De Novo Splice Site Variant of ARID1B Associated with Pathogenesis of Coffin-Siris Syndrome

Overview

Journal Mol Genet Genomic Med

Specialty Genetics

Date 2019 Oct 20

PMID 31628733

Citations 7

Authors

Laura Pranckeniene

Evelina Siavriene

Lucie Gueneau

Egle Preiksaitiene

Violeta Mikstiene

Alexandre Reymond

Vaidutis Kucinskas

Affiliations

Soon will be listed here.

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.

Citing Articles

De novo variation in ARID1B gene causes Coffin-Siris syndrome 1 in a Chinese family with excessive early-onset high myopia.

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Growth Hormone Deficiency due to p.(Gln467Argfs*64) Mutation in the Gene in a Girl with Coffin-Siris Syndrome.

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Prenatal genetic testing in 19 fetuses with corpus callosum abnormality.

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The relative fitness of the de novo variants in general Lithuanian population vs. in individuals with intellectual disability.

Pranckeniene L, Kucinskas V Eur J Hum Genet. 2021; 30(3):332-338.

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