Publications by authors named "Xavier Jeunemaitre"

221 Publications

Genetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases.

Nat Commun 2021 Oct 15;12(1):6031. Epub 2021 Oct 15.

Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.

Fibromuscular dysplasia (FMD) is an arteriopathy associated with hypertension, stroke and myocardial infarction, affecting mostly women. We report results from the first genome-wide association meta-analysis of six studies including 1556 FMD cases and 7100 controls. We find an estimate of SNP-based heritability compatible with FMD having a polygenic basis, and report four robustly associated loci (PHACTR1, LRP1, ATP2B1, and LIMA1). Transcriptome-wide association analysis in arteries identifies one additional locus (SLC24A3). We characterize open chromatin in arterial primary cells and find that FMD associated variants are located in arterial-specific regulatory elements. Target genes are broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. We find significant genetic overlap between FMD and more common cardiovascular diseases and traits including blood pressure, migraine, intracranial aneurysm, and coronary artery disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-26174-2DOI Listing
October 2021

The variety of genetic defects explains the phenotypic heterogeneity of Familial Hyperkalemic Hypertension.

Kidney Int Rep 2021 Oct 2;6(10):2639-2652. Epub 2021 Aug 2.

Université de Paris, INSERM, Paris Cardiovascular Research Centre, Paris, France.

Introduction: Familial hyperkalemic hypertension is a rare inherited form of arterial hypertension. Four genes are responsible for this disease, the variants of these genes cause disruption in the regulation of ion transport in the distal renal tubule. Whether the genotype explains the large phenotypic heterogeneity has not been fully explored.

Methods: We retrospectively analyzed clinical and genetic data of 153 cases (84 probands, 69 relatives) with familial hyperkalemic hypertension.

Results: Pathogenic variants (25 novel variants) were identified as follows: (n = 50), (n = 16), acidic motif (n = 11), acidic motif (n = 4) and intron 1 deletions (n = 3). cases were mainly observed in the -related cases (9 of 12) and recessive cases were only observed in -related cases (14 of 50). More severe forms were observed in recessive and cases that were also associated with growth retardation. Patients with acidic motif variants had a typical biological phenotype and lower frequency of hypertension conversely to variants affecting the same motif. Patients with heterozygous and deletions had milder forms. Familial screening in 178 relatives allowed detection and care for 69 positive cases. Blood pressure and hyperkalemia were improved by hydrochlorothiazide in all groups.

Conclusions: This study confirms the phenotypic variability ranging from the severe and early forms associated with and recessive genotypes through intermediate forms associated with dominant, and deletion to mild form associated with acidic motif genotype and reinforces the interest of genetic screening to better orientate medical care and genetic counseling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ekir.2021.07.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484123PMC
October 2021

Genome-Wide Association Meta-Analysis Supports Genes Involved in Valve and Cardiac Development to Associate With Mitral Valve Prolapse.

Circ Genom Precis Med 2021 Oct 31;14(5):e003148. Epub 2021 Aug 31.

PARCC, Inserm, Université de Paris, F-75015, Paris, France (M.Y., S.K., X.J., N.B.-N.).

Background: Mitral valve prolapse (MVP) is a common cardiac valve disease, which affects 1 in 40 in the general population. Previous genome-wide association study has identified 6 risk loci for MVP. But these loci explained only partially the genetic risk for MVP. We aim to identify additional risk loci for MVP by adding data set from the UK Biobank.

Methods: We also incorporated 434 MVP cases and 4527 controls from the UK Biobank for discovery analyses. Genetic association was conducted using SNPTEST and meta-analyses using METAL. We used Functional Mapping and Annotation of Genome-Wide Association Studies for post-genome-wide association study annotations and Multi-marker Analysis of GenoMic Annotation for gene-based and gene-set analyses.

Results: We found Trans-Omics for Precision Medicine imputation to perform better in terms of accuracy in the lower ranges of minor allele frequency below 0.1. Our updated meta-analysis included UK Biobank study for ≈8 million common single-nucleotide polymorphisms (minor allele frequency >0.01) and replicated the association on Chr2 as the top association signal near . We identified an additional risk locus on Chr1 () and 2 suggestive risk loci on chr8 () and chr19 (), all driven by common variants. Gene-based association using Multi-marker Analysis of GenoMic Annotation revealed 6 risk genes for MVP with pronounced expression levels in cardiovascular tissues, especially the heart and globally part of enriched GO terms related to cardiac development.

Conclusions: We report an updated meta-analysis genome-wide association study for MVP using dense imputation coverage and an improved case-control sample. We describe several loci and genes with MVP spanning biological mechanisms highly relevant to MVP, especially during valve and heart development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.120.003148DOI Listing
October 2021

Male Sex Is Associated With Cervical Artery Dissection in Patients With Fibromuscular Dysplasia.

J Am Heart Assoc 2021 06 17;10(11):e018311. Epub 2021 May 17.

Department of Neurology Inserm U1237 Normandie UniversitéUniversité Caen NormandieCHU Caen Normandie Caen France.

Background Cervical artery dissection (CeAD) is a frequent manifestation of fibromuscular dysplasia (FMD). However, risk factors for CeAD are unknown. We investigated factors associated with CeAD in the ARCADIA (Assessment of Renal and Cervical Artery Dysplasia) registry. Methods and Results The ARCADIA registry includes women or men aged ≥18 years, with a diagnosis of renal, cervical, or intracranial artery FMD, who were prospectively recruited at 16 university hospitals in France and Belgium. Diagnosis of acute or past CeAD at inclusion was established on imaging according to standard diagnostic criteria. Associations between potential determinants and CeAD were assessed by logistic regression analyses. Among 469 patients (75 men) with FMD, 65 (13.9%) had CeAD. Patients with CeAD were younger, more likely to be men, have a history of migraine, and less likely to have a history of hypertension than patients without CeAD. In the multivariable analysis, male sex (odds ratio [OR], 2.66; 95% CI, 1.34-5.25), history of migraine (OR, 1.90; 95% CI, 1.06-3.39), age ≥50 years (OR, 0.41; 95% CI, 0.23-0.73), history of hypertension (OR, 0.35; 95% CI, 0.20-0.64), and involvement of ≥3 vascular beds (OR, 2.49; 95% CI, 1.15-5.40) were significantly associated with CeAD. To validate the association between CeAD and sex, we performed a systematic review. We collected additional data on sex from 2 published studies and unpublished data from the US Registry for Fibromuscular Dysplasia and the European/International FMD Registry. In the pooled analysis (289 CeAD, 1933 patients), male sex was significantly associated with CeAD (OR, 2.04; 95% CI, 1.41-2.95; =0%). Conclusions In patients with FMD, male sex and multisite involvement are associated with CeAD, in addition to other previously known risk factors. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02884141.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.120.018311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483547PMC
June 2021

Acute decrease of urine calcium by amiloride in healthy volunteers under high sodium diet.

Nephrol Dial Transplant 2021 Apr 29. Epub 2021 Apr 29.

Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland and Service of Nephrology, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.

Background: Amiloride is a competitive blocker of the epithelial sodium channel (ENaC) in the renal collecting duct. It is a less potent diuretic than thiazides or loop diuretics, but is often used in association for its potassium-sparing profile. Whether amiloride has hypocalciuric effect similar to thiazides remains unclear. Animal studies and experiments on cell lines suggested that amiloride increases calcium reabsorption in the distal nephron, but human studies are scarce.

Methods: We performed a post hoc analysis of a study with 48 healthy males (age, 23.2 ± 3.9 years) who were assigned to a high sodium (Na)/low potassium (K) diet for 7 days before receiving 20 mg of amiloride p.o. Urinary excretions of electrolytes were measured at 3 and 6 hours afterward; we calculated the relative changes in urinary excretion rates after amiloride administration.

Results: The high Na/low K diet led to an expected suppression of plasma renin and aldosterone. Amiloride showed a mild natriuretic effect associated with a decreased kaliuresis. Urinary calcium excretion dropped substantially (by 80%) 3 hours after amiloride administration and remained low at the 6th hour. At the same time, fractional excretion of lithium decreased by a third, reflecting an increased proximal tubular reabsorption.

Conclusion: During a high Na/low K diet, amiloride had a strong acute hypocalciuric effect, most probably mediated by increased proximal calcium reabsorption, even though distal effect cannot be excluded. Further studies should establish if chronic amiloride or combined amiloride/thiazide treatment may decrease calciuria more efficiently and be useful in preventing kidney stones.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfab159DOI Listing
April 2021

Periodontal (formerly type VIII) Ehlers-Danlos syndrome: Description of 13 novel cases and expansion of the clinical phenotype.

Clin Genet 2021 08 29;100(2):206-212. Epub 2021 Apr 29.

Clinique Dermatologique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

Periodontal Ehlers-Danlos syndrome (pEDS) is a rare condition caused by pathogenic variants in the C1R and C1S genes, encoding subunits C1r and C1s of the first component of the classical complement pathway. It is characterized by early-onset periodontitis with premature tooth loss, pretibial hyperpigmentation and skin fragility. Rare arterial complications have been reported, but venous insufficiency is rarely described. Here we report 13 novel patients carrying heterozygous pathogenic variants in C1R and C1S including three novel C1S variants (c.962G > C, c.961 T > G and c.961 T > A). In addition to the pEDS phenotype, three patients and one relative displayed widespread venous insufficiency leading to persistent varicose leg ulcers. One patient suffered an intracranial aneurysm with familial vascular complications including thoracic and abdominal aortic aneurysm and dissection and intracranial aneurysm rupture. This work confirms that vascular complications can occur, although they are not frequent, which leads us to propose to carry out a first complete non-invasive vascular evaluation at the time of the diagnosis in pEDS patients. However, larger case series are needed to improve our understanding of the link between complement pathway activation and connective tissue alterations observed in these patients, and to better assess the frequency, type and consequences of the vascular complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.13972DOI Listing
August 2021

Management and outcomes of hypertrophic cardiomyopathy in young adults.

Arch Cardiovasc Dis 2021 Jun-Jul;114(6-7):465-473. Epub 2021 Mar 17.

Cardiology department, Hôpital européen Georges Pompidou, AP-HP, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris cité, 75006 Paris, France; INSERM CMR970, Paris cardiovascular research centre (PARCC), 75015 Paris, France. Electronic address:

Background: Management of young adults with hypertrophic cardiomyopathy (HCM) is challenging.

Aims: To evaluate the profile of young adults (16-25 years) with HCM included in the French prospective HCM registry.

Methods: Patients were compared according to occurrence of major adverse cardiac events (MACE), comprising sudden cardiac death (SCD) events (implantable cardioverter defibrillator [ICD] discharge, SCD, sustained ventricular tachycardia), atrial fibrillation/embolic stroke, heart failure hospitalisation and unexplained syncope, at a mean follow-up of 4.4±2.2 years.

Results: At baseline, among 61 patients (20.5±3.0 years; 16 women, 26.2%), 13 (21.3%) had a prophylactic ICD, 24.6% a family history of SCD, 29.5% obstruction, 86.0% magnetic resonance imaging myocardial fibrosis, 11.8% abnormal exercise blood pressure and 52.8% a European Society of Cardiology (ESC) 5-year SCD score<4% (24.5%≥6%). At follow-up, 15 patients (24.6%; seven women; all with fibrosis) presented 17 MACE, comprising: SCD events (n=7, 41.2%; including three patients with an ICD, five with at least one SCD major classical risk factor and an ESC score≥5% and two with no risk factors and an ESC score<4%); atrial fibrillation/stroke (n=6, 35.3%); heart failure (n=1, 5.9%); syncope (n=3, 17.6%). An ICD was implanted in 11 patients (four for secondary prevention), but in only 61.5% of patients with a score≥6%. Only obstruction significantly increased MACE risk (odds ratio 3.96; P=0.035), with a non-significant trend towards a lower risk in men (OR 0.29; P=0.065).

Conclusions: In young adults with HCM, MACE are common in the short term, especially in obstructive HCM and women, mostly arrhythmic in origin. Prophylactic ICD implantation is frequent and does not strictly follow the guidelines, while the use of European/USA guidelines is helpful but imperfect in identifying SCD risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.acvd.2020.12.006DOI Listing
September 2021

Vascular Ehlers-Danlos syndrome (vEDS): CT and histologic findings of pleural and lung parenchymal damage.

Eur Radiol 2021 Aug 2;31(8):6275-6285. Epub 2021 Mar 2.

Université de Paris - Service de Pneumologie et Soins Intensifs, Centre de Compétences Maladies Rares Pulmonaires - Hôpital Européen Georges Pompidou - AP-HP - INSERM UMRS 1140, Paris, France.

Objectives: To describe CT features of lung involvement in patients with vascular Ehlers-Danlos syndrome (vEDS), a rare genetic condition caused by pathogenic variants within the COL3A1 gene, characterized by recurrent arterial, digestive, and pulmonary events.

Material And Methods: All consecutive vEDS patients referred to the national tertiary referral center for vEDS, between 2004 and 2016, were included. Chest CT scans obtained during the initial vascular work-up were reviewed retrospectively by two chest radiologists for lung involvement. Five surgical samples underwent histologic examination.

Results: Among 136 enrolled patients (83 women, 53 men; mean age 37 years) with molecularly confirmed vEDS, 24 (17.6%) had a history of respiratory events: 17 with pneumothorax, 4 with hemothorax, and 3 with hemoptysis that required thoracic surgery in 11. CT scans detected lung parenchymal abnormalities in 78 (57.3%) patients: emphysema (mostly centrilobular and paraseptal) in 44 (32.3%), comparable for smokers and non-smokers; clusters of calcified small pulmonary nodules in 9 (6.6%); and cavitated nodules in 4 (2.9%). Histologic examination of surgical samples found arterial abnormalities, emphysema with alveolar ruptures in 3, accompanied by diffuse hemorrhage and increased hemosiderin resorption.

Conclusion: In vEDS patients, identification of lung parenchymal abnormalities is common on CT. The most frequently observed CT finding was emphysema suggesting alveolar wall rupture which might facilitate the diagnostic screening of the disease in asymptomatic carriers of a genetic COL3A1 gene mutation. The prognostic value and evolution of these parenchymal abnormalities remain to be evaluated.

Key Points: • Patients with vEDS can have lung parenchymal changes on top of or next to thoracal vascular abnormalities and that these changes can be present in asymptomatic cases. • The presence of these parenchymal changes is associated with a slightly higher incidence of respiratory events (although not statistically significant). • Identification of the described CT pattern by radiologists and chest physicians may facilitate diagnostic screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00330-021-07710-6DOI Listing
August 2021

Spontaneous Cervical Artery Dissection in Vascular Ehlers-Danlos Syndrome: A Cohort Study.

Stroke 2021 May 1;52(5):1628-1635. Epub 2021 Mar 1.

AP-HP, Hôpital Européen Georges Pompidou, Département de Génétique, Centre de Référence des Maladies Vasculaires Rares, Paris, France (S.A., C.B., A.L., N.D., X.J., M.F.).

Background And Purpose: Vascular Ehlers-Danlos syndrome is a rare inherited connective tissue disorder because of pathogenic variants in the gene. Arterial complications can affect all anatomic areas and about 25% involve supra-aortic trunks (SATs) but no systematic assessment of cervical artery lesions has been made. The primary objective was to determine an accurate prevalence of spontaneous SAT lesions in a large series of patients with vascular Ehlers-Danlos syndrome at diagnosis and during follow-up. Secondary objectives were to study their neurological consequences (transient ischemic attack or stroke) and the possible relationships with sex, genotype, ascertainment status.

Methods: A retrospective review of a monocentric cohort of patients with molecularly proven vascular Ehlers-Danlos syndrome followed in a tertiary referral center from 2000 to 2017.

Results: One hundred forty-four patients were analyzed, 56.9% (n=82) had SAT lesions: 64.6% females, 74.4% index-case patients. Most lesions were identified in early arterial assessment (48% at first work-up, mean age of 35.7±13.0 years). Cumulative incidence of a first identification of a SAT lesion was 41.7% at 40 years old. On the complete period of survey, 183 SAT lesions (with 132 dissections and 33 aneurysms) were identified, mainly in internal carotid arteries (56.3%) and vertebral arteries (28.9%), more rarely in patients with null mutations (=0.008). Transient ischemic attack or stroke were reported in n=16 (19.5%) of the 82 patients with SAT lesions without relation with age, sex, treatment, or hypertension.

Conclusions: Cervical artery lesions are frequent and mostly asymptomatic in patients with vascular Ehlers-Danlos syndrome. Local dissections and aneurysms are the most frequent type of lesions, but transient ischemic attack or stroke seem rare.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.120.032106DOI Listing
May 2021

Mutation affecting the conserved acidic WNK1 motif causes inherited hyperkalemic hyperchloremic acidosis.

J Clin Invest 2020 12;130(12):6379-6394

Université de Paris, INSERM, PARCC, F-75006, Paris, France.

Gain-of-function mutations in with no lysine (K) 1 (WNK1) and WNK4 genes are responsible for familial hyperkalemic hypertension (FHHt), a rare, inherited disorder characterized by arterial hypertension and hyperkalemia with metabolic acidosis. More recently, FHHt-causing mutations in the Kelch-like 3-Cullin 3 (KLHL3-CUL3) E3 ubiquitin ligase complex have shed light on the importance of WNK's cellular degradation on renal ion transport. Using full exome sequencing for a 4-generation family and then targeted sequencing in other suspected cases, we have identified new missense variants in the WNK1 gene clustering in the short conserved acidic motif known to interact with the KLHL3-CUL3 ubiquitin complex. Affected subjects had an early onset of a hyperkalemic hyperchloremic phenotype, but normal blood pressure values"Functional experiments in Xenopus laevis oocytes and HEK293T cells demonstrated that these mutations strongly decrease the ubiquitination of the kidney-specific isoform KS-WNK1 by the KLHL3-CUL3 complex rather than the long ubiquitous catalytically active L-WNK1 isoform. A corresponding CRISPR/Cas9 engineered mouse model recapitulated both the clinical and biological phenotypes. Renal investigations showed increased activation of the Ste20 proline alanine-rich kinase-Na+-Cl- cotransporter (SPAK-NCC) phosphorylation cascade, associated with impaired ROMK apical expression in the distal part of the renal tubule. Together, these new WNK1 genetic variants highlight the importance of the KS-WNK1 isoform abundance on potassium homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI94171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685730PMC
December 2020

Interplay Between Statins, Cav1 (Caveolin-1), and Aldosterone.

Hypertension 2020 09 3;76(3):962-967. Epub 2020 Aug 3.

From the Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital (A.V.H., R.M.E., G.RM., L.H.P., J.S.W., G.H.W., G.K.A.), Harvard Medical School, Boston, MA.

Statin use is associated with lower aldosterone levels. We hypothesized that caveolin-1 may be important for the uptake of statins into the adrenal gland and would affect statin's aldosterone-lowering effects. The aim of this study was to test whether the caveolin-1 risk allele (rs926198) would affect aldosterone levels associated with statin use. The Hypertensive Pathotype database includes healthy and hypertensive individuals who have undergone assessment of adrenal hormones. Individuals were studied off antihypertensive medications but were maintained on statins if prescribed by their personal physician. Adrenal hormones were measured at baseline and after 1 hour of angiotensin II stimulation on both high- and low-sodium diets. A mixed-model repeated-measures analysis was employed with a priori selected covariates of age, sex, body mass index, and protocol (low versus high sodium, baseline versus angiotensin II stimulated aldosterone). A total of 250 individuals were included in the study; 31 individuals were taking statins (12.4%) and 219 were not. Among statin users, carrying a caveolin-1 risk allele resulted in a 25% (95% CI, 1-43.2) lower aldosterone level (=0.04). However, among nonstatin users, carrying a caveolin-1 risk allele resulted in no significant effect on aldosterone levels (=0.38). Additionally, the interaction between caveolin-1 risk allele and statin use on aldosterone levels was significant (=0.03). These findings suggest caveolin-1 risk allele carrying individuals are likely to receive the most benefit from statin's aldosterone-lowering properties; however, due to the observational nature of this study, these findings need further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.14777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418929PMC
September 2020

Vascular manifestations and kyphoscoliosis due to a novel mutation of PLOD1 gene.

Acta Cardiol 2021 Jul 4;76(5):557-558. Epub 2020 Aug 4.

Vascular Medicine Division and Regional Competence Center for Rare Vascular and Systemic Autoimmune Diseases, Nancy University Hospital, Vandoeuvre-lès-Nancy, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/00015385.2020.1802904DOI Listing
July 2021

Rare loss-of-function mutations of PTGIR are enriched in fibromuscular dysplasia.

Cardiovasc Res 2021 03;117(4):1154-1165

Department of Radiology, Assistance-publique-hôpitaux de Paris, Hopital Européen Georges Pompidou, F-75015 Paris, France.

Aims: Fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection (SCAD) are related, non-atherosclerotic arterial diseases mainly affecting middle-aged women. Little is known about their physiopathological mechanisms. We aimed to identify rare genetic causes to elucidate molecular mechanisms implicated in FMD and SCAD.

Methods And Results: We analysed 29 exomes that included familial and sporadic FMD. We identified one rare loss-of-function variant (LoF) (frequencygnomAD = 0.000075) shared by two FMD sisters in the prostaglandin I2 receptor gene (PTGIR), a key player in vascular remodelling. Follow-up was conducted by targeted or Sanger sequencing (1071 FMD and 363 SCAD patients) or lookups in exome (264 FMD) or genome sequences (480 SCAD), all independent and unrelated. It revealed four additional LoF allele carriers, in addition to several rare missense variants, among FMD patients, and two LoF allele carriers among SCAD patients, including one carrying a rare splicing mutation (c.768 + 1C>G). We used burden test to test for enrichment in patients compared to gnomAD controls, which detected a putative enrichment in FMD (PTRAPD = 8 × 10-4), but not a significant enrichment (PTRAPD = 0.12) in SCAD. The biological effects of variants on human prostaclycin receptor (hIP) signalling and protein expression were characterized using transient overexpression in human cells. We confirmed the LoFs (Q163X and P17RfsX6) and one missense (L67P), identified in one FMD and one SCAD patient, to severely impair hIP function in vitro.

Conclusions: Our study shows that rare genetic mutations in PTGIR are enriched among FMD patients and found in SCAD patients, suggesting a role for prostacyclin signalling in non-atherosclerotic stenosis and dissection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cvr/cvaa161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983006PMC
March 2021

Communication of genetic information to at-risk relatives during the multidisciplinary monitoring of vascular Ehlers-Danlos syndrome in a French referral clinic.

J Genet Couns 2020 10 5;29(5):828-837. Epub 2020 Jan 5.

Centre de Référence des Maladies Vasculaires Rares, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.

Vascular Ehlers-Danlos syndrome (vEDS) is a rare inherited disorder leading to arterial, digestive, and uterine complications due to pathogenic COL3A1 variants. Identification of causal variants allows family screening, provided that relatives have previously been informed, according to a 2013 French Decree. The aims of our study were to assess the communication of genetic information to at-risk relatives, the impact of diagnosis disclosure and to highlight a possible link between the experience of vEDS patients and ability to communicate about genetic information. A total of n = 51 vEDS adult probands answered a questionnaire during a clinical visit. Communication to relatives was considered effective if the proband gave information to some or all first-degree relatives and considered easily achieved if it was disclosed to all relatives less than a month after the diagnosis and without difficulty. Personal and family vEDS experiences of probands were also assessed. Effective communication of information to relatives was remarkably high (98%). Siblings were the most frequently informed relatives (82%). Women informed their at-risk relatives of genetic family screening faster (p = .006) and easier (p = .004) than men. There was no difference in the disclosure of information to relatives before and after 2013 in our multidisciplinary clinic. Regarding the lived experience of vEDS patients, they felt anxious (78%) at diagnosis disclosure but also considered this diagnosis as an opportunity to start a medical follow-up (82%) putting an end to diagnosis delay. Our findings highlight for the first time that the ability to easily inform at-risk first-degree relatives is related to the relief felt during vEDS-positive diagnosis disclosure (p = .04). In order to improve the communication of genetic information to relatives, we believe that psychological support should systematically be part of the multidisciplinary monitoring, just as medical follow-up and genetic counseling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jgc4.1211DOI Listing
October 2020

Carotid Stiffness Assessment With Ultrafast Ultrasound Imaging in Case of Bicuspid Aortic Valve.

Front Physiol 2019 23;10:1330. Epub 2019 Oct 23.

VASC European Research Network, Centre de Référence des Maladies Vasculaires Rares, Hôpital Européen Georges-Pompidou, AP-HP, Paris, France.

Aims: To compare the carotid stiffness and flow parameters by ultrafast ultrasound imaging (UF), in bicuspid aortic valve (BAV) patients to first-degree relatives (controls).

Methods: BAV patients ( = 92) and controls ( = 48) were consecutively included at a reference center for BAV. Aortic valve and ascending aorta were evaluated by echocardiography. Common carotid arteries were evaluated by UF with a linear probe. A high frame rate (2,000 frames/s) was used to measure the pulse wave velocity (PWV). The arterial diameter change over the cardiac cycle was obtained by UF-Doppler imaging. This allowed us to measure the distensibility and the maximal rate of systolic distension (MRSD). The wall shear stress (WSS) was measured based on the same acquisitions, by analyzing blood flow velocities close to the carotid walls.

Results: BAV patients had significantly larger aortic diameters ( < 0.001) at the Valsalva sinus and at the tubular ascending aorta but no larger carotid diameters. No significant differences were found in carotid stiffness parameters (distensibility, MRSD, and PWV), even though these patients had a higher aortic stiffness. Carotid stiffness correlated linearly with age and similar slopes were obtained for BAV patients and controls. No difference in carotid WSS was found between BAV patients and controls.

Conclusion: Our results clearly show that the carotid stiffness and flow parameters are not altered in case of BAV compared with controls.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2019.01330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819321PMC
October 2019

High-throughput sequencing contributes to the diagnosis of tubulopathies and familial hypercalcemia hypocalciuria in adults.

Kidney Int 2019 12 16;96(6):1408-1416. Epub 2019 Sep 16.

Department of Genetics, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Paris, France. Electronic address:

Hereditary tubulopathies are rare diseases with unknown prevalence in adults. Often diagnosed in childhood, hereditary tubulopathies can nevertheless be evoked in adults. Precise diagnosis can be difficult or delayed due to insidious development of symptoms, comorbidities and polypharmacy. Here we evaluated the diagnostic value of a specific panel of known genes implicated in tubulopathies in adult patients and compared to our data obtained in children. To do this we analyzed 1033 non-related adult patients of which 744 had a clinical diagnosis of tubulopathy and 289 had a diagnosis of familial hypercalcemia with hypocalciuria recruited by three European reference centers. Three-quarters of our tubulopathies cohort included individuals with clinical suspicion of Gitelman syndrome, kidney hypophosphatemia and kidney tubular acidosis. We detected pathogenic variants in 26 different genes confirming a genetic diagnosis of tubulopathy in 29% of cases. In 16 cases (2.1%) the genetic testing changed the clinical diagnosis. The diagnosis of familial hypercalcemia with hypocalciuria was confirmed in 12% of cases. Thus, our work demonstrates the genetic origin of tubulopathies in one out of three adult patients, half of the rate observed in children. Hence, establishing a precise diagnosis is crucial for patients, in order to guide care, to survey and prevent chronic complications, and for genetic counselling. At the same time, this work enhances our understanding of complex phenotypes and enriches the database with the causal variants described.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2019.08.027DOI Listing
December 2019

Prognostic value of the 12-lead surface electrocardiogram in sarcomeric hypertrophic cardiomyopathy: data from the REMY French register.

Europace 2020 01;22(1):139-148

Département de Cardiologie et Maladies Vasculaires, INSERM CMR970, Paris Cardiovascular Research Center - PARCC, Paris, France.

Aims: To identify independent electrocardiogram (ECG) predictors of long-term clinical outcome based on standardized analysis of the surface ECG in a large multicentre cohort of patients with sarcomeric hypertrophic cardiomyopathy (HCM).

Methods And Results: Retrospective observational study from the REMY French HCM clinical research observatory. Primary endpoint was a composite of all-cause mortality, major non-fatal arrhythmic events, hospitalization for heart failure (HF), and stroke. Secondary endpoints were components of the primary endpoint. Uni- and multivariable Cox proportional hazard regression analysis was performed to identify independent predictors. Among 994 patients with HCM, only 1.8% had a strictly normal baseline ECG. The most prevalent abnormalities were inverted T waves (63.7%), P-wave abnormalities (30.4%), and abnormal Q waves (25.5%). During a mean follow-up of 4.0 ± 2.0 years, a total of 272 major cardiovascular events occurred in 217 patients (21.8%): death or heart transplant in 98 (9.8%), major arrhythmic events in 40 (4.0%), HF hospitalization in 115 (11.6%), and stroke in 23 (2.3%). At multivariable analysis using ECG covariates, prolonged QTc interval, low QRS voltage, and PVCs of right bundle branch block pattern predicted worse outcome, but none remained independently associated with the primary endpoint after adjustment on main demographic and clinical variables. For secondary endpoints, abnormal Q waves independently predicted all-cause death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.23-4.47; P = 0.009] and prolonged QTc the risk of HF hospitalization (HR 1.006, 95% CI 1.001-1.011; P = 0.024).

Conclusion: The 12-lead surface ECG has no independent value to predict the primary outcome measure in patients with HCM. The 12-lead surface ECG has been widely used as a screening tool in HCM but its prognostic value remains poorly known. The value of baseline surface ECG to predict long-term clinical outcomes was studied in a cohort of 994 patients with sarcomeric HCM. The surface ECG has no significant additional value to predict outcome in this patient population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/europace/euz272DOI Listing
January 2020

Classical Ehlers-Danlos syndrome with a propensity to arterial events: A new report on a French family with a COL1A1 p.(Arg312Cys) variant.

Clin Genet 2020 02 1;97(2):357-361. Epub 2019 Oct 1.

Assistance-Publique Hôpitaux de Paris, Hôpital européen Georges Pompidou, Centre de référence des maladies vasculaires rares, Service de génétique, Paris, France.

Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of connective tissue disorders. Overlapping features including arterial aneurysms/dissections in both classical and vascular EDS are a major challenge in the clinical diagnosis of these subtypes. The COL1A1 p.(Arg312Cys) variant leads to a phenotype of classical EDS with a propensity to arterial complications. Our report describes a two-generation family with one individual presenting with a dissection of the right external iliac artery. The primary suspicion of vascular EDS with the unsatisfactory identification of a COL3A1 benign variant was secondarily readjusted with the identification of COL1A1 p.(Arg312Cys) variant. This raises the question of the association of COL1A1 p.(Arg312Cys) with arterial complications and the need for a gene panel including not only the usual genes tested in search of classical or vascular EDS but also COL1A1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.13643DOI Listing
February 2020

A plasma proteogenomic signature for fibromuscular dysplasia.

Cardiovasc Res 2020 01;116(1):63-77

The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1030, New York, NY 10029, USA.

Aims: Fibromuscular dysplasia (FMD) is a poorly understood disease that predominantly affects women during middle-life, with features that include stenosis, aneurysm, and dissection of medium-large arteries. Recently, plasma proteomics has emerged as an important means to understand cardiovascular diseases. Our objectives were: (i) to characterize plasma proteins and determine if any exhibit differential abundance in FMD subjects vs. matched healthy controls and (ii) to leverage these protein data to conduct systems analyses to provide biologic insights on FMD, and explore if this could be developed into a blood-based FMD test.

Methods And Results: Females with 'multifocal' FMD and matched healthy controls underwent clinical phenotyping, dermal biopsy, and blood draw. Using dual-capture proximity extension assay and nuclear magnetic resonance-spectroscopy, we evaluated plasma levels of 981 proteins and 31 lipid sub-classes, respectively. In a discovery cohort (Ncases = 90, Ncontrols = 100), we identified 105 proteins and 16 lipid sub-classes (predominantly triglycerides and fatty acids) with differential plasma abundance in FMD cases vs. controls. In an independent cohort (Ncases = 23, Ncontrols = 28), we successfully validated 37 plasma proteins and 10 lipid sub-classes with differential abundance. Among these, 5/37 proteins exhibited genetic control and Bayesian analyses identified 3 of these as potential upstream drivers of FMD. In a 3rd cohort (Ncases = 506, Ncontrols = 876) the genetic locus of one of these upstream disease drivers, CD2-associated protein (CD2AP), was independently validated as being associated with risk of having FMD (odds ratios  = 1.36; P = 0.0003). Immune-fluorescence staining identified that CD2AP is expressed by the endothelium of medium-large arteries. Finally, machine learning trained on the discovery cohort was used to develop a test for FMD. When independently applied to the validation cohort, the test showed a c-statistic of 0.73 and sensitivity of 78.3%.

Conclusion: FMD exhibits a plasma proteogenomic and lipid signature that includes potential causative disease drivers, and which holds promise for developing a blood-based test for this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cvr/cvz219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918065PMC
January 2020

Genetic association study between T-786C NOS3 polymorphism and essential hypertension in an Algerian population of the Oran city.

Diabetes Metab Syndr 2019 Mar - Apr;13(2):1317-1320. Epub 2019 Feb 13.

INSERM, UMR970 Paris Cardiovascular Research Center (PARCC), Paris, F-75015, France; Paris-Descartes University, Sorbonne Paris Cité, Paris, 75006, France.

Background: Essential hypertension is an important risk factor for the development of cardiovascular disease. Important candidate genes such as NOS3 gene have been widely studied and reported to be associated with essential hypertension (HTN) in human populations.

Aim: We aim in this study to analyze the relationship between NOS3 -786T/C, a common genetic variant and HTN in a sample of the Algerian population of the Oran city.

Methods: A case-control study has been performed in 154 subjects including 77 hypertensives and 77 normotensives. The recruitment of these subjects was done in local Health Centers of the city of Oran, West Algeria. HTN was defined as elevated systolic blood pressure SBD≥140  mmHg and or sustained diastolic blood pressure DBP≥90  mmHg, measured using an Omron Automatic BP Monitor - M-3W machine. Consents were obtained from all participants. Polymerase chain reaction (PCR) combined with restrictive fragment length polymorphism (RFLP) was used to genotype the NOS -786T/C variant.

Results: The distribution of the allelic frequencies did not differ between cases and controls (OR = 1.48; 95%CI [0.94-2.32], P = 0.09). However, after adjustment with the age, sex, and body mass index, we observed significant association between NOS -786C allele and HTN status (OR = 2.08; 95%CI [1.18-3.66], P = 0.01).

Conclusion: Our results indicate that the C allele of the NOS3 gene is associated with increased risk of essential hypertension in this sample of the Algerian population of the Oran city. Further validation in larger samples is needed to confirm this finding.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dsx.2019.02.024DOI Listing
December 2019

Resistance to Insulin in Patients with Gitelman Syndrome and a Subtle Intermediate Phenotype in Heterozygous Carriers: A Cross-Sectional Study.

J Am Soc Nephrol 2019 08 8;30(8):1534-1545. Epub 2019 Jul 8.

Department of Genetics,

Background: Gitelman syndrome is a salt-losing tubulopathy caused by mutations in the gene, which encodes the thiazide-sensitive sodium-chloride cotransporter. Previous studies suggested an intermediate phenotype for heterozygous carriers.

Methods: To evaluate the phenotype of heterozygous carriers of pathogenic mutations, we performed a cross-sectional study of patients with Gitelman syndrome, heterozygous carriers, and healthy noncarriers. Participants measured their BP at home for three consecutive days before hospital admission for blood and urine sampling and an oral glucose tolerance test.

Results: We enrolled 242 participants, aged 18-75 years, including 81 heterozygous carriers, 82 healthy noncarriers, and 79 patients with Gitelman syndrome. The three groups had similar age, sex ratio, and body mass index. Compared with healthy noncarriers, heterozygous carriers showed significantly higher serum calcium concentration (=0.01) and a trend for higher plasma aldosterone (=0.06), but measures of home BP, plasma and urine electrolytes, renin, parathyroid hormone, vitamin D, and response to oral glucose tolerance testing were similar. Patients with Gitelman syndrome had lower systolic BP and higher heart rate than noncarriers and heterozygote carriers; they also had significantly higher fasting serum glucose concentration, higher levels of markers of insulin resistance, and a three-fold higher sensitivity to overweight. According to oral glucose tolerance testing, approximately 14% of patients with Gitelman syndrome were prediabetic, compared with 5% of heterozygous carriers and 4% of healthy noncarriers.

Conclusions: Heterozygous carriers had a weak intermediate phenotype, between that of healthy noncarriers and patients with Gitelman syndrome. Moreover, the latter are at risk for development of type 2 diabetes, indicating the heightened importance of body weight control in these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2019010031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683723PMC
August 2019

FLNC pathogenic variants in patients with cardiomyopathies: Prevalence and genotype-phenotype correlations.

Clin Genet 2019 10 18;96(4):317-329. Epub 2019 Jul 18.

APHP, UF Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Service de Biochimie Métabolique, Hôpitaux Universitaires de la Pitié- Salpêtrière- Charles Foix, Paris, France.

Pathogenic variants in FLNC encoding filamin C have been firstly reported to cause myopathies, and were recently linked to isolated cardiac phenotypes. Our aim was to estimate the prevalence of FLNC pathogenic variants in subtypes of cardiomyopathies and to study the relations between phenotype and genotype. DNAs from a cohort of 1150 unrelated index-patients with isolated cardiomyopathy (700 hypertrophic, 300 dilated, 50 restrictive cardiomyopathies, and 100 left ventricle non-compactions) have been sequenced on a custom panel of 51 cardiomyopathy disease-causing genes. An FLNC pathogenic variant was identified in 28 patients corresponding to a prevalence ranging from 1% to 8% depending on the cardiomyopathy subtype. Truncating variants were always identified in patients with dilated cardiomyopathy, while missense or in-frame indel variants were found in other phenotypes. A personal or family history of sudden cardiac death (SCD) was significantly higher in patients with truncating variants than in patients carrying missense variants (P = .01). This work reported the first observation of a left ventricular non-compaction associated with a unique probably causal variant in FLNC which highlights the role of FLNC in cardiomyopathies. A correlation between the nature of the variant and the cardiomyopathy subtype was observed as well as with SCD risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.13594DOI Listing
October 2019

Natural History and Surgical Management of Colonic Perforations in Vascular Ehlers-Danlos Syndrome: A Retrospective Review.

Dis Colon Rectum 2019 07;62(7):859-866

AP-HP, Hôpital Européen Georges Pompidou, Service de génétique, Centre de Référence des Maladies Vasculaires Rares, Paris, France.

Background: Vascular Ehlers-Danlos syndrome is a rare and severe genetic condition leading to spontaneous, potentially life-threatening arterial and digestive complications. Colonic ruptures are a common feature of the disease, but clear recommendations on their management are lacking.

Objective: This study aimed to identify surgery-related morbidity and 30-day postoperative mortality after colonic perforation.

Design: This was a retrospective review.

Setting: A large cohort of patients with vascular Ehlers-Danlos syndrome was followed in a tertiary referral center.

Patients: Between 2000 and 2016, the French National Reference Centre for Rare Vascular Diseases (HEGP, AP-HP, Paris, France) followed 148 patients with molecularly proven vascular Ehlers-Danlos syndrome.

Main Outcome Measures: The primary outcomes measured were surgery-related morbidity and 30-day postoperative mortality.

Results: Of 133 patients with molecularly proven vascular Ehlers-Danlos syndrome, 30 (22%) had a history of colonic perforation and 15 (50%) were males. These subjects were diagnosed with vascular Ehlers-Danlos syndrome at a younger age than patients with a history of GI events without colonic perforation (p = 0.0007). There were 46 colonic perforations, median 1.0 event per patient (interquartile range, 1.0-2.0). Reperforations occurred in 14 (47%) patients, mostly males. Surgical management consisted of Hartmann procedures or subtotal abdominal colectomies, with a nonnegligible rate of reperforation following partial colonic resection (11 patients, 41%).

Limitations: The main limitations of this work are its retrospective design and that the diagnosis of vascular Ehlers-Danlos syndrome was made after colonic perforations in a majority of patients.

Conclusion: Colonic perforations seem more severe in males, with a high rate of reperforation after Hartmann procedure. Subtotal colectomy may reduce digestive morbidity, particularly in male patients. Additional studies are required to identify other predictors of reperforation. See Video Abstract at http://links.lww.com/DCR/A937.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/DCR.0000000000001383DOI Listing
July 2019

Pseudoxanthoma elasticum with prominent arterial calcifications evoking CD73 deficiency.

Vasc Med 2019 10 4;24(5):461-464. Epub 2019 Jun 4.

Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Centre de Référence des Maladies Vasculaires Rares, Paris, France.

Pseudoxanthoma elasticum (PXE) is a rare disorder characterized by skin, eye, and cardiovascular lesions due to ectopic mineralization and fragmentation of elastic fibers of connective tissues. We present an atypical case of PXE with diffuse vascular calcification and negligible skin and eye lesions. The patient was a 37-year-old man suffering from severe bilateral arterial calcifications in superficial femoral and posterior tibial arteries. Eye fundoscopy and skin examination were first considered normal. This phenotype suggested first the diagnosis of Arterial Calcification due to Deficiency of CD73 (ACDC) characterized by mutations in gene. However, we found two variants in gene, and no variant in NT5E. Skin reexamination revealed few lateral skin papules confined to the scalp. Phenotypic overlap was described in vascular calcification disorders, between GACI and PXE phenotypes, and we discuss here expansion of this overlap, including ACDC phenotype. Identification of these expanding and overlapping phenotypes was enabled by genetic screening of the corresponding genes, in a systematic approach. We propose to create a calcification next generation sequencing (NGS) panel with , and genes to improve the molecular diagnosis of vascular calcification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1358863X19853360DOI Listing
October 2019

Primary cilia defects causing mitral valve prolapse.

Sci Transl Med 2019 05;11(493)

Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital Research Institute, Harvard Medical School, 185 Cambridge St., Boston, MA 02114, USA.

Mitral valve prolapse (MVP) affects 1 in 40 people and is the most common indication for mitral valve surgery. MVP can cause arrhythmias, heart failure, and sudden cardiac death, and to date, the causes of this disease are poorly understood. We now demonstrate that defects in primary cilia genes and their regulated pathways can cause MVP in familial and sporadic nonsyndromic MVP cases. Our expression studies and genetic ablation experiments confirmed a role for primary cilia in regulating ECM deposition during cardiac development. Loss of primary cilia during development resulted in progressive myxomatous degeneration and profound mitral valve pathology in the adult setting. Analysis of a large family with inherited, autosomal dominant nonsyndromic MVP identified a deleterious missense mutation in a cilia gene, A mouse model harboring this variant confirmed the pathogenicity of this mutation and revealed impaired ciliogenesis during development, which progressed to adult myxomatous valve disease and functional MVP. Relevance of primary cilia in common forms of MVP was tested using pathway enrichment in a large population of patients with MVP and controls from previously generated genome-wide association studies (GWAS), which confirmed the involvement of primary cilia genes in MVP. Together, our studies establish a developmental basis for MVP through altered cilia-dependent regulation of ECM and suggest that defects in primary cilia genes can be causative to disease phenotype in some patients with MVP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aax0290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331025PMC
May 2019

Genome-Wide Association Study-Driven Gene-Set Analyses, Genetic, and Functional Follow-Up Suggest GLIS1 as a Susceptibility Gene for Mitral Valve Prolapse.

Circ Genom Precis Med 2019 05;12(5):e002497

INSERM, UMR970, Paris Cardiovascular Research Center, France (M.Y., A.G., S.K., A.A.H., X.J., N.B.-N.).

Background Mitral valve prolapse (MVP) is a common heart valve disease, the most frequent indication for valve repair or replacement. MVP is characterized by excess extracellular matrix secretion and cellular disorganization, which leads to bulky valves that are unable to coapt correctly during ventricular systole resulting in mitral regurgitation, and it is associated with sudden cardiac death. Here we aim to characterize globally the biological mechanisms underlying genetic susceptibility to MVP to better characterize its triggering mechanisms. Methods We applied i-GSEA4GWAS and DEPICT, two pathway enrichment tools to MVP genome-wide association studies. We followed-up the association with MVP in an independent dataset of cases and controls. This research was conducted using the UK Biobank Resource. Immunohistochemistry staining for Glis1 (GLIS family zinc finger 1) was conducted in developing heart of mice. Knockdown of Glis1 using morpholinos was performed in zebrafish animals 72 hours postfertilization. Results We show that genes at risk loci are involved in biological functions relevant to actin filament organization, cytoskeleton biology, and cardiac development. The enrichment for positive regulation of transcription, cell proliferation, and migration motivated the follow-up of GLIS1, a transcription factor from the Krüppel-like zinc finger family. In combination with previously available data, we now report a genome-wide significant association with MVP (odds ratio, 1.20; P=4.36×10), indicating that Glis1 is expressed during embryonic development predominantly in nuclei of endothelial and interstitial cells of mitral valves in mouse. We also show that Glis1 knockdown causes atrioventricular regurgitation in developing hearts in zebrafish. Conclusions Our findings define globally molecular and cellular mechanisms underlying common genetic susceptibility to MVP and implicate established and unprecedented mechanisms. Through the GLIS1 association and function, we point at regulatory functions during cardiac development as common mechanisms to mitral valve degeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.119.002497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532425PMC
May 2019

Vascular Ehlers-Danlos Syndrome: Long-Term Observational Study.

J Am Coll Cardiol 2019 04;73(15):1948-1957

AP-HP, Hôpital Européen Georges Pompidou, Département de Génétique, Centre de Référence des Maladies Vasculaires Rares, Paris, France; INSERM, U 970, Paris Centre de Recherche Cardiovasculaire-PARCC, Paris, France; Université Paris Sorbonne Cité, Faculté de Médecine Paris Descartes, Paris, France. Electronic address:

Background: Vascular Ehlers-Danlos syndrome (vEDS) is a rare genetic connective tissue disorder secondary to pathogenic variants within the COL3A1 gene, resulting in exceptional arterial and organ fragility and premature death. The only published clinical trial to date demonstrated the benefit of celiprolol on arterial morbimortality.

Objectives: The authors herein describe the outcomes of a large cohort of vEDS patients followed ≤17 years in a single national referral center.

Methods: All patients with molecularly confirmed vEDS were included in a retrospective cohort study. After an initial work-up, patients were treated or recommended for treatment with celiprolol (≤400 mg/day) in addition to usual care and scheduled for yearly follow-up. vEDS-related events and deaths were collected and recorded for each patient.

Results: Between 2000 and 2017, 144 patients (median age at diagnosis 34.5 years, 91 probands) were included in this study. After a median follow-up of 5.3 years, overall patient survival was high (71.6%; 95% confidence interval: 50% to 90%) and dependent on the type of COL3A1 variant, age at diagnosis, and medical treatment. At the end of the study period, almost all patients (90.3%) were treated with celiprolol alone or in combination. More than two-thirds of patients remained clinically silent, despite a large number (51%) with previous arterial events or arterial lesions at molecular diagnosis. Patients treated with celiprolol had a better survival than others (p = 0.0004). The observed reduction in mortality was dose-dependent: the best protection was observed at the dose of 400 mg/day versus <400 mg/day (p = 0.003). During the period surveyed, the authors observed a statistically significant difference in the ratio of hospitalizations for acute arterial events/hospitalizations for regular follow-up before and after 2011.

Conclusions: In this long-term survey, vEDS patients exhibited a low annual occurrence of arterial complications and a high survival rate, on which the overall medical care seems to have a positive influence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2019.01.058DOI Listing
April 2019

Severe Arterial Hypertension from Cullin 3 Mutations Is Caused by Both Renal and Vascular Effects.

J Am Soc Nephrol 2019 05 9;30(5):811-823. Epub 2019 Apr 9.

Institut National de la Santé et de la Recherche Médicale U970, Paris Cardiovascular Research Center, Paris, France;

Background: Mutations in four genes, WNK lysine deficient protein kinase 1 and 4 ( and ), kelch like family member 3 (), or Cullin 3 (), can result in familial hyperkalemic hypertension (FHHt), a rare Mendelian form of human arterial hypertension. Although all mutations result in an increased abundance of WNK1 or WNK4, all FHHt-causing mutations, resulting in the skipping of exon 9, lead to a more severe phenotype.

Methods: We created and compared two mouse models, one expressing the mutant Cul3 protein ubiquitously () and the other specifically in vascular smooth muscle cells (). We conducted pharmacologic investigations on isolated aortas and generated stable and inducible HEK293 cell lines that overexpress the wild-type Cul3 or mutant Cul3 (Cul39) protein.

Results: As expected, mice showed marked hypertension with significant hyperkalemia, hyperchloremia and low renin. BP increased significantly in mice, independent of any measurable effect on renal transport. Only mice displayed increased expression of the sodium chloride cotransporter and phosphorylation by the WNK-SPAK kinases. Both models showed altered reactivity of isolated aortas to phenylephrine and acetylcholine, as well as marked acute BP sensitivity to the calcium channel blocker amlodipine. Aortas from mice showed increased expression of RhoA, a key molecule involved in regulation of vascular tone, compared with aortas from control mice. We also observed increased RhoA abundance and in Cul39-expressing cells, caused by decreased ubiquitination.

Conclusions: Mutations in cause severe hypertension by affecting both renal and vascular function, the latter being associated with activation of RhoA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2017121307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493989PMC
May 2019

Accuracy of Clinical Diagnostic Criteria for Patients With Vascular Ehlers-Danlos Syndrome in a Tertiary Referral Centre.

Circ Genom Precis Med 2019 03;12(3):e001996

AP-HP, Hôpital Européen Georges Pompidou, Département de Génétique, Centre de Référence des Maladies Vasculaires Rares, Paris (P.H., J.A., S.A., A.L.,J.M.M., X.J., M.F.).

Background: Vascular Ehlers-Danlos syndrome is a rare inherited connective tissue disease secondary to mutations within the COL3A1 gene. The diagnosis of vascular Ehlers-Danlos syndrome is challenging, and patient selection for genetic testing relies on diagnostic criteria, which have never been evaluated.

Methods: All patients seen at a dedicated tertiary referral center for a suspicion of vascular Ehlers-Danlos syndrome between January 2001 and March 2016 were retrospectively included in a diagnostic accuracy study. Major and minor diagnostic criteria of the Villefranche classification were tested for sensitivity, specificity, positive and negative predictive values, according to results of genetic testing.

Results: N=519 patients were eligible for analysis dividing into n=384 probands and n=135 relatives. A pathogenic COL3A1 variant was identified in n=165 (31.8%) patients. The Villefranche criteria were met for n=248 patients with a sensitivity of 79% (95% CI, 0.72-0.85) and a negative predictive value of 87% (95% CI, 0.83-0.91). Diagnostic accuracy was highest for symptomatic probands (sensitivity 92%; negative predictive value 95%) with limited specificity (60%). Probands ≤25 years had the worst diagnostic performance. The revised diagnostic Criteria (2017) were less accurate than the Villefranche classification (overall diagnostic odds-ratio, 4.17 versus 7.8; probands diagnostic odds-ratio, 4.04 versus 18.1; and probands ≤25 years diagnostic odds-ratio, 2.36 versus 5.1) mainly due to a lack of sensitivity.

Conclusions: The Villefranche criteria provide accurate detection of symptomatic probands in specialized practice but have limited specificity. The revised diagnostic criteria for vascular Ehlers-Danlos syndrome have increased specificity, but its overall performance is poorer. The early clinical diagnosis of probands without family history is not addressed by both diagnostic classifications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.117.001996DOI Listing
March 2019
-->