De novo splice site variant of ARID1B associated with pathogenesis of Coffin–Siris syndrome. Issue 12 (19th October 2019)

• Record Type: Journal Article
• Authors: Pranckėnienė, Laura; Siavrienė, Evelina; Gueneau, Lucie; Preikšaitienė, Eglė; Mikštienė, Violeta; Reymond, Alexandre; Kučinskas, Vaidutis
• Is Part Of: Molecular genetics & genomic medicine. Volume 7:Issue 12(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-10-19
• Subjects: ARID1B -- cDNA functional analysis -- Coffin–Siris syndrome -- de novo splice site variant -- intellectual disability -- skipping of exon 19 -- WES; Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1002/mgg3.1006
• Languages: English
• ISSNs: 2324-9269

Abstract

Abstract: Background: Coffin–Siris syndrome is an extremely rare syndrome associated with developmental and congenital anomalies. It is caused by heterozygous pathogenic variants of ARID1A, ARID1B, SMARCA4, SMARCB1, SMARCE1, and SOX11 . Methods: This case study presents the whole exome sequencing of a patient with characteristic clinical features of Coffin–Siris syndrome. Analysis included Sanger sequencing of complementary DNA and bioinformatic analysis of the variant. Results: Analysis of cDNA Sanger sequencing data revealed that the donor splice site variant led to skipping of exon 19. Further, bioinformatic analysis predicted abnormal splicing in a translational frameshift of 11 amino acids and the creation of a premature termination codon. Results found a novel de novo splice site variant c.5025+2T>C in the ARID1B and truncated 1 633 amino acid protein NP_065783.3:p. (Thr1633Valfs*11). Conclusion: Truncated ARID1B resulted in loss of the BAF250 domain, which is part of SWI/SNF‐like ATP‐dependent chromatin remodeling complex. The severe clinical manifestation presented by the proband was attributed to the disappearance of the BAF250 domain in the ARID1B protein. Our finding provides strong evidence that this pathogenic variant of exon 19 caused a frameshift mutation in the ARID1B at the terminal exon, resulting in the expression of a severe phenotype of CSS. Abstract : This case study examined the whole exome sequencing of a patient with characteristic clinical features of Coffin–Siris syndrome and found a novel de novo splice site variant c.5025+2T>C in the ARID1B . Analysis of cDNA Sanger sequencing data obtained from this patient revealed that the donor splice site variant led to skipping of exon 19. The severe clinical manifestation that our proband presented with; cumulated in disappearance of the BAF250 domain in the ARID1B protein. Thus, providing strong evidence that this pathogenic variant of exon 19 caused frameshift mutation in the ARID1B at the terminal exon resulting in the expression of a severe phenotype of CSS.