malkiewicz J, Bukjiok CJ, Lewis T, Bayrak-Toydemir P. Hereditary hemorrhagic telangiectasia: two distinct ENG deletions in one family. Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by aberrant vascular development. Mutations in endoglin ( ENG) or activin A receptor type II-like 1 ( ACVRL1) account for around 90% of HHT patients, 10% of those are large deletions or duplications. We report here the first observation of two distinct, large ENG deletions segregating in one pedigree. An ENG exon 4-7 deletion was observed in a patient with HHT. This deletion was identified in several affected family members. However, some affected family members had an ENG exon 3 deletion instead. These deletions were detected by multiplex ligation-dependent probe amplification and confirmed by mRNA sequencing and an oligo-CGH array. Linkage analysis revealed that one individual with the exon 3 deletion inherited the same chromosome from his mother who has the exon 4-7 deletion. This finding has important clinical implications because it shows that targeted family-specific mutation analysis for exon deletions could have led to the misdiagnosis of some affected family members. [ABSTRACT FROM AUTHOR]

Hereditary haemorrhagic telangiectasia (HHT) is a heterogeneous multisystemic dysplasia of the vascular tissue. This autosomal dominant inherited disorder shows a wide variation in its phenotypic expression. Between 8 and 78% of the HHT patients show arteriovenous malformations of the liver. The molecular basis for hepatic manifestation is still unknown. Two genes are known to play a major role in the development of HHT: activin A receptor type II-like 1 gene ( ACVRL1) and ENG. Previously, we and others showed that hepatic involvement is associated with mutations in the ACVRL1 gene, but rarely caused by ENG mutations. Here, we report about the sequencing analysis of a new cohort of 18 adult HHT patients. In these patients, we identified eight novel (four in ACVRL1 and four in ENG) and eight already known mutations. Statistical analysis of our entire data revealed significant differences in the distribution of ACVRL1 and ENG mutations among HHT patients with and without liver involvement (p = 0.0016). The positive predictive value for type 2 HHT ( ACVRL1 positive) patients to develop liver disease until the age of 52 years is 68.4%. We conclude that molecular genetic testing of HHT patients is important for prognosis with respect to liver disease. [ABSTRACT FROM AUTHOR]

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal-dominant disease characterized by recurrent epistaxis, mucocutaneous telangiectasias and visceral arteriovenous malformations. Mutations in endoglin ( ENG) and activin A receptor type II-like kinase 1 ( ACVRL1 or ALK1) have been found in patients with HHT. We have screened a total of 51 unselected German index cases with the suspected diagnosis of HHT. We identified 30 different mutations in 32 cases (62.7%) by direct sequencing. Among these mutations, 11 of 13 ENG mutations and 12 of 17 ACVRL1 mutations were not previously reported in the literature. Two of the ACVRL1 mutations were each shared by two families. An analysis of the genotype–phenotype correlation is consistent with a more common frequency of pulmonary arteriovenous malformations in patients with ENG mutations than in patients with ACVRL1 mutations in our collective. [ABSTRACT FROM AUTHOR]