Abstract:

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.

Key words: Coffin-Siris syndrome, growth retardation, high-throughput sequencing