RT Journal Article
SR Electronic
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
FD BMJ Publishing Group Ltd
SP 61
OP 70
DO 10.1136/jmedgenet-2014-102748
VO 52
IS 1
A1 Cyril Mignot
A1 Laetitia Lambert
A1 Laurent Pasquier
A1 Thierry Bienvenu
A1 Andrée Delahaye-Duriez
A1 Boris Keren
A1 Jérémie Lefranc
A1 Aline Saunier
A1 Lila Allou
A1 Virginie Roth
A1 Mylène Valduga
A1 Aissa Moustaïne
A1 Stéphane Auvin
A1 Catherine Barrey
A1 Sandra Chantot-Bastaraud
A1 Nicolas Lebrun
A1 Marie-Laure Moutard
A1 Marie-Christine Nougues
A1 Anne-Isabelle Vermersch
A1 Bénédicte Héron
A1 Eva Pipiras
A1 Delphine Héron
A1 Laurence Olivier-Faivre
A1 Jean-Louis Guéant
A1 Philippe Jonveaux
A1 Christophe Philippe
YR 2015
UL http://jmg.bmj.com/content/52/1/61.abstract
AB 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.