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Original article
WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation
  1. Cyril Mignot1,
  2. Laetitia Lambert2,
  3. Laurent Pasquier3,
  4. Thierry Bienvenu4,
  5. Andrée Delahaye-Duriez5,
  6. Boris Keren1,
  7. Jérémie Lefranc6,
  8. Aline Saunier7,
  9. Lila Allou8,
  10. Virginie Roth7,
  11. Mylène Valduga7,
  12. Aissa Moustaïne7,
  13. Stéphane Auvin9,
  14. Catherine Barrey10,
  15. Sandra Chantot-Bastaraud11,
  16. Nicolas Lebrun4,
  17. Marie-Laure Moutard12,
  18. Marie-Christine Nougues12,
  19. Anne-Isabelle Vermersch13,
  20. Bénédicte Héron12,14,
  21. Eva Pipiras5,
  22. Delphine Héron1,
  23. Laurence Olivier-Faivre15,
  24. Jean-Louis Guéant8,
  25. Philippe Jonveaux7,8,
  26. Christophe Philippe7,8
  1. 1Département 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
  2. 2Unité Fonctionnelle de Génétique Clinique, Service de Médecine Néonatale, Maternité Régionale Universitaire, Nancy, France
  3. 3Service de Génétique Clinique, Hôpital Sud, CLAD Ouest, Rennes, France
  4. 4Laboratoire de Biochimie et Génétique Moléculaire, GH Cochin-Broca-Hôtel Dieu, APHP, Inserm U1016, Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
  5. 5Unité de Cytogénétique, Hôpital Jean Verdier, APHP, CHU-Paris 13, Bondy, France
  6. 6Service de Pédiatrie, Centre Hospitalo-Universitaire Morvan, Brest, France
  7. 7Laboratoire de Génétique Médicale, Centre Hospitalier Régional et Universitaire, Vandoeuvre-les-Nancy, France.
  8. 8Université de Lorraine, Inserm U954 Nutrition-Genetics-Environmental Risk Exposure, Medical Faculty, Vandoeuvre-les-Nancy, France
  9. 9APHP, Hôpital Robert Debré, Service de Neurologie Pédiatrique; Univ Paris Diderot, Sorbonne Paris Cité, INSERM UMR1141, Paris, France
  10. 10Service de Pédiatrie, Hôpital Saint-Camille, Bry-sur-Marne, France
  11. 11Service de Génétique et d'Embryologie Médicale, APHP, Hôpital Armand Trousseau, Paris, France
  12. 12Service de Neuropédiatrie, APHP, Hôpital Armand Trousseau, Paris, France
  13. 13Unité de Neurophysiologie Pédiatrique, APHP, Hôpital Armand Trousseau, Paris, France
  14. 14Service de Pédiatrie, APHP, Hôpital Jean Verdier, Bondy, France
  15. 15Medical 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
  1. Correspondence to Dr Christophe Philippe, Laboratoire de génétique médicale, Centre Hospitalier Régional et Universitaire, Rue du Morvan, Vandoeuvre-les-Nancy 54511 cedex 1, France; c.philippe{at}


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.

  • infantile
  • intellectual disability
  • genotype/phenotype correlations
  • high throughput data mining

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