TY - JOUR T1 - <em>WWOX</em>-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation JF - Journal of Medical Genetics JO - J Med Genet SP - 61 LP - 70 DO - 10.1136/jmedgenet-2014-102748 VL - 52 IS - 1 AU - Cyril Mignot AU - Laetitia Lambert AU - Laurent Pasquier AU - Thierry Bienvenu AU - Andrée Delahaye-Duriez AU - Boris Keren AU - Jérémie Lefranc AU - Aline Saunier AU - Lila Allou AU - Virginie Roth AU - Mylène Valduga AU - Aissa Moustaïne AU - Stéphane Auvin AU - Catherine Barrey AU - Sandra Chantot-Bastaraud AU - Nicolas Lebrun AU - Marie-Laure Moutard AU - Marie-Christine Nougues AU - Anne-Isabelle Vermersch AU - Bénédicte Héron AU - Eva Pipiras AU - Delphine Héron AU - Laurence Olivier-Faivre AU - Jean-Louis Guéant AU - Philippe Jonveaux AU - Christophe Philippe Y1 - 2015/01/01 UR - http://jmg.bmj.com/content/52/1/61.abstract N2 - 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. ER -