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De novo splice site variant of ARID1B associated with pathogenesis of Coffin–Siris syndrome

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Zeitschriftentitel: Molecular Genetics & Genomic Medicine
Personen und Körperschaften: Pranckėnienė, Laura, Siavrienė, Evelina, Gueneau, Lucie, Preikšaitienė, Eglė, Mikštienė, Violeta, Reymond, Alexandre, Kučinskas, Vaidutis
In: Molecular Genetics & Genomic Medicine, 7, 2019, 12
Format: E-Article
Sprache: Englisch
veröffentlicht:
Wiley
Schlagwörter:
Genetics (clinical)
Genetics
Molecular Biology
Details
Zusammenfassung: <jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Coffin–Siris syndrome is an extremely rare syndrome associated with developmental and congenital anomalies. It is caused by heterozygous pathogenic variants of <jats:italic>ARID1A</jats:italic>, <jats:italic>ARID1B</jats:italic>, <jats:italic>SMARCA4</jats:italic>, <jats:italic>SMARCB1</jats:italic>, <jats:italic>SMARCE1</jats:italic>, and <jats:italic>SOX11</jats:italic>.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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&gt;C in the <jats:italic>ARID1B</jats:italic> and truncated 1 633 amino acid protein NP_065783.3:p. (Thr1633Valfs*11).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>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 <jats:italic>ARID1B</jats:italic> at the terminal exon, resulting in the expression of a severe phenotype of CSS.</jats:p></jats:sec>
ISSN: 2324-9269
DOI: 10.1002/mgg3.1006