Cheng Shuangxi, Wang Qingming, Hong Xiaochun, Chen Aixin, Yuan Haiming
Dongguan Maternal and Child Health Care Hospital, Dongguan, Guangdong 523120, China.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2022 Mar 10;39(3):312-315. doi: 10.3760/cma.j.cn511374-20201214-00874.
To explore the genetic basis for a child featuring complex cortical dysplasia and other brain malformations (CDCBM3).
Genomic DNA was extracted from peripheral blood samples from the patient and his parents. Whole exome sequencing (WES) was carried out for the family trio. Suspected variant was verified by Sanger sequencing.
The proband, a 1-year-and-2-month old Chinese boy, had presented with motor developmental delay, lissencephaly, severe cognitive impairments, absent speech and congenital laryngomalacia. WES revealed that he has harbored a heterozygous missense variant of the KIF2A gene, namely NM_001098511.2: c.952G>A, p.Gly318Arg (GRCh37/hg19). The highly conserved residue is located around the ATP nucleotide-binding pocket in the kinesin motor domain (PM1). The variant was not found in the Genome Aggregation Database and the 1000 Genomes Project (PM2), and was predicted to be deleterious on the gene product by multiple in silico prediction tools (PP3). This variant was unreported previously and was de novo in origin (PS2). Based on the ACMG guidelines, it was categorized as likely pathogenic (PS2+PM1+PM2+PP3). Furthermore, the congenital laryngomalacia found in our patient was absent in previously reported CDCBM3 cases.
The novel variant of the KIF2A gene probably underlay the disorders in the proband. Above finding has expanded the phenotypic and mutational spectrum of CDCBM3.
探讨一名患有复杂皮质发育异常及其他脑畸形（CDCBM3）儿童的遗传基础。
从患者及其父母的外周血样本中提取基因组DNA。对该三联体家庭进行全外显子组测序（WES）。通过桑格测序验证疑似变异。
先证者为一名1岁2个月大的中国男孩，表现为运动发育迟缓、无脑回畸形、严重认知障碍、无语言能力及先天性喉软化症。WES显示他携带KIF2A基因的一个杂合错义变异，即NM_001098511.2:c.952G>A，p.Gly318Arg（GRCh37/hg19）。该高度保守的残基位于驱动蛋白运动域的ATP核苷酸结合口袋周围（PM1）。该变异在基因组聚合数据库和千人基因组计划中未被发现（PM2），并且多种计算机预测工具预测该变异对基因产物有害（PP3）。此变异先前未被报道，且为新发变异（PS2）。根据美国医学遗传学与基因组学学会（ACMG）指南，其被分类为可能致病（PS2+PM1+PM2+PP3）。此外，我们患者中发现的先天性喉软化症在先前报道的CDCBM3病例中未出现。
KIF2A基因的新变异可能是先证者疾病的病因。上述发现扩展了CDCBM3的表型和突变谱。
