Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism
Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism
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DOI：
10.1186/s13229-019-0286-0
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发表时间：
2019-10-22
期刊：
影响因子：
6.2
通讯作者：
Kim, Cheol-Hee
中科院分区：
文献类型：
--
作者：
Kim, Hyung-Goo;Rosenfeld, Jill A.;Kim, Cheol-Hee
背景PHF 21 A与智力残疾和颅面畸形相关，这是基于其在Potocki-Shaffer综合征区域11p11.2的缺失以及在3例平衡易位患者中的破坏。此外，最近报道了3例PHF 21 A新发截短突变患者。在这里，我们分析了来自7个PHF 21 A突变的无关个体的基因组数据，并提供了详细的临床描述，进一步扩展了与PHF 21 A单倍不足相关的表型。方法采用全外显子组测序、桑格测序、GeneMatcher测序、靶基因板测序、MiSeq测序等技术进行鉴定和确认。采用RT-qPCR检测PHF 21 A在13种不同脑组织中的正常表达模式。进行蛋白质-DNA建模以证实错义突变的致病性。结果共发现7个杂合突变，其中6个为新发突变（1个为非母体突变）。突变包括四个移码，两名患者中的一个无义突变，以及AT Hook结构域中的一个杂合错义突变，预测是有害的，可能导致PHF 21 A功能丧失。我们还发现了一个新的C-末端结构域组成的一个内在的无序区域。该结构域在6名患者中被截短，因此可能在PHF 21 A的功能中发挥重要作用，表明单倍不足是7名患者表型中可能的潜在机制。我们的研究结果通过增加自闭症谱系障碍、癫痫、肌张力减退和神经行为问题扩展了PHF 21 A突变的表型谱。此外，PHF 21 A在人胎脑中高度表达，这与神经发育表型一致。结论PHF 21 A中AT Hook结构域和/或一个内在紊乱区域的破坏性无义、移码和错义突变与自闭症谱系障碍、癫痫、肌张力减退、神经行为问题、手指变细、单指和并指畸形以及智力残疾和颅面畸形相关。这表明PHF 21 A参与自闭症谱系障碍和智力残疾，其单倍不足导致不同的神经系统表型。
Background PHF21A has been associated with intellectual disability and craniofacial anomalies based on its deletion in the Potocki-Shaffer syndrome region at 11p11.2 and its disruption in three patients with balanced translocations. In addition, three patients with de novo truncating mutations in PHF21A were reported recently. Here, we analyze genomic data from seven unrelated individuals with mutations in PHF21A and provide detailed clinical descriptions, further expanding the phenotype associated with PHF21A haploinsufficiency. Methods Diagnostic trio whole exome sequencing, Sanger sequencing, use of GeneMatcher, targeted gene panel sequencing, and MiSeq sequencing techniques were used to identify and confirm variants. RT-qPCR was used to measure the normal expression pattern of PHF21A in multiple human tissues including 13 different brain tissues. Protein-DNA modeling was performed to substantiate the pathogenicity of the missense mutation. Results We have identified seven heterozygous coding mutations, among which six are de novo (not maternal in one). Mutations include four frameshifts, one nonsense mutation in two patients, and one heterozygous missense mutation in the AT Hook domain, predicted to be deleterious and likely to cause loss of PHF21A function. We also found a new C-terminal domain composed of an intrinsically disordered region. This domain is truncated in six patients and thus likely to play an important role in the function of PHF21A, suggesting that haploinsufficiency is the likely underlying mechanism in the phenotype of seven patients. Our results extend the phenotypic spectrum of PHF21A mutations by adding autism spectrum disorder, epilepsy, hypotonia, and neurobehavioral problems. Furthermore, PHF21A is highly expressed in the human fetal brain, which is consistent with the neurodevelopmental phenotype. Conclusion Deleterious nonsense, frameshift, and missense mutations disrupting the AT Hook domain and/or an intrinsically disordered region in PHF21A were found to be associated with autism spectrum disorder, epilepsy, hypotonia, neurobehavioral problems, tapering fingers, clinodactyly, and syndactyly, in addition to intellectual disability and craniofacial anomalies. This suggests that PHF21A is involved in autism spectrum disorder and intellectual disability, and its haploinsufficiency causes a diverse neurological phenotype.