ARID1B遺伝子におけるコフィン・シリス症候群の原因となる新規バリアントの同定

Coffin-Siris Syndrome (CSS) is a neurodevelopmental disorder caused by variants in genes encoding BRG1- and BRM-associated factor (BAF) chromatin-remodeling complex. ARID1B gene variants are the most common cause of CSS. This study aimed to identify novel pathogenic ARID1B variants in patients clinically diagnosed with CSS and to explore their pathogenic role. In this study, eight patients clinically diagnosed with CSS were enrolled, and whole exome sequencing (WES) was performed to identify potential pathogenic variants. Heterozygous variants in the ARID1B gene were identified in six patients, including one previously reported pathogenic nonsense variant and five novel pathogenic truncating variants. The combined annotation-dependent depletion (CADD) scores of the five novel variants were significantly above the mutation significance cutoff (MSC), suggesting their potential pathogenicity. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), these five novel variants were classified as pathogenic.

Our findings add five novel variants to the list of known pathogenic variants of the ARID1B gene. This study further clarifies an enhanced connection between ARID1B gene variants and CSS and expands the variant spectrum of CSS.

• Coffin-Siris syndrome (CSS) is a rare neurodevelopmental disorder characterized by developmental delay, intellectual disability, and hypoplasia of the fifth digits or nails. • Pathogenic variants in genes encoding subunits of the BAF chromatin-remodeling complex are the major genetic causes of CSS, with ARID1B being the most frequently mutated gene, and most variants of which are truncating and lead to haploinsuffucuency.

• Five novel heterozygous truncating variants in ARID1B were identified in eight patients clinically diagnosed with Coffin-Siris syndrome. • All novel variants showed high CADD scores and were classified as pathogenic according to ACMG guidelines.