Coffin-Siris Syndrome: Genotype-Phenotype Clustering and Novel Variants
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Background: Coffin-Siris syndrome (CSS) is a rare disease characterized by features such as developmental delay, intellectual disability, unique facial feature, hypoplasia of the fifth finger or toe, hypertrichosis, and sparse scalp hair. CSS is currently diagnosed through a molecular genetic test that detects heterozygous pathogenic variants and deletion/duplication in the causative genes. Methods: We retrospectively reviewed the medical records of 23 suspected patients with CSS enrolled in the rare disease diagnostic program of the Korean Disease Control and Prevention Agency from January 2017 to December 2020, including whole-exome sequencing (WES) reports. Statistical analysis was performed using cluster analysis through Jaccard/Tanimoto similarity test using the R version 4.2.0. Results: Eight cases were genetically diagnosed with the CSS. Five cases were identified to have a novel variant: ARID1B (NM_020732.3) Gln958*, Asn1320*, Gly1696*, Gly806Trpfs*, and SMARCA4 (NM_001128849.1) Asn916Ser. Central nervous system symptoms were observed in all ARID1B cases, and the fifth digit hypoplasia was observed in all SMARCA4 cases. SMARCA4 Asn916Ser was identified as de novo. A similarity network was identified using cluster analysis, a relatively fresh approach to genotype-phenotype analysis. Conclusions: We reported eight patients diagnosed with CSS, five of whom have novel genetic variants of ARID1B or SMARCA4. A novel case of SMARCA4 was de novo. This study contributes to describing the CSS phenotype. Future studies may facilitate easier diagnosis of CSS in patients who present with atypical traits as more in-depth genetic testing, such as WES, is applied to rare disorders.
Abstract
Background: Coffin-Siris syndrome (CSS) is a rare disease characterized by features such as developmental delay, intellectual disability, unique facial feature, hypoplasia of the fifth finger or toe, hypertrichosis, and sparse scalp hair. CSS is currently diagnosed through a molecular genetic test that detects heterozygous pathogenic variants and deletion/duplication in the causative genes. Methods: We retrospectively reviewed the medical records of 23 suspected patients with CSS enrolled in the rare disease diagnostic program of the Korean Disease Control and Prevention Agency from January 2017 to December 2020, including whole-exome sequencing (WES) reports. Statistical analysis was performed using cluster analysis through Jaccard/Tanimoto similarity test using the R version 4.2.0. Results: Eight cases were genetically diagnosed with the CSS. Five cases were identified to have a novel variant: ARID1B (NM_020732.3) Gln958*, Asn1320*, Gly1696*, Gly806Trpfs*, and SMARCA4 (NM_001128849.1) Asn916Ser. Central nervous system symptoms were observed in all ARID1B cases, and the fifth digit hypoplasia was observed in all SMARCA4 cases. SMARCA4 Asn916Ser was identified as de novo. A similarity network was identified using cluster analysis, a relatively fresh approach to genotype-phenotype analysis. Conclusions: We reported eight patients diagnosed with CSS, five of whom have novel genetic variants of ARID1B or SMARCA4. A novel case of SMARCA4 was de novo. This study contributes to describing the CSS phenotype. Future studies may facilitate easier diagnosis of CSS in patients who present with atypical traits as more in-depth genetic testing, such as WES, is applied to rare disorders.
참고문헌 (22)
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