目的 对3例Coffin-Siris综合征患儿进行临床表型分析和基因变异位点鉴定,明确其致病原因。方法 采用染色体微阵列分析、家系全外显子组测序分析、家系全基因组测序分析、一代测序等多种基因检测方法进行病因学确诊。采集患儿3外周血建立永生化淋巴细胞系,用蛋白免疫印迹法检测患儿3 ARID1B蛋白表达。结果 3例患儿均因发育迟缓就诊,均合并有面容异常。患儿1伴宫内发育不全,患儿2伴反复上呼吸道感染,患儿3伴智力落后和手部异常体征。3例患儿染色体微阵列分析结果均为阴性。患儿1和患儿2采用家系全外显子组测序分析得到致病基因位点。患儿1 SMARCB1基因存在一个未见报道的新生杂合剪切变异c.363-3C>G,患儿2 ARID1B基因存在一个未见报道的新生杂合剪切变异c.3550+1(IVS13)G>A。患儿3家系全外显子组未检测到变异,经家系全基因组测序分析发现ARID1B基因携带新生杂合第11号外显子部分缺失,此位点也尚未有文献报道。蛋白免疫印迹法结果显示患儿3 ARID1B蛋白水平的表达量明显下降。结论 Coffin-siris综合征患者临床表现多样,主要以发育落后为主诉。多种基因诊断方法的综合运用,结合临床表现,可帮助确诊Coffin-Siris综合征。

Objective To perform the phenotypic analysis and identify genetic variation locus in three patients with Coffin-Siris Syndrome (CSS). Methods Chromosome microarray analysis (CMA), trio-whole exome sequencing analysis (trio-WES), trio-whole genome sequencing analysis (trio-WGS), and Sanger sequencing were used for genetic diagnosis. The peripheral blood example of patient 3 was collected to establish an immortalized lymphocyte line, and the ARID1B protein expression was detected by Western Bolt (WB). Results All three patients visited the hospital for developmental retardation, and they all had facial dysmorphism. Patient 1 had intrauterine growth restriction, patient 2 was accompanied by recurrent upper respiratory tract infection, patient 3 had intellectual disability and abnormal hand manifestations. The CMA results of three patients were negative. The pathogenic gene loci of patient 1 and patient 2 were obtained by trio-WES analysis. Patient 1 has a de novo heterozygous splicing site mutation of c.363-3C>G in SMARCB1. There was a de novo heterozygous splicing site mutation of c.3550+1(IVS13) G>A in the ARID1B gene of patient 2. No pathogenic variations were identified in patient 3 by trio-WES. However, trio-WGS analysis revealed a de novo heterozygous exon 11 deletion in the ARID1B gene of patient 3. The three de novo mutations have not been reported previously. WB showed a significant decrease of ARID1B protein level in immortalized lymphocytes from patient 3. Conclusions The clinical manifestations of Coffin-Siris syndrome are diverse, and featured mainly as developmental retardation. The application of multiple genetic testing methods can help to confirm diagnosis of the Coffin-Siris syndrome.