Sofronova Viktoriia, Fukushima Yu, Masuno Mitsuo, Naka Mami, Nagata Miho, Ishihara Yasuki, Miyashita Yohei, Asano Yoshihiro, Moriwaki Takahito, Iwata Rina, Terawaki Seigo, Yamanouchi Yasuko, Otomo Takanobu
Department of Molecular and Genetic Medicine, Kawasaki Medical School, Kurashiki, Japan.
Laboratory of Molecular Medicine and Human Genetics, North-Eastern Federal University, Yakutsk, Russia.
Hum Genome Var. 2022 Jul 25;9(1):26. doi: 10.1038/s41439-022-00203-y.
Coffin-Siris syndrome (CSS) is a congenital disorder that is characterized by an absent/hypoplastic fifth distal phalanx, psychomotor developmental delay, and coarse facial features. One of the causative genes, ARID1B (AT-rich interactive domain-containing protein 1B), encodes components of the BAF chromatin remodeling complexes. Here, we report a case of a 3-year 8-month-old male with a novel nonsense variant (NM_001374820.1:c.4282C > T, p.(Gln1428*)) in the ARID1B gene, which was identified with whole-exome sequencing. He showed clinical symptoms of cleft soft palate, distinctive facial features (flat nasal bridge, thick eyebrows, and long eyelashes), right cryptorchidism, and hypertrichosis that partially overlapped with CSS. One of the most characteristic features of CSS is absent/hypoplastic fifth distal phalanx. He showed no obvious clinical finding in the lengths of his fingers or in the formation of his fingernails. However, radiographic analyses of the metacarpophalangeal bones revealed shortening of all the distal phalanges and fifth middle phalanges, suggesting brachydactyly. We performed mRNA analyses and revealed that both nonsense-mediated decay and nonsense-associated altered splicing were simultaneously caused by the c.4282C > T nonsense variant. The proband's clinical manifestations fit the previously reported criteria of disease for CSS or intellectual disability with ARID1B variant. Altogether, we suggest that c.4282C > T is a pathogenic variant that causes this clinical phenotype.
科芬-西里斯综合征（CSS）是一种先天性疾病，其特征为第五指远端指骨缺如/发育不全、精神运动发育迟缓以及面部特征粗糙。致病基因之一，ARID1B（富含AT交互结构域蛋白1B），编码BAF染色质重塑复合体的组成部分。在此，我们报告一例3岁8个月大的男性患者，通过全外显子测序鉴定出其ARID1B基因存在一种新的无义变异（NM_001374820.1:c.4282C＞T，p.(Gln1428*)）。他表现出腭裂、独特的面部特征（鼻梁扁平、眉毛浓密、睫毛长）、右侧隐睾以及多毛症等临床症状，这些症状部分与CSS重叠。CSS最具特征性的表现之一是第五指远端指骨缺如/发育不全。他的手指长度和指甲形成未发现明显临床异常。然而，掌指骨的影像学分析显示所有远端指骨和第五中指骨缩短，提示短指畸形。我们进行了mRNA分析，发现c.4282C＞T无义变异同时导致了无义介导的mRNA降解和无义相关的可变剪接。先证者的临床表现符合先前报道的CSS或伴有ARID1B变异的智力障碍的疾病标准。总之，我们认为c.4282C＞T是导致这种临床表型的致病变异。
