Determine the variant detection rate for ENG, ACVRL1, and SMAD4 in individuals who meet consensus (Curaçao) criteria for the clinical diagnosis of hereditary hemorrhagic telangiectasia.
Review of HHT ...center database for individuals with three or more HHT diagnostic criteria, in whom molecular genetic analysis for ENG, ACVRL1, and SMAD4 had been performed.
A variant known or suspected to be causal was detected in ENG in 67/152 (44.1%; 95% confidence interval CI, 36.0-52.4%), ACVRL1 in 79/152 (52.0%; 95% CI, 43.7-60.1%), and SMAD4 in 2/152 (1.3%; 95% CI, 0.2-4.7%) family probands with definite HHT. Only 4/152 (2.6%; 95% CI, 0.7-6.6%) family probands did not have a variant in one of these genes.
Previous reports of the variant detection rate for ENG and ACVRL1 in HHT patients have come from laboratories, which receive samples from clinicians with a wide range of expertise in recognizing clinical manifestations of HHT. These studies suggest a significantly lower detection rate (~75-85%) than we have found in patients who meet strictly applied consensus criteria (96.1%). Analysis of SMAD4 adds an additional detection rate of 1.3%. HHT as defined by the Curaçao criteria is highly predictive of a causative variant in either ENG or ACVRL1.
Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia characterized by telangiectases and arteriovenous malformations (AVMs) in particular locations described in consensus clinical ...diagnostic criteria published in 2000. Two genes in the transforming growth factor-beta (TGF-β) signaling pathway, ENG and ACVRL1, were discovered almost two decades ago, and mutations in these genes have been reported to cause up to 85% of HHT. In our experience, approximately 96% of individuals with HHT have a mutation in these two genes, when published (Curaçao) diagnostic criteria for HHT are strictly applied. More recently, two additional genes in the same pathway, SMAD4 and GDF2, have been identified in a much smaller number of patients with a similar or overlapping phenotype to HHT. Yet families still exist with compelling evidence of a hereditary telangiectasia disorder, but no identifiable mutation in a known gene. Recent availability of whole exome and genome testing has created new opportunities to facilitate gene discovery, identify genetic modifiers to explain clinical variability, and potentially define an increased spectrum of hereditary telangiectasia disorders. An expanded approach to molecular diagnostics for inherited telangiectasia disorders that incorporates a multi-gene next generation sequencing (NGS) HHT panel is proposed.
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder that presents with telangiectases in skin and mucosae, and arteriovenous malformations (AVMs) in internal organs ...such as lungs, liver, and brain. Mutations in ENG (endoglin), ACVRL1 (ALK1), and MADH4 (Smad4) genes account for over 95% of HHT. Localized telangiectases and AVMs are present in different organs, with frequencies which differ among affected individuals. By itself, HHT gene heterozygosity does not account for the focal nature and varying presentation of the vascular lesions leading to the hypothesis of a “second-hit” that triggers the lesions. Accumulating research has identified a variety of triggers that may synergize with HHT gene heterozygosity to generate the vascular lesions. Among the postulated second-hits are: mechanical trauma, light, inflammation, vascular injury, angiogenic stimuli, shear stress, modifier genes, and somatic mutations in the wildtype HHT gene allele. The aim of this review is to summarize these triggers, as well as the functional mechanisms involved.
The NFIX gene encodes a DNA‐binding protein belonging to the nuclear factor one (NFI) family of transcription factors. Pathogenic variants of NFIX are associated with two autosomal dominant Mendelian ...disorders, Malan syndrome (MIM 614753) and Marshall–Smith syndrome (MIM 602535), which are clinically distinct due to different disease‐causing mechanisms. NFIX variants associated with Malan syndrome are missense variants mostly located in exon 2 encoding the N‐terminal DNA binding and dimerization domain or are protein‐truncating variants that trigger nonsense‐mediated mRNA decay (NMD) resulting in NFIX haploinsufficiency. NFIX variants associated with Marshall–Smith syndrome are protein‐truncating and are clustered between exons 6 and 10, including a recurrent Alu‐mediated deletion of exons 6 and 7, which can escape NMD. The more severe phenotype of Marshall–Smith syndrome is likely due to a dominant‐negative effect of these protein‐truncating variants that escape NMD. Here, we report a child with clinical features of Malan syndrome who has a de novo NFIX intragenic duplication. Using genome sequencing, exon‐level microarray analysis, and RNA sequencing, we show that this duplication encompasses exons 6 and 7 and leads to NFIX haploinsufficiency. To our knowledge, this is the first reported case of Malan Syndrome caused by an intragenic NFIX duplication.
Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) is a disorder of development of the vasculature characterized by telangiectases and arteriovenous malformations in specific ...locations. It is one of most common monogenic disorders, but affected individuals are frequently not diagnosed. The most common features of the disorder, nosebleeds, and telangiectases on the lips, hands, and oral mucosa are often quite subtle. Optimal management requires an understanding of the specific presentations of these vascular malformations, especially their locations and timing during life. Telangiectases in the nasal and gastrointestinal mucosa and brain arteriovenous malformations generally present with hemorrhage. However, complications of arteriovenous malformations in the lungs and liver are generally the consequence of blood shunting through these abnormal blood vessels, which lack a capillary bed and thus result in a direct artery-to-vein connection. Mutations in at least five genes are thought to result in hereditary hemorrhagic telangiectasia, but mutations in two genes (ENG and ACVRL1/ALK1) cause approximately 85% of cases. The frequency of arteriovenous malformations in particular organs and the occurrence of certain rare symptoms are dependent on the gene involved. Molecular genetic testing is used to establish the genetic subtype of hereditary hemorrhagic telangiectasia in a clinically affected individual and family, and for early diagnosis to allow for appropriate screening and preventive treatment.
The NONO gene encodes a nuclear protein involved in RNA metabolism. Hemizygous loss‐of‐function NONO variants have been associated with syndromic intellectual disability and with left ventricular ...noncompaction (LVNC). A two‐year‐old boy presented to the University of Utah's Penelope Undiagnosed Disease Program with developmental delay, nonfamilial features, relative macrocephaly, and dilated cardiomyopathy with LVNC and Ebstein anomaly. Brain MRI showed a thick corpus callosum, mild Chiari I malformation, and a flattened pituitary. Exome sequencing identified a novel intronic deletion (c.154+5_154+6delGT) in the NONO gene. Splicing studies demonstrated intron 4 read‐through and the use of an alternative donor causing the frameshift p.Asn52Serfs*6. Family segregation analysis showed that the variant occurred de novo in the boy's unaffected mother. MRI and endocrine findings suggest that hypopituitarism may contribute to growth failure, abnormal thyroid hormone levels, cryptorchidism, or delayed puberty in patients with NONO‐associated disease. Also, including this case LVNC has been observed in five out of eight patients, and this report also confirms an association between loss of NONO and Ebstein anomaly. In some cases, unrelated individuals share the same pathogenic NONO variants but do not all have clinically significant LVNC, suggesting that additional modifiers may contribute to cardiac phenotypes.
In studies of families with rare disease, it is common to screen for de novo mutations, as well as recessive or dominant variants that explain the phenotype. However, the filtering strategies and ...software used to prioritize high-confidence variants vary from study to study. In an effort to establish recommendations for rare disease research, we explore effective guidelines for variant (SNP and INDEL) filtering and report the expected number of candidates for de novo dominant, recessive, and autosomal dominant modes of inheritance. We derived these guidelines using two large family-based cohorts that underwent whole-genome sequencing, as well as two family cohorts with whole-exome sequencing. The filters are applied to common attributes, including genotype-quality, sequencing depth, allele balance, and population allele frequency. The resulting guidelines yield ~10 candidate SNP and INDEL variants per exome, and 18 per genome for recessive and de novo dominant modes of inheritance, with substantially more candidates for autosomal dominant inheritance. For family-based, whole-genome sequencing studies, this number includes an average of three de novo, ten compound heterozygous, one autosomal recessive, four X-linked variants, and roughly 100 candidate variants following autosomal dominant inheritance. The slivar software we developed to establish and rapidly apply these filters to VCF files is available at https://github.com/brentp/slivar under an MIT license, and includes documentation and recommendations for best practices for rare disease analysis.
EPHB4 variants were recently reported to cause capillary malformation–arteriovenous malformation 2 (CM-AVM2). CM-AVM2 mimics RASA1-related CM-AVM1 and hereditary hemorrhagic telangiectasia (HHT), as ...clinical features include capillary malformations (CMs), telangiectasia, and arteriovenous malformations (AVMs). Epistaxis, another clinical feature that overlaps with HHT, was reported in several cases. Based on the clinical overlap of CM-AVM2 and HHT, we hypothesized that patients considered clinically suspicious for HHT with no variant detected in an HHT gene (ENG, ACVRL1, or SMAD4) may have an EPHB4 variant.
Exome sequencing or a next-generation sequencing panel including EPHB4 was performed on individuals with previously negative molecular genetic testing for the HHT genes and/or RASA1.
An EPHB4 variant was identified in ten unrelated cases. Seven cases had a pathogenic EPHB4 variant, including one with mosaicism. Three cases had an EPHB4 variant of uncertain significance. The majority had epistaxis (6/10 cases) and telangiectasia (8/10 cases), as well as CMs. Two of ten cases had a central nervous system AVM.
Our results emphasize the importance of considering CM-AVM2 as part of the clinical differential for HHT and other vascular malformation syndromes. Yet, these cases highlight significant differences in the cutaneous presentations of CM-AVM2 versus HHT.
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