Lab Med Online.  2023 Apr;13(2):91-96. 10.47429/lmo.2023.13.2.91.

Coffin-Siris Syndrome: Genotype-Phenotype Clustering and Novel Variants

• Jang J
• Chae SW
• Shin HS
• Cho SI
• Kim B
• Lee Js
• Kim MJ
• Park SS
• Seong Mw

• KMID: 2552731
• DOI: http://doi.org/10.47429/lmo.2023.13.2.91

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 ARID1Bcases, 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.

Keyword

Coffin-Siris syndrome; Genotype; Phenotype; Cluster; Novel variant

Figure

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  Fig. 1 Frequency of phenotypes observed using gene and cluster analysis. (A) The frequency of phenotypes observed in each causative gene was expressed as a percentage of the total cases of each gene. (B) The number of same phenotypes observed in the combination of cases was expressed as a matrix. (C) A dendrogram based on the matrix depicted in (B). (D) Cluster analysis using Jaccard/Tanimoto similarity test for (B). (E) Networks with significant phenotypic similarities between each case was plotted as a graph based on the matrix depicted in (D), when the P≤0.01 was applied to (D) as a cutoff. The distance between each node is meaningless. Abbreviations: DD/ID, developmental delay/intellectual disability; GI, gastrointestinal; GU, genitourinary; CNS, central nervous system.

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