Zhao Xiuying, Chen Tao, Fu Binsha, Fu Zhifu, Xu Kaishou, Zhou Wei
Department of Pediatrics, the First Affiliated Hospital of Jinan University, Guangzhou, China.
Department of Children's Rehabilitation, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, China.
Mol Genet Genomic Med. 2023 Oct;11(10):e2225. doi: 10.1002/mgg3.2225. Epub 2023 Jun 18.
KIF2A-related tubulinopathy (MIM: #615411) is a very rare disorder that was clinically characterized as microcephaly, epilepsy, motor developmental disorder (MDD), and various malformations of cortical development, but intellectual disability (ID) or global developmental delay (GDD) was rarely reported in the patients.
Quad whole-exome sequencing (WES) was performed on the proband, the older brother, and their parents. Sanger sequencing was used to verify the candidate gene variant.
The proband, a 23-month-old boy, was previously diagnosed with GDD, and his brother, aged nine years, had ID; both were born to a healthy couple. Quad-WES detected a novel heterozygous KIF2A variant, c.1318G>A (p.G440R), in both the brothers but not in the parents. In-silico analysis revealed that the variants G440R and G318R (which were previously reported in the only reported patient with GDD) lead to markedly enlarged side chains and hinder ATP's emplacement in the NBD pocket.
The type of KIF2A variants that sterically hinder ATP emplacing in KIF2A NBD pocket may be associated with the intellectual disability phenotype; however, further studies are needed. Findings in this case also suggest a rare parental germline mosaicism of KIF2A G440R.
与驱动蛋白家族成员2A（KIF2A）相关的微管蛋白病（MIM：#615411）是一种非常罕见的疾病，其临床特征为小头畸形、癫痫、运动发育障碍（MDD）以及各种皮质发育畸形，但患者中很少有智力障碍（ID）或全面发育迟缓（GDD）的报道。
对先证者、其哥哥及其父母进行四重全外显子测序（WES）。采用桑格测序法验证候选基因变异。
先证者为一名23个月大的男孩，此前被诊断为GDD，他9岁的哥哥有ID；两人的父母均健康。四重全外显子测序在两兄弟中均检测到一种新的杂合KIF2A变异，即c.1318G>A（p.G440R），而在父母中未检测到。计算机分析显示，变异G440R和G318R（先前在唯一报道的患有GDD的患者中报道过）导致侧链明显增大，并阻碍ATP在核苷结合域（NBD）口袋中的定位。
在空间上阻碍ATP在KIF2A的NBD口袋中定位的KIF2A变异类型可能与智力障碍表型有关；然而，还需要进一步研究。该病例的研究结果还提示了KIF2A G440R罕见的亲代生殖系嵌合现象。
