De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms
De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms
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DOI：
10.1038/s41431-018-0292-2
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发表时间：
2019-05-01
影响因子：
5.2
通讯作者：
de Vries, Bert B. A.
中科院分区：
文献类型：
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作者：
Jansen, Sandra;van der Werf, Ilse M.;de Vries, Bert B. A.
确定通过下一代测序技术鉴定的基因组变异的致病性可以得到表型相似个体中相同基因中的复发性破坏性变体的支持。然而，在没有可识别的综合征特征的轻度-中度智力残疾（ID）个体中解释特定基因的新变体可能具有挑战性，并且通常需要反向表型分析。我们描述了24个人与从头致病变异，或部分缺失，F盒蛋白11基因（FBXO 11，也称为VIT 1和PRMT 9）。FBXO 11是SCF（SKP 1-cullin-F-box）复合物的一部分，SCF复合物是一种多蛋白E3泛素连接酶复合物，催化蛋白质的泛素化，用于蛋白酶体降解。通过下一代测序鉴定了22种变体，包括2种框内缺失、11种错义变体、1种典型剪接位点变体和8种导致截短蛋白或降解转录物的无义或移码变体。剩余的两个变体通过阵列比较基因组杂交鉴定，并且由FBXO 11的部分缺失组成。所有人都有严重的边缘性ID和行为问题（自闭症谱系障碍，注意力缺陷/多动障碍，焦虑，攻击），在他们中的大多数人观察。最相关的共同面部特征包括薄上唇和上唇旁正中峰之间的宽而突出的空间。其他特征为张力减退和关节过度松弛。我们发现，FBXO 11的从头变异导致ID的综合征形式。目前的系列显示了反向表型在解释新的遗传变异的个人谁最初似乎没有一个明确的可识别的表型的权力。
Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar individuals. However, interpretation of novel variants in a specific gene in individuals with mild-moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in, or partial deletion of, the F-box only protein 11 gene (FBXO11, also known as VIT1 and PRMT9). FBXO11 is part of the SCF (SKP1-cullin-F-box) complex, a multi-protein E3 ubiquitin-ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. Twenty-two variants were identified by next-generation sequencing, comprising 2 in-frame deletions, 11 missense variants, 1 canonical splice site variant, and 8 nonsense or frameshift variants leading to a truncated protein or degraded transcript. The remaining two variants were identified by array-comparative genomic hybridization and consisted of a partial deletion of FBXO11. All individuals had borderline to severe ID and behavioral problems (autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, aggression) were observed in most of them. The most relevant common facial features included a thin upper lip and a broad prominent space between the paramedian peaks of the upper lip. Other features were hypotonia and hyperlaxity of the joints. We show that de novo variants in FBXO11 cause a syndromic form of ID. The current series show the power of reverse phenotyping in the interpretation of novel genetic variances in individuals who initially did not appear to have a clear recognizable phenotype.