title: Blepharocheilodontic syndrome is a CDH1 pathway-related disorder due to mutations in CDH1 and CTNND1.
abstract: Blepharocheilodontic (BCD) syndrome is a rare autosomal dominant condition characterized by eyelid malformations, cleft lip/palate, and ectodermal dysplasia. The molecular basis of BCD syndrome remains unknown.
  
  
  
  We recruited 11 patients from 8 families and performed exome sequencing for 5 families with de novo BCD syndrome cases and targeted Sanger sequencing in the 3 remaining families.
  
  
  
  We identified five CDH1 heterozygous missense mutations and three CTNND1 heterozygous truncating mutations leading to loss-of-function or haploinsufficiency. Establishment of detailed genotype-phenotype correlations was not possible because of the size of the cohort; however, the phenotype seems to appear more severe in case of CDH1 mutations. Functional analysis of CDH1 mutations confirmed their deleterious impact and suggested accelerated E-cadherin degradation.
  
  
  
  Mutations in CDH1 encoding the E-cadherin were previously reported in hereditary diffuse gastric cancer as well as in nonsyndromic cleft lip/palate. Mutations in CTNND1 have never been reported before. The encoded protein, p120ctn, prevents E-cadherin endocytosis and stabilizes its localization at the cell surface. Conditional deletion of Cdh1 and Ctnnd1 in various animal models induces features reminiscent of BCD syndrome and underlines critical role of the E-cadherin-p120ctn interaction in eyelid, craniofacial, and tooth development. Our data assert BCD syndrome as a CDH1 pathway-related disorder due to mutations in CDH1 and CTNND1 and widen the phenotypic spectrum of E-cadherin anomalies.Genet Med advance online publication 09 March 2017.
authors.affiliation: Department of Medical Genetics, Lille University Hospital, CHU Lille, Lille, France.|EA7364 RADEME (Research Team on Rare Developmental and Metabolic Diseases), Lille 2 University, Lille, France.|Lille University School of Medicine, Lille 2 University, Lille, France.
authors.forename: Jamal
authors.identifier: 0000-0002-7111-0050
authors.initials: J
authors.lastname: Ghoumid
authors.affiliation: Department of Medical Genetics, Lille University Hospital, CHU Lille, Lille, France.|EA7364 RADEME (Research Team on Rare Developmental and Metabolic Diseases), Lille 2 University, Lille, France.
authors.forename: Morgane
authors.initials: M
authors.lastname: Stichelbout
authors.affiliation: EA7364 RADEME (Research Team on Rare Developmental and Metabolic Diseases), Lille 2 University, Lille, France.|Department of Biochemistry and Molecular Biology, Lille University Hospital, CHU Lille, Lille, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Jourdain
authors.affiliation: Department of Medical Genetics, Lille University Hospital, CHU Lille, Lille, France.|EA7364 RADEME (Research Team on Rare Developmental and Metabolic Diseases), Lille 2 University, Lille, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Frenois
authors.affiliation: Department of Medical Genetics, Lille University Hospital, CHU Lille, Lille, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lejeune-Dumoulin
authors.affiliation: Department of Medical Genetics, Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, and Eastern Biology and Pathology Centre, Bron, France.
authors.forename: Marie-Pierre
authors.identifier: 0000-0002-7889-4863
authors.initials: MP
authors.lastname: Alex-Cordier
authors.affiliation: Department of Medical Genetics, St Etienne University Hospital, Saint Priez en Jarez, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Lebrun
authors.affiliation: EA7364 RADEME (Research Team on Rare Developmental and Metabolic Diseases), Lille 2 University, Lille, France.|Lille University School of Medicine, Lille 2 University, Lille, France.|Department of Plastic, Reconstructive and Aesthetic Surgery, Lille University Hospital, CHU Lille, Lille, France.
authors.forename: Pierre
authors.identifier: 0000-0002-2955-5291
authors.initials: P
authors.lastname: Guerreschi
authors.affiliation: EA7364 RADEME (Research Team on Rare Developmental and Metabolic Diseases), Lille 2 University, Lille, France.|Lille University School of Medicine, Lille 2 University, Lille, France.|Department of Plastic, Reconstructive and Aesthetic Surgery, Lille University Hospital, CHU Lille, Lille, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Duquennoy-Martinot
authors.affiliation: EA7364 RADEME (Research Team on Rare Developmental and Metabolic Diseases), Lille 2 University, Lille, France.|Lille University School of Medicine, Lille 2 University, Lille, France.|Department of Pediatric Neurosurgery, Lille University Hospital, CHU Lille, Lille, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Vinchon
authors.affiliation: Lille University School of Medicine, Lille 2 University, Lille, France.|Department of Oral and Maxillofacial, Lille University Hospital, CHU Lille, Lille, France.
authors.forename: Joel
authors.initials: J
authors.lastname: Ferri
authors.affiliation: IGBMC Microarray and Sequencing Platform, Illkirch, France.
authors.forename: Matthieu
authors.identifier: 0000-0002-3272-7322
authors.initials: M
authors.lastname: Jung
authors.affiliation: IGBMC Microarray and Sequencing Platform, Illkirch, France.
authors.forename: Serge
authors.identifier: 0000-0001-9339-9513
authors.initials: S
authors.lastname: Vicaire
authors.affiliation: Department of Medical Genetics, Lille University Hospital, CHU Lille, Lille, France.|EA7364 RADEME (Research Team on Rare Developmental and Metabolic Diseases), Lille 2 University, Lille, France.|Lille University School of Medicine, Lille 2 University, Lille, France.
authors.forename: Clemence
authors.identifier: 0000-0003-3884-2054
authors.initials: C
authors.lastname: Vanlerberghe
authors.affiliation: EA7364 RADEME (Research Team on Rare Developmental and Metabolic Diseases), Lille 2 University, Lille, France.|Department of Biochemistry and Molecular Biology, Lille University Hospital, CHU Lille, Lille, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Escande
authors.affiliation: Department of Medical Genetics, Lille University Hospital, CHU Lille, Lille, France.|EA7364 RADEME (Research Team on Rare Developmental and Metabolic Diseases), Lille 2 University, Lille, France.|Lille University School of Medicine, Lille 2 University, Lille, France.
authors.forename: Florence
authors.identifier: 0000-0002-1368-1023
authors.initials: F
authors.lastname: Petit
authors.affiliation: Department of Medical Genetics, Lille University Hospital, CHU Lille, Lille, France.|EA7364 RADEME (Research Team on Rare Developmental and Metabolic Diseases), Lille 2 University, Lille, France.|Lille University School of Medicine, Lille 2 University, Lille, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Manouvrier-Hanu
mesh_terms: D015703:Antigens, CD; D015820:Cadherins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051177:Catenins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002971:Cleft Lip / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D002972:Cleft Palate / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D019295:Computational Biology; D004252:DNA Mutational Analysis; D004483:Ectropion / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D019066:Facies; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation; D021381:Protein Transport; D014071:Tooth Abnormalities / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D000095002:Delta Catenin
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D051177:Catenins; D000095002:Delta Catenin; C000722347:CTNND1 protein, human