Itai Toshiyuki, Miyatake Satoko, Tsuchida Naomi, Saida Ken, Narahara Sho, Tsuyusaki Yu, Castro Matheus Augusto Araujo, Kim Chong Ae, Okamoto Nobuhiko, Uchiyama Yuri, Koshimizu Eriko, Hamanaka Kohei, Fujita Atsushi, Mizuguchi Takeshi, Matsumoto Naomichi
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
Clinical Genetics Department, Yokohama City University Hospital, Yokohama, Kanagawa, Japan.
J Hum Genet. 2022 Jan;67(1):1-7. doi: 10.1038/s10038-021-00957-3. Epub 2021 Jul 7.
Heterozygous variants in CLTC, which encode the clathrin heavy chain protein, cause neurodevelopmental delay of varying severity, and often accompanied by dysmorphic features, seizures, hypotonia, and ataxia. To date, 28 affected individuals with CLTC variants have been reported, although their phenotypes have not been fully elucidated. Here, we report three novel de novo CLTC (NM_001288653.1) variants in three individuals with previously unreported clinical symptoms: c.3662_3664del:p.(Leu1221del) in individual 1, c.2878T>C:p.(Trp960Arg) in individual 2, and c.2430+1G>T:p.(Glu769_Lys810del) in individual 3. Consistent with previous reports, individuals with missense or small in-frame variants were more severely affected. Unreported symptoms included a brain defect (cystic lesions along the lateral ventricles of the brain in individuals 1 and 3), kidney findings (high-echogenic kidneys in individual 1 and agenesis of the left kidney and right vesicoureteral reflux in individual 3), respiratory abnormality (recurrent pneumonia in individual 1), and abnormal hematological findings (anemia in individual 1 and pancytopenia in individual 3). Of note, individual 1 even exhibited prenatal abnormality (fetal growth restriction, cystic brain lesions, high-echogenic kidneys, and a heart defect), suggesting that CLTC variants should be considered when abnormal prenatal findings in multiple organs are detected.
编码网格蛋白重链蛋白的CLTC基因杂合变异会导致不同严重程度的神经发育迟缓，且常伴有畸形特征、癫痫发作、肌张力减退和共济失调。迄今为止，已有28例携带CLTC变异的患者被报道，尽管他们的表型尚未完全阐明。在此，我们报告了3例具有此前未报道临床症状的患者的3种新的CLTC（NM_001288653.1）基因变异：患者1为c.3662_3664del:p.(Leu1221del)，患者2为c.2878T>C:p.(Trp960Arg)，患者3为c.2430+1G>T:p.(Glu769_Lys810del)。与之前的报道一致，携带错义或小的框内变异的患者受影响更严重。未报道的症状包括脑缺陷（患者1和患者3脑侧脑室囊性病变）、肾脏表现（患者1肾高回声，患者3左肾缺如及右膀胱输尿管反流）、呼吸异常（患者1反复肺炎）和血液学异常（患者1贫血，患者3全血细胞减少）。值得注意的是，患者1甚至出现了产前异常（胎儿生长受限、脑囊性病变、肾高回声和心脏缺陷），这表明当检测到多个器官的产前异常时，应考虑CLTC基因变异。
