title: Treacher Collins syndrome: a clinical and molecular study based on a large series of patients.
abstract: OBJECTIVE
  Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:,TCOF1, POLR1D, and POLR1C.
  
  
  METHODS
  We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype-genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D, and the type of mutation or its localization in the TCOF1 gene.
  
  
  RESULTS
  We identified 92/146 patients (63%) with a molecular anomaly within TCOF1, 9/146 (6%) within POLR1D, and none within POLR1C. Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encompassing TCOF1 and CAMK2A in particular. Congenital cardiac defects occurred more frequently among patients with TCOF1 mutation (7/92, 8%) than reported in the literature.
  
  
  CONCLUSIONS
  Even though TCOF1 and POLR1D were associated with extreme clinical variability, we found no phenotype-genotype correlation. In cases with a typical phenotype of TCS, 6/146 (4%) remained with an unidentified molecular defect.
authors: Service de Génétique Médicale, Unité de Génétique Clinique, CHU de Nantes, Nantes, France.|Département de Génétique Médicale, CHRU Montpellier, Faculté de Médecine de Montpellier-Mimes, Université Montpellier 1, Inserm U1183, Montpellier, France.
authors: Marie
authors: http://orcid.org/0000-0003-1010-5618
authors: M
authors: Vincent
authors: Département de Génétique Médicale, CHRU Montpellier, Faculté de Médecine de Montpellier-Mimes, Université Montpellier 1, Inserm U1183, Montpellier, France.
authors: David
authors: http://orcid.org/0000-0001-6928-6287
authors: D
authors: Geneviève
authors: Inserm U1132, Hôpital Lariboisière, Paris, France.
authors: Agnès
authors: http://orcid.org/0000-0002-1966-3213
authors: A
authors: Ostertag
authors: Centre de Référence des Surdités Génétiques, Service de Génétique Médicale, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
authors: Sandrine
authors: S
authors: Marlin
authors: Service de Génétique Médicale, CHU Bordeaux, Laboratoire MRGM, EA4576, Université de Bordeaux, Bordeaux, France.
authors: Didier
authors: D
authors: Lacombe
authors: Service de Génétique Médicale, CH Le Mans, Le Mans, France.
authors: Dominique
authors: D
authors: Martin-Coignard
authors: Département de Génétique Médicale, CHRU Montpellier, Faculté de Médecine de Montpellier-Mimes, Université Montpellier 1, Inserm U1183, Montpellier, France.
authors: Christine
authors: C
authors: Coubes
authors: Service de Génétique Médicale, Unité de Génétique Clinique, CHU de Nantes, Nantes, France.
authors: Albert
authors: A
authors: David
authors: Service de Génétique Médicale, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.|Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, Paris, France.|Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Unité INSERM U-116, Paris, France.
authors: Stanislas
authors: S
authors: Lyonnet
authors: Service de Génétique Médicale, Hôpital Erasme, ULB, Brussels, Belgium.
authors: Catheline
authors: C
authors: Vilain
authors: Clinique de Génétique "Guy Fontaine," CHRU Lille, Lille, France.
authors: Anne
authors: A
authors: Dieux-Coeslier
authors: Clinique de Génétique "Guy Fontaine," CHRU Lille, Lille, France.
authors: Sylvie
authors: S
authors: Manouvrier
authors: Service de Génétique Médicale, Unité de Génétique Clinique, CHU de Nantes, Nantes, France.
authors: Bertrand
authors: B
authors: Isidor
authors: Service de Génétique Médicale, CHU La Réunion, La Réunion, France.
authors: Marie-Line
authors: ML
authors: Jacquemont
authors: Service de Génétique Médicale, CHU Toulouse, Toulouse, France.
authors: Sophie
authors: S
authors: Julia
authors: Service de Génétique Médicale, CHG Le Havre, Le Havre, France.
authors: Valérie
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authors: Layet
authors: Service de Génétique Médicale, CHU Bordeaux, Laboratoire MRGM, EA4576, Université de Bordeaux, Bordeaux, France.
authors: Sophie
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authors: Naudion
authors: Service de Génétique Clinique, Hôpital sud, CHU de Rennes, Université Rennes 1, UMR 6290 CNRS, Groupe GPLD, Rennes, France.
authors: Sylvie
authors: S
authors: Odent
authors: Service de Génétique Clinique, Hôpital sud, CHU de Rennes, Université Rennes 1, UMR 6290 CNRS, Groupe GPLD, Rennes, France.
authors: Laurent
authors: L
authors: Pasquier
authors: Service de Génétique Médicale, CHU Bordeaux, Laboratoire MRGM, EA4576, Université de Bordeaux, Bordeaux, France.
authors: Sybille
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authors: Pelras
authors: Service de Génétique Médicale, CHU de Marseille, AP-HM, Marseille, France.
authors: Nicole
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authors: Philip
authors: Service de Génétique Médicale, CHU Liège, Liège, Belgium.
authors: Geneviève
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authors: Pierquin
authors: Service de Génétique Médicale, CHU St Etienne, St Etienne, France.
authors: Fabienne
authors: F
authors: Prieur
authors: Service de Génétique Médicale, Hôpital de Marrakech, Marrakech, Maroc.
authors: Nisrine
authors: N
authors: Aboussair
authors: Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, Paris, France.|Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Unité INSERM U-116, Paris, France.
authors: Tania
authors: T
authors: Attie-Bitach
authors: Service de Génétique Médicale, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
authors: Geneviève
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authors: Baujat
authors: Département de Génétique Médicale, CHRU Montpellier, Faculté de Médecine de Montpellier-Mimes, Université Montpellier 1, Inserm U1183, Montpellier, France.
authors: Patricia
authors: P
authors: Blanchet
authors: Service d'ORL, Hôpital Lapeyronie, CHRU Montpellier, Montpellier, France.
authors: Catherine
authors: C
authors: Blanchet
authors: Service de Génétique Médicale, CHU Strasbourg, Strasbourg, France.
authors: Hélène
authors: H
authors: Dollfus
authors: Service de Génétique Médicale, CHU Strasbourg, Strasbourg, France.
authors: Bérénice
authors: B
authors: Doray
authors: Service de Génétique Médicale, CHU Strasbourg, Strasbourg, France.
authors: Elise
authors: E
authors: Schaefer
authors: Service de Génétique, Hospices Civils de Lyon, Groupement Hospitalier Est, Hôpital Femme Mère Enfant et Centre de Recherche en Neurosciences de Lyon (CRNL), INSERM U1028, UMR CNRS 5292, Université Claude Bernard Lyon 1, Villeurbanne, France.
authors: Patrick
authors: P
authors: Edery
authors: Service de Génétique Médicale, CHU Nice, Nice, France.
authors: Fabienne
authors: F
authors: Giuliano
authors: Service de Génétique Médicale, CHU Rouen, Rouen, France.
authors: Alice
authors: A
authors: Goldenberg
authors: Service de Génétique Médicale, CHU Bordeaux, Laboratoire MRGM, EA4576, Université de Bordeaux, Bordeaux, France.
authors: Cyril
authors: C
authors: Goizet
authors: Service de Génétique Médicale, CHU Angers, Angers, France.
authors: Agnès
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authors: Guichet
authors: Service de Chirurgie Plastique et Craniofaciale Pédiatrique, CHU Montpellier, Montpellier, France.
authors: Christian
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authors: Herlin
authors: Service de Génétique Clinique, Pôle de Néonatologie, Maternité Régionale CHRU de Nancy, Nancy, France.
authors: Laetitia
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authors: Lambert
authors: Pôle Enfants, Service de Médecine Infantile et Génétique Clinique, CHU de Nancy, Nancy, France.
authors: Bruno
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authors: Leheup
authors: Service de Génétique Médicale, Hôpital Antoine Béclère, Clamart, France.
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authors: Service de Génétique Médicale, Unité de Génétique Clinique, CHU de Nantes, Nantes, France.
authors: Sandra
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authors: Mercier
authors: APHP, Département de Génétique, Hôpital Trousseau et Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors: Cyril
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authors: Mignot
authors: APHP, Service de Neuropédiatrie, Hôpital Trousseau, Paris, France.
authors: Marie-Laure
authors: ML
authors: Moutard
authors: Département de Génétique Médicale, CHRU Montpellier, Faculté de Médecine de Montpellier-Mimes, Université Montpellier 1, Inserm U1183, Montpellier, France.
authors: Marie-José
authors: MJ
authors: Perez
authors: Département de Génétique Médicale, CHRU Montpellier, Faculté de Médecine de Montpellier-Mimes, Université Montpellier 1, Inserm U1183, Montpellier, France.
authors: Lucile
authors: L
authors: Pinson
authors: Département de Génétique Médicale, CHRU Montpellier, Faculté de Médecine de Montpellier-Mimes, Université Montpellier 1, Inserm U1183, Montpellier, France.
authors: Jacques
authors: J
authors: Puechberty
authors: Département de Génétique Médicale, CHRU Montpellier, Faculté de Médecine de Montpellier-Mimes, Université Montpellier 1, Inserm U1183, Montpellier, France.
authors: Marjolaine
authors: M
authors: Willems
authors: Service de Génétique Médicale, CHU La Réunion, La Réunion, France.
authors: Hanitra
authors: H
authors: Randrianaivo
authors: Kateline
authors: K
authors: Szakszon
authors: Klinikai Genetikai Kôzpont, Gyermekklinika, Debrecen, Hungria.
authors: Kateline
authors: K
authors: Szaskon
authors: Service de Génétique Médicale, CHU Tours, Tours, France.
authors: Annick
authors: http://orcid.org/0000-0002-5999-5300
authors: A
authors: Toutain
authors: Fédération de Génétique, Hôpital Robert Debré, APHP Paris, Paris, France.
authors: Alain
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authors: Verloes
authors: Pôle Enfants, Service de Médecine Infantile et Génétique Clinique, CHU de Nancy, Nancy, France.
authors: Jacqueline
authors: J
authors: Vigneron
authors: Département de Génétique Médicale, CHRU Montpellier, Faculté de Médecine de Montpellier-Mimes, Université Montpellier 1, Inserm U1183, Montpellier, France.
authors: Elodie
authors: E
authors: Sanchez
authors: Département de Génétique Médicale, CHRU Montpellier, Faculté de Médecine de Montpellier-Mimes, Université Montpellier 1, Inserm U1183, Montpellier, France.
authors: Pierre
authors: P
authors: Sarda
authors: UF de Génétique Moléculaire, Service de Biochimie et Biologie Moléculaire, Hôpital Lariboisière, Paris, France.
authors: Jean-Louis
authors: JL
authors: Laplanche
authors: UF de Génétique Moléculaire, Service de Biochimie et Biologie Moléculaire, Hôpital Lariboisière, Paris, France.
authors: Corinne
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authors: Collet
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D012321:DNA-Directed RNA Polymerases / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008342:Mandibulofacial Dysostosis / Q000175:diagnosis / Q000235:genetics*; D008831:Microcephaly / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010445:Peptide Elongation Factors / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics*; D017415:Ribonucleoprotein, U5 Small Nuclear / Q000235:genetics; D017384:Sequence Deletion; D055815:Young Adult
chemical_list: C581608:EFTUD2 protein, human; D009687:Nuclear Proteins; D010445:Peptide Elongation Factors; D010750:Phosphoproteins; D017415:Ribonucleoprotein, U5 Small Nuclear; C105442:TCOF1 protein, human; D012321:DNA-Directed RNA Polymerases; C569283:POLR1C protein, human; C569282:POLR1D protein, human