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J Med Genet. 2015 Jan;52(1):61-70. doi: 10.1136/jmedgenet-2014-102748. Epub 2014 Nov 19.

WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation.

Author information

1
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.
2
Unité Fonctionnelle de Génétique Clinique, Service de Médecine Néonatale, Maternité Régionale Universitaire, Nancy, France.
3
Service de Génétique Clinique, Hôpital Sud, CLAD Ouest, Rennes, France.
4
Laboratoire de Biochimie et Génétique Moléculaire, GH Cochin-Broca-Hôtel Dieu, APHP, Inserm U1016, Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
5
Unité de Cytogénétique, Hôpital Jean Verdier, APHP, CHU-Paris 13, Bondy, France.
6
Service de Pédiatrie, Centre Hospitalo-Universitaire Morvan, Brest, France.
7
Laboratoire de Génétique Médicale, Centre Hospitalier Régional et Universitaire, Vandoeuvre-les-Nancy, France.
8
Université de Lorraine, Inserm U954 Nutrition-Genetics-Environmental Risk Exposure, Medical Faculty, Vandoeuvre-les-Nancy, France.
9
APHP, Hôpital Robert Debré, Service de Neurologie Pédiatrique; Univ Paris Diderot, Sorbonne Paris Cité, INSERM UMR1141, Paris, France.
10
Service de Pédiatrie, Hôpital Saint-Camille, Bry-sur-Marne, France.
11
Service de Génétique et d'Embryologie Médicale, APHP, Hôpital Armand Trousseau, Paris, France.
12
Service de Neuropédiatrie, APHP, Hôpital Armand Trousseau, Paris, France.
13
Unité de Neurophysiologie Pédiatrique, APHP, Hôpital Armand Trousseau, Paris, France.
14
Service de Neuropédiatrie, APHP, Hôpital Armand Trousseau, Paris, France Service de Pédiatrie, APHP, Hôpital Jean Verdier, Bondy, France.
15
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.
16
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.

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.

KEYWORDS:

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

PMID:
25411445
DOI:
10.1136/jmedgenet-2014-102748
[Indexed for MEDLINE]

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