WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation
WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation
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DOI：
10.1136/jmedgenet-2014-102748
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发表时间：
2015-01-01
影响因子：
4
通讯作者：
Philippe, Christophe
中科院分区：
文献类型：
--
作者：
Mignot, Cyril;Lambert, Laetitia;Philippe, Christophe
背景在两个常染色体隐性脊髓小脑共济失调12型家族的8名个体和两个患有婴儿癫痫性脑病（IEE）的兄弟姐妹中报告了WWOX纯合突变，其中一名在DNA采样前死亡。方法通过结合阵列比较基因组杂交、靶向桑格测序和下一代测序，结果共鉴定出8个WWOX等位基因，包括4个缺失、1个4碱基对移码缺失、1个错义突变和2个无义突变。基因型-表型相关性出现在7个已报道的家庭。携带两个预测无效等位基因的4例患者的表型特征为（1）几乎没有精神障碍，自发运动性差，从出生起就没有眼神接触，（2）在出生后第1周开始出现耐药性癫痫，（3）可能的视网膜变性，获得性小头畸形和过早死亡。这与不太严重的常染色体隐性遗传性脊髓小脑共济失调12型表型，由于亚形等位基因。在符合这种相关性，在两个兄弟姐妹携带一个无效等位基因和错义突变的表型是intermediate.Conclusions我们的结果通过不同的分子技术相结合，无疑是入罪WWOX作为一个基因隐性IEE和说明高通量数据挖掘的有用性，为罕见的常染色体隐性遗传病的基因识别。包含FRA 16 D脆性位点的WWOX基因座的结构可能解释了为什么在遗传数据库中经常报告组成性缺失，这表明WWOX相关脑病虽然可能罕见，但可能并不例外。
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.