Specifications of the ACMG/AMP variant curation guidelines for hereditary hemorrhagic telangiectasia genes - ENG and ACVRL1

13 p.-1 fig.-3 tab.The 2015 ACMG/AMP standards and guidelines for interpretation of sequence variants are widely used by laboratories, including for variant curation of the hereditary hemorrhagic telangiectasia (HHT) genes. However, the need for gene- and disease-specific modifications and specifications of these general guidelines to optimize and standardize variant classification was recognized at the time of publication. With this goal, the ClinGen HHT variant curation expert panel was formed. Here, we describe our recommended HHT-specific variant classification criteria and the outcomes from pilot testing of 30 variants of the ENG and ACVRL1 genes. Eight of the original ACMG/AMP rules were determined to not be applicable for ENG- or ACVRL1-related HHT or were previously recommended by ClinGen for removal, two rules were unmodified, and the remaining 18 rules were modified according to HHT specifications or previous ClinGen general recommendations. This study demonstrates the importance of HHT-specific criteria in the optimization and standardization of HHT variant classification and conflicting classification resolution. © 2024 Desiree DeMille et al.The authors would like to acknowledge the support of the ClinGen Sequence Variant Interpretation Working Group and the Hemostasis/Thrombosis Clinical Domain Working Group, especially Kristy Lee. The authors would also like to acknowledge the participation of previous ClinGen HHT VCEP members: Pernille Tørring, Hans Kristian Ploos van Amstel, and Helen Arthur. CLS acknowledges support from the NIHR Imperial Biomedical Research Centre. LJ acknowledges support from Knut and Alice Wallenberg Foundation grant (2018.0042) and Swedish Research Council grant (2020-04936). CB was supported by Consejo Superior de Investigaciones Cientificas (CSIC) of Spain. CC, CO,and AS are funded by the Italian Ministry of University and Research, “Fondo Beneficenza Intesa Sanpaolo,” and Banca d’Italia. ClinGen is primarily funded by the National Human Genome Research Institute (NHGRI) with cofunding from the National Cancer Institute (NCI), through the following grants: Baylor/Stanford (U24HG009649), Broad/Geisinger(U24HG006834), and UNC/Kaiser (U24HG009650).Peer reviewe

Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency

Purpose Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved. Methods Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated. Results Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated. Conclusions This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features

Wiskott-Aldrich syndrome protein-mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells

Mutations in Wiskott-Aldrich syndrome (WAS) protein (WASp), a regulator of actin dynamics in hematopoietic cells, cause WAS, an X-linked primary immunodeficiency characterized by recurrent infections and a marked predisposition to develop autoimmune disorders. The mechanisms that link actin alterations to the autoimmune phenotype are still poorly understood. We show that chronic activation of plasmacytoid dendritic cells (pDCs) and elevated type-I interferon (IFN) levels play a role in WAS autoimmunity. WAS patients display increased expression of type-I IFN genes and their inducible targets, alteration in pD

Maladie de Rendu-Osler

La maladie de Rendu Osler, encore appelée télangiectasie hémorragique héréditaire (HHT) touche une personne sur 5 000 à 8 000. Une large étude épidémiologique réalisée en France a montré une concentration géographique dans le Jura. Cette pathologie se définit par la présence d’épistaxis, de télangiectasies cutanées ou muqueuses et une transmission de type autosomique dominant. Les complications des télangiectasies cutanées ou muqueuses sont plutôt hémorragiques alors que les manifestations viscérales, moins fréquentes, se compliquent de fistules artérioveineuses dans le poumon, le foie ou le système nerveux. Les gènes responsables de cette pathologie, ENG, ACVRL1, MADH4, interviennent tous dans la voie de signalisation de la famille TGFβ dans la cellule endothéliale. La découverte récente de BMP9 comme étant le ligand du récepteur ALK1 et de son corécepteur l’endogline montre que cette voie de signalisation contrôle la phase de maturation de l’angiogenèse. L’invalidation de ces gènes dans des modèles murins reproduit la maladie et a permis de confirmer que cette pathologie serait due à une hyperprolifération endothéliale. La prise en charge est encore actuellement symptomatique, cependant le caractère angiogénique de cette pathologie laisse entrevoir une possibilité thérapeutique intéressante par le biais de modulateurs de cette angiogenèse

Altered expressions of CXCR4 and CD26 on T-helper lymphocytes in hereditary hemorrhagic telangiectasia

International audienceBackground Hereditary hemorrhagic telangiectasia (HHT) is a rare genetic disease characterized by a deregulated neo-angiogenesis. Besides a mainly vascular phenotype (muco-cutaneous telangiectases, arteriovenous malformations), a specific risk of infection is suggested by case series of severe and atypical infections as well as by reports of decreased T and natural killer (NK) lymphocyte counts. As some evidence supports a dysregulation of the CXCR4/CXCL12 chemotactic axis of HHT endothelial cells, we hypothesized that a similar phenomenon could occur on lymphocytes.Methods Eighteen HHT patients with history of severe infection (HSI) were matched in age and sex with 18 HHT without HSI and 18 healthy control subjects (HC). We assessed the cell count and the surface expression of CXCR4 and CD26 (CXCL12 inactivating peptidase) of circulating T-helper and T-cytotoxic lymphocytes (including naive, memory and activated subsets) and NK cells.Results The overall HHT group of 36 patients exhibited a reduction of circulating T-helper lymphocytes compared to HC (median: 517 vs. 1026 cells/mm 3 , p < 0.0001), correlated with age (r = − 0.46, p = 0.005), requirement of intravenous iron or blood transfusions (median: 291 vs. 627 cells/mm 3 , p = 0.03) and CXCR4 surface expression (r = 0.353, p = 0.0345). CXCR4 and CD26 membrane expression were both decreased on HHT T-helper lymphocytes (median MFI ratio: 4.49 vs. 5.74 for CXCR4 and 3.21 vs. 4.33 for CD26, p = 0.03 and 0.0018 respectively) with an unchanged CXCR4/CD26 ratio. The HHT group with HSI had a higher CXCR4/CD26 ratio on the total T-lymphocyte population, as well as on the T-helper population and its naive subset (median on naive T-helper cells: 2.34 vs. 1.32, p = 0.0002).Conclusions Our findings support a dysregulation of the CXCL12/CXCR4 chemotaxis of T-helper lymphocytes in HHT patients, potentially linked to their T-helper lymphopenia and susceptibility to infection

Pulmonary vascular manifestations of hereditary hemorrhagic telangiectasia (Rendu-Osler disease)

International audienceHereditary hemorrhagic telangiectasia (HHT) or Rendu-OslerWeber disease is a genetic disorder with autosomal dominance and variable penetrance, characterized by epistaxis, telangiectasia and visceral manifestations of the disease. The estimated minimal prevalence is 1/10,000 inhabitants. The diagnosis is established on clinical criteria, and may be further confirmed by the identification of causative mutations in either the ENG or the ACVRL1 gene coding for endoglin and ALK1, respectively. Pulmonary vascular manifestations of HHT include pulmonary arteriovenous malformations (PAVMs; especially in patients with ENG mutations) and less frequently pulmonary hypertension (especially in patients with ACVRL1 mutations). In 15-33% of patients with HHT, PAVMs consist of abnormal communications between pulmonary arteries and pulmonary veins, causing right-to-left shunting, and thus, frequently hypoxemia and dyspnea on exertion, although PAVMs may remain asymptomatic and frequently undiagnosed unless complications occur. PAVMs result in severe and frequent complications often at a young age, which may reveal the diagnosis, e. g. transient ischemic attack and cerebral stroke (10-19% of patients), systemic severe infections and abscesses (including cerebral abscess in 5-19% of patients), and rarely massive hemoptysis or hemothorax. Infections in HHT are related to the right-to-left shunting that bypasses the pulmonary capillaries and facilitates the passage of septic or aseptic emboli into the systemic and especially cerebral circulation, and potentially to minor defects in innate immunity. Treatment of PAVMs based on transcatheter coil vaso-occlusion of the feeding artery significantly decreases right-to-left shunting, hypoxemia and dyspnea on exertion, and reduces the risk of systemic complications. Long-term follow-up is warranted after transcatheter vaso-occlusion of PAVMs due to frequent recanalization of treated PAVMs and development or growth of treated PAVMs. Patients with HHT should be informed of the risk of PAVM and potentially severe complications occurring in heretofore asymptomatic subjects. All adult patients with HHT should be proposed systematic screening for PAVM, by contrast echocardiography (preceded by anteroposterior chest radiograph) or computed tomography of the chest. Pulmonary hypertension is rare in HHT, and may be due either to systemic arteriovenous shunting in the liver increasing cardiac output or be clinically and histologically indistinguishable from idiopathic pulmonary arterial hypertension. Pulmonary hypertension is detected by systematic examination of right cardiac cavities and tricuspid regurgitation flow at echocardiography, and the diagnosis is established by right heart catheterization

Pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia : Follow-up and pathophysiologic considerations

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Comment on Kilian et al. Comparing Characteristics and Treatment of Brain Vascular Malformations in Children and Adults with HHT. <i>J. Clin. Med.</i> 2023, <i>12</i>, 2704

We read with interest the recent article by Killian et al. regarding the characteristics and treatment of brain vascular malformations (VMs) in children and adults with hereditary hemorrhagic telangiectasia (HHT) [...