Comprehensive genetic analysis confers high diagnostic yield in 16 Japanese patients with corpus callosum anomalies
Comprehensive genetic analysis confers high diagnostic yield in 16 Japanese patients with corpus callosum anomalies
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DOI：
10.1038/s10038-021-00932-y
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发表时间：
2021-05
影响因子：
3.5
通讯作者：
Sachiko Miyamoto;Mitsuhiro Kato;Takuya Hiraide;T. Shiohama;T. Goto;Akira Hojo;Akio Ebata;Manabu Suzuki;Kozue Kobayashi;P. Chong;R. Kira;H. Matsushita;H. Ikeda;K. Hoshino;M. Matsufuji;N. Moriyama;Masayuki Furuyama;Tatsuya Yamamoto;M. Nakashima;H. Saitsu
中科院分区：
文献类型：
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作者：
Sachiko Miyamoto;Mitsuhiro Kato;Takuya Hiraide;T. Shiohama;T. Goto;Akira Hojo;Akio Ebata;Manabu Suzuki;Kozue Kobayashi;P. Chong;R. Kira;H. Matsushita;H. Ikeda;K. Hoshino;M. Matsufuji;N. Moriyama;Masayuki Furuyama;Tatsuya Yamamoto;M. Nakashima;H. Saitsu
胼胝体异常(CCA)是一种常见的先天性脑畸形，病因多样。虽然最重要的病因之一是遗传因素，但CCA的遗传背景是异质性的，各种类型的变异可能是病因。在这项研究中，我们分析了16例日本患者的临床特征和颈动脉畸形的遗传背景。我们观察到伴随CCA的常见表型：智能障碍(100%)、运动发育迟缓(93.8%)、癫痫(60%)和面部变形(50%)。头颅MRI表现为(侧脑室后角增大，占84.6%)和小脑池增大(占41.7%)。16例患者中有9例(56.3%)存在基因改变，包括8例从头改变(ARID1B、CDK8、HIVEP2和TCF4的2个拷贝数变异和变异)和1个TBCK的隐性变异。在3个无亲缘关系的个体中发现了新的ARID1B变异，表明ARID1B变异是CCA的主要遗传原因。18q21.31-QTER包含TCF4的新TCF4变异和体细胞嵌合体缺失提示TCF4异常与CCAs有关。这项研究对CCA患者进行了全外显子组测序，证明了全面的基因分析将有助于研究CCA的各种原因变异。
Corpus callosum anomalies (CCA) is a common congenital brain anomaly with various etiologies. Although one of the most important etiologies is genetic factors, the genetic background of CCA is heterogenous and diverse types of variants are likely to be causative. In this study, we analyzed 16 Japanese patients with corpus callosum anomalies to delineate clinical features and the genetic background of CCAs. We observed the common phenotypes accompanied by CCAs: intellectual disability (100%), motor developmental delay (93.8%), seizures (60%), and facial dysmorphisms (50%). Brain magnetic resonance imaging showed colpocephaly (enlarged posterior horn of the lateral ventricles, 84.6%) and enlarged supracerebellar cistern (41.7%). Whole exome sequencing revealed genetic alterations in 9 of the 16 patients (56.3%), including 8 de novo alterations (2 copy number variants and variants inARID1B,CDK8,HIVEP2, andTCF4) and a recessive variant ofTBCK. De novoARID1Bvariants were identified in three unrelated individuals, suggesting thatARID1Bvariants are major genetic causes of CCAs. A de novoTCF4variant and somatic mosaic deletion at 18q21.31-qter encompassingTCF4suggest an association ofTCF4abnormalities with CCAs. This study, which analyzes CCA patients usung whole exome sequencing, demonstrates that comprehensive genetic analysis would be useful for investigating various causal variants of CCAs.