title: WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation.
abstract: BACKGROUND
  Homozygous mutations in WWOX were reported in eight individuals of two families with autosomal recessive spinocerebellar ataxia type 12 and in two siblings with infantile epileptic encephalopathy (IEE), including one who deceased prior to DNA sampling.
  
  
  METHODS
  By combining array comparative genomic hybridisation, targeted Sanger sequencing and next generation sequencing, we identified five further patients from four families with IEE due to biallelic alterations of WWOX.
  
  
  RESULTS
  We identified eight deleterious WWOX alleles consisting in four deletions, a four base-pair frameshifting deletion, one missense and two nonsense mutations. Genotype-phenotype correlation emerges from the seven reported families. The phenotype in four patients carrying two predicted null alleles was characterised by (1) little if any psychomotor acquisitions, poor spontaneous motility and absent eye contact from birth, (2) pharmacoresistant epilepsy starting in the 1st weeks of life, (3) possible retinal degeneration, acquired microcephaly and premature death. This contrasted with the less severe autosomal recessive spinocerebellar ataxia type 12 phenotype due to hypomorphic alleles. In line with this correlation, the phenotype in two siblings carrying a null allele and a missense mutation was intermediate.
  
  
  CONCLUSIONS
  Our results obtained by a combination of different molecular techniques undoubtedly incriminate WWOX as a gene for recessive IEE and illustrate the usefulness of high throughput data mining for the identification of genes for rare autosomal recessive disorders. The structure of the WWOX locus encompassing the FRA16D fragile site might explain why constitutive deletions are recurrently reported in genetic databases, suggesting that WWOX-related encephalopathies, although likely rare, may not be exceptional.
authors.affiliation: Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, APHP; Centre de Référence des Déficiences Intellectuelles de Causes Rares, UPMC Univ Paris 06 Groupe de Recherche Clinique "Déficience Intellectuelle et Autisme", Paris, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Mignot
authors.affiliation: Unité Fonctionnelle de Génétique Clinique, Service de Médecine Néonatale, Maternité Régionale Universitaire, Nancy, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Lambert
authors.affiliation: Service de Génétique Clinique, Hôpital Sud, CLAD Ouest, Rennes, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Pasquier
authors.affiliation: Laboratoire de Biochimie et Génétique Moléculaire, GH Cochin-Broca-Hôtel Dieu, APHP, Inserm U1016, Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Bienvenu
authors.affiliation: Unité de Cytogénétique, Hôpital Jean Verdier, APHP, CHU-Paris 13, Bondy, France.
authors.forename: Andrée
authors.initials: A
authors.lastname: Delahaye-Duriez
authors.affiliation: Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, APHP; Centre de Référence des Déficiences Intellectuelles de Causes Rares, UPMC Univ Paris 06 Groupe de Recherche Clinique "Déficience Intellectuelle et Autisme", Paris, France.
authors.forename: Boris
authors.initials: B
authors.lastname: Keren
authors.affiliation: Service de Pédiatrie, Centre Hospitalo-Universitaire Morvan, Brest, France.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Lefranc
authors.affiliation: Laboratoire de Génétique Médicale, Centre Hospitalier Régional et Universitaire, Vandoeuvre-les-Nancy, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Saunier
authors.affiliation: Université de Lorraine, Inserm U954 Nutrition-Genetics-Environmental Risk Exposure, Medical Faculty, Vandoeuvre-les-Nancy, France.
authors.forename: Lila
authors.initials: L
authors.lastname: Allou
authors.affiliation: Laboratoire de Génétique Médicale, Centre Hospitalier Régional et Universitaire, Vandoeuvre-les-Nancy, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Roth
authors.affiliation: Laboratoire de Génétique Médicale, Centre Hospitalier Régional et Universitaire, Vandoeuvre-les-Nancy, France.
authors.forename: Mylène
authors.initials: M
authors.lastname: Valduga
authors.affiliation: Laboratoire de Génétique Médicale, Centre Hospitalier Régional et Universitaire, Vandoeuvre-les-Nancy, France.
authors.forename: Aissa
authors.initials: A
authors.lastname: Moustaïne
authors.affiliation: APHP, Hôpital Robert Debré, Service de Neurologie Pédiatrique; Univ Paris Diderot, Sorbonne Paris Cité, INSERM UMR1141, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Auvin
authors.affiliation: Service de Pédiatrie, Hôpital Saint-Camille, Bry-sur-Marne, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Barrey
authors.affiliation: Service de Génétique et d'Embryologie Médicale, APHP, Hôpital Armand Trousseau, Paris, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Chantot-Bastaraud
authors.affiliation: Laboratoire de Biochimie et Génétique Moléculaire, GH Cochin-Broca-Hôtel Dieu, APHP, Inserm U1016, Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lebrun
authors.affiliation: Service de Neuropédiatrie, APHP, Hôpital Armand Trousseau, Paris, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Moutard
authors.affiliation: Service de Neuropédiatrie, APHP, Hôpital Armand Trousseau, Paris, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Nougues
authors.affiliation: Unité de Neurophysiologie Pédiatrique, APHP, Hôpital Armand Trousseau, Paris, France.
authors.forename: Anne-Isabelle
authors.initials: AI
authors.lastname: Vermersch
authors.affiliation: Service de Neuropédiatrie, APHP, Hôpital Armand Trousseau, Paris, France Service de Pédiatrie, APHP, Hôpital Jean Verdier, Bondy, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Héron
authors.affiliation: Unité de Cytogénétique, Hôpital Jean Verdier, APHP, CHU-Paris 13, Bondy, France.
authors.forename: Eva
authors.initials: E
authors.lastname: Pipiras
authors.affiliation: Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, APHP; Centre de Référence des Déficiences Intellectuelles de Causes Rares, UPMC Univ Paris 06 Groupe de Recherche Clinique "Déficience Intellectuelle et Autisme", Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Héron
authors.affiliation: Medical Genetics Unit, Centre Hospitalier Universitaire de Dijon; Research Unit EA 4271 Génétique des Anomalies du Développement, Université de Bourgogne, PRES Bourgogne-Franche Comté, Dijon, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Olivier-Faivre
authors.affiliation: Université de Lorraine, Inserm U954 Nutrition-Genetics-Environmental Risk Exposure, Medical Faculty, Vandoeuvre-les-Nancy, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Guéant
authors.affiliation: Laboratoire de Génétique Médicale, Centre Hospitalier Régional et Universitaire, Vandoeuvre-les-Nancy, France. Université de Lorraine, Inserm U954 Nutrition-Genetics-Environmental Risk Exposure, Medical Faculty, Vandoeuvre-les-Nancy, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Jonveaux
authors.affiliation: Laboratoire de Génétique Médicale, Centre Hospitalier Régional et Universitaire, Vandoeuvre-les-Nancy, France. Université de Lorraine, Inserm U954 Nutrition-Genetics-Environmental Risk Exposure, Medical Faculty, Vandoeuvre-les-Nancy, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Philippe
mesh_terms: D018389:Codon, Nonsense / Q000235:genetics; D055028:Comparative Genomic Hybridization; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020125:Mutation, Missense / Q000235:genetics; D010088:Oxidoreductases / Q000235:genetics*; D010641:Phenotype; D013036:Spasms, Infantile / Q000235:genetics* / Q000473:pathology; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D018389:Codon, Nonsense; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human
keywords: genotype/phenotype correlations; high throughput data mining; infantile; intellectual disability