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Alain Verloes

Bio: Alain Verloes is an academic researcher from University of Paris. The author has contributed to research in topics: Microcephaly & Noonan syndrome. The author has an hindex of 73, co-authored 450 publications receiving 19231 citations. Previous affiliations of Alain Verloes include Institut Universitaire de France & Max Planck Society.


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Journal ArticleDOI
TL;DR: A novel, putative winged helix/forkhead transcription factor gene, FOXL2, that is mutated to produce truncated proteins in type I families and larger proteins inType II, represents a candidate gene for the polled/intersex syndrome XX sex-reversal goat.
Abstract: In type I blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), eyelid abnormalities are associated with ovarian failure. Type II BPES shows only the eyelid defects, but both types map to chromosome 3q23. We have positionally cloned a novel, putative winged helix/forkhead transcription factor gene, FOXL2, that is mutated to produce truncated proteins in type I families and larger proteins in type II. Consistent with an involvement in those tissues, FOXL2 is selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it appears predominantly in the ovary. FOXL2 represents a candidate gene for the polled/intersex syndrome XX sex-reversal goat.

904 citations

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TL;DR: A genome screen of nine BSCL families from two geographical clusters revealed mutations in a gene homologous to the murine guanine nucleotide-binding protein, γ3-linked gene (Gng3lg) in all BSCL2-linked families, of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.
Abstract: Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome (BSCL), is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia A locus (BSCL1) has been mapped to 9q34 with evidence of heterogeneity Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway) We identified a new disease locus, designated BSCL2, within the 25-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13 Analysis of 20 additional families of various ethnic origins led to the identification of 11 families in which the disease cosegregates with the 11q13 locus; the remaining families provide confirmation of linkage to 9q34 Sequence analysis of genes located in the 11q13 interval disclosed mutations in a gene homologous to the murine guanine nucleotide-binding protein (G protein), gamma3-linked gene (Gng3lg) in all BSCL2-linked families BSCL2 is most highly expressed in brain and testis and encodes a protein (which we have called seipin) of unknown function Most of the variants are null mutations and probably result in a severe disruption of the protein These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance

672 citations

Journal ArticleDOI
TL;DR: Dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders of Cardio-facio-cutaneous syndrome, which phenotypically overlaps with Noonan and Costello syndrome.
Abstract: Cardio-facio-cutaneous (CFC) syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. It phenotypically overlaps with Noonan and Costello syndrome, which are caused by mutations in PTPN11 and HRAS, respectively. In 43 individuals with CFC, we identified two heterozygous KRAS mutations in three individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders.

553 citations

Journal ArticleDOI
TL;DR: In this paper, the p63 gene mutations were detected in almost all (40/43) individuals affected with EEC syndrome, in 35 individuals with nonsyndromic split hand-split foot malformation (SHFM), and in three families with the EEC-like condition limb-mammary syndrome (LMS), which is characterized by ectrodactyly, cleft palate, and mammary-gland abnormalities.
Abstract: p63 mutations have been associated with EEC syndrome (ectrodactyly, ectodermal dysplasia, and cleft lip/palate), as well as with nonsyndromic split hand–split foot malformation (SHFM). We performed p63 mutation analysis in a sample of 43 individuals and families affected with EEC syndrome, in 35 individuals affected with SHFM, and in three families with the EEC-like condition limb-mammary syndrome (LMS), which is characterized by ectrodactyly, cleft palate, and mammary-gland abnormalities. The results differed for these three conditions. p63 gene mutations were detected in almost all (40/43) individuals affected with EEC syndrome. Apart from a frameshift mutation in exon 13, all other EEC mutations were missense, predominantly involving codons 204, 227, 279, 280, and 304. In contrast, p63 mutations were detected in only a small proportion (4/35) of patients with isolated SHFM. p63 mutations in SHFM included three novel mutations: a missense mutation (K193E), a nonsense mutation (Q634X), and a mutation in the 3′ splice site for exon 5. The fourth SHFM mutation (R280H) in this series was also found in a patient with classical EEC syndrome, suggesting partial overlap between the EEC and SHFM mutational spectra. The original family with LMS (van Bokhoven et al. 1999) had no detectable p63 mutation, although it clearly localizes to the p63 locus in 3q27. In two other small kindreds affected with LMS, frameshift mutations were detected in exons 13 and 14, respectively. The combined data show that p63 is the major gene for EEC syndrome, and that it makes a modest contribution to SHFM. There appears to be a genotype-phenotype correlation, in that there is a specific pattern of missense mutations in EEC syndrome that are not generally found in SHFM or LMS.

345 citations

Journal ArticleDOI
TL;DR: Verloes et al. as discussed by the authors defined CHARGE association as the nonrandom cluster of developmentalanomalies that results from early teratogenic events that overlap in time and space.
Abstract: Alain Verloes*Clinical Genetics Unit, Hoˆpital Robert Debre´, Paris, France‘‘CHARGE association’’ is a well-known entity of unknownorigin. It was originally delineated by Bryan Hall [1979] in17 children with multiple congenital anomalies (MCA) includ-ingchoanal atresiaand,independently by Hittneretal.[1979]in 10 MCA patients with coloboma, hence the eponymic Hall–Hittner syndrome which is sometimes used for it Graham,2001. Pagon et al. [1981] coined ‘‘CHARGE,’’ an acronym sum-marizing the five cardinal clinical features: ocular Coloboma,Heart defects of any type, Atresia of the choanae, Retardation(ofgrowthand/orofdevelopment), Genitalanomalies,andEaranomalies (abnormal pinnae or hearing loss). Classically, tomake a diagnosis of CHARGE complex, 4/7 signs need to bepresent [Oley et al., 1988], and one should be either choanalatresiaoracoloboma[Pagonetal.,1981].Manyotherdevelop-mental anomalies have been reported in CHARGE beyond theacronymic components [Pagon et al., 1981; Oley et al., 1988;Blake et al., 1998; Tellier et al., 1998; Gorlin et al., 2001].Amongthose,oticmalformations,anomaliesofthecranialandCNS midline structures, hypophyseal disorders, and brain-stem dysfunctions have to be stressed as emerging problemshidden beyond the historical cardinal features.Terminological Difficulty: Charge is notan Association, but a SyndromeAn association is the nonrandom cluster of developmentalanomalies that results from early teratogenic events thatoverlap in time and space. Whereas the term association isappropriate for VATER, which is a generalized blastogenicdefect, CHARGE is characterized by very specific develop-mentalanomaliesoftheopticvesicle,oticcapsule,midlineCNSstructures,andupperpharynx.CHARGEissupposedtoresultfrom abnormal differentiation of cephalic mesoderm andectoderm (otic placode and 1st branchial cleft), abnormalsetting (differentiation, migration, survival) of neural crestcells, abnormal interaction of neural crests (forming e.a. 1stand 2nd arch) with the cephalic mesoderm and the developingforebrain, and concomitant disorder in the development ofthe rhombencephalon out of which the neural crest cells havemigrated. CHARGE is thus a complex neurocristopathy, thetiming of which extends from blastogenesis (3rd week) to afterthe9thweekofgestation[Siebertetal.,1985;KirbyandWaldo,1990;Linetal.,1990].Eventhoughthecauseisnotknown,theterm ‘‘CHARGE syndrome’’ [Lubinsky, 1994; Amiel et al.,2001]isprobablymoreappropriate,andtheterm‘‘association’’should be dropped.Semicircular Canals in Charge Syndrome:An Underweighted and Overlooked Diagnostic ClueCochleovestibular abnormalities have recently been showntobeanimportantadditionaldysplasiainCHARGEsyndrome[Morgan et al., 1993; Murofushi et al., 1997; Dhooge et al.,1998; Amiel et al., 2001] In CHARGE, semicircular canals canbe aplastic and vestibular functions may be severely reduced.Cranial imaging frequently reveals absence or abnormality ofthe semicircular canals and, less frequently, hypoplasia of theupper turn of the cochlea or, in more severe cases, Mondinianomaly. In middle ear, hypoplastic long process of the incus,abnormal/absent oval window, and absence of stapediusmuscle are described. Facial nerve may show aberrant coursein the temporal bone, sometimes related with facial palsy.From an embryological point of view, inner ear develops fromthe ectodermally-derived otic placode, whereas middle andouter ear develop between the 5th and the 9th week from theectodermally-derived 1st branchial cleft and from the mesen-chyme (of neural crest origin) of the 1st and 2nd arches.Anatomical anomalies of middle and inner ear were notdirectly considered at the time where CHARGE was coined,probably because technical limits of medical imaging did notallow evaluation of these signs. Anomalies of the semicircularcanals are present in more than 80% of scanned CHARGEchildren [Morgan et al., 1993]. In another recent review ofcongenitalaplasiaofsemi-circularcanalswith‘‘relativelywell-formed cochlea’’ retrospectively selected in a population ofchildren candidate for inner ear implant electrode, Satar et al.[2003] presented a series of 15 patients. Ten of them werediagnosed as CHARGE syndrome. Among those, 85% of thecochleas were mildly or moderately dysplastic. Combined,those two series illustrate the high frequency and the highspecificity of canalar anomalies in CHARGE, a point furtherstressed in a recent review [Stjernholm, 2003]. Although theimportance of inner ear anomalies has been stressed, thepracticalconclusionshavenotbeencompletelydrawnintermsof diagnostic rules and syndrome definition.Variability of Expression in Charge:No Rules for an Old ProblemCHARGEwascoined22yearsagoandhasbeenshowntobeasuccessful acronym giving a simple rule of the thumb formaking or rejecting a diagnosis. Nevertheless, any dysmor-phologist knows how often he/she is led to the diagnosis of‘‘partial’’ or ‘‘atypical’’ CHARGE in patients who, usually,presents only with choanal atresia and some other signs.Curiously, this point has never been adequately discussed in*Correspondence to: Alain Verloes, Clinical Genetics Unit,Hoˆpital Robert Debre´, Paris, France.E-mail: alain.verloes@rdb.ap-hop-paris.frReceived 9 April 2004; Accepted 2 June 2004DOI 10.1002/ajmg.a.30559 2005 Wiley-Liss, Inc.

328 citations


Cited by
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Journal ArticleDOI
TL;DR: March 5, 2019 e1 WRITING GROUP MEMBERS Emelia J. Virani, MD, PhD, FAHA, Chair Elect On behalf of the American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee.
Abstract: March 5, 2019 e1 WRITING GROUP MEMBERS Emelia J. Benjamin, MD, ScM, FAHA, Chair Paul Muntner, PhD, MHS, FAHA, Vice Chair Alvaro Alonso, MD, PhD, FAHA Marcio S. Bittencourt, MD, PhD, MPH Clifton W. Callaway, MD, FAHA April P. Carson, PhD, MSPH, FAHA Alanna M. Chamberlain, PhD Alexander R. Chang, MD, MS Susan Cheng, MD, MMSc, MPH, FAHA Sandeep R. Das, MD, MPH, MBA, FAHA Francesca N. Delling, MD, MPH Luc Djousse, MD, ScD, MPH Mitchell S.V. Elkind, MD, MS, FAHA Jane F. Ferguson, PhD, FAHA Myriam Fornage, PhD, FAHA Lori Chaffin Jordan, MD, PhD, FAHA Sadiya S. Khan, MD, MSc Brett M. Kissela, MD, MS Kristen L. Knutson, PhD Tak W. Kwan, MD, FAHA Daniel T. Lackland, DrPH, FAHA Tené T. Lewis, PhD Judith H. Lichtman, PhD, MPH, FAHA Chris T. Longenecker, MD Matthew Shane Loop, PhD Pamela L. Lutsey, PhD, MPH, FAHA Seth S. Martin, MD, MHS, FAHA Kunihiro Matsushita, MD, PhD, FAHA Andrew E. Moran, MD, MPH, FAHA Michael E. Mussolino, PhD, FAHA Martin O’Flaherty, MD, MSc, PhD Ambarish Pandey, MD, MSCS Amanda M. Perak, MD, MS Wayne D. Rosamond, PhD, MS, FAHA Gregory A. Roth, MD, MPH, FAHA Uchechukwu K.A. Sampson, MD, MBA, MPH, FAHA Gary M. Satou, MD, FAHA Emily B. Schroeder, MD, PhD, FAHA Svati H. Shah, MD, MHS, FAHA Nicole L. Spartano, PhD Andrew Stokes, PhD David L. Tirschwell, MD, MS, MSc, FAHA Connie W. Tsao, MD, MPH, Vice Chair Elect Mintu P. Turakhia, MD, MAS, FAHA Lisa B. VanWagner, MD, MSc, FAST John T. Wilkins, MD, MS, FAHA Sally S. Wong, PhD, RD, CDN, FAHA Salim S. Virani, MD, PhD, FAHA, Chair Elect On behalf of the American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee

5,739 citations

Journal ArticleDOI
TL;DR: This year's edition of the Statistical Update includes data on the monitoring and benefits of cardiovascular health in the population, metrics to assess and monitor healthy diets, an enhanced focus on social determinants of health, a focus on the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors, implementation strategies, and implications of the American Heart Association’s 2020 Impact Goals.
Abstract: Background: The American Heart Association, in conjunction with the National Institutes of Health, annually reports on the most up-to-date statistics related to heart disease, stroke, and cardiovas...

5,078 citations

01 Feb 2015
TL;DR: In this article, the authors describe the integrative analysis of 111 reference human epigenomes generated as part of the NIH Roadmap Epigenomics Consortium, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression.
Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

4,409 citations

Journal ArticleDOI
TL;DR: Patients With Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic) A Collaborative Report from the American Association for Vascular Surgery/Society for V vascular surgery,* Society for Cardiovascular Angiography and Interventions, Society forVascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines.
Abstract: Patients With Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic) A Collaborative Report from the American Association for Vascular Surgery/Society for Vascular Surgery,* Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease) Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation

3,239 citations