Sequencing of selected chromatin remodelling genes reveals increased burden of rare missense variants in ASD patients from the Japanese population

Abstract

Chromatin remodelling is an important process in neural development and is related to autism spectrum disorder (ASD) and schizophrenia (SCZ) aetiology. To further elucidate the involvement of chromatin remodelling genes in the genetic aetiology of ASD and SCZ in the Japanese population, we performed a case–control study. Targeted sequencing was conducted on coding regions of four BAF chromatin remodelling complex genes: SMARCA2, SMARCA4, SMARCC2, and ARID1B in 185 ASD, 432 SCZ patients, and 517 controls. 27 rare non-synonymous variants were identified in ASD and SCZ patients, including 25 missense, one in-frame deletion in SMRACA4, and one frame-shift variant in SMARCC2. Association analysis was conducted to investigate the burden of rare variants in BAF genes in ASD and SCZ patients. Significant enrichment of rare missense variants in BAF genes, but not synonymous variants, was found in ASD compared to controls. Rare pathogenic variants indicated by in silico tools were significantly enriched in ASD, but not statistically significant in SCZ. Pathogenic-predicted variants were located in disordered binding regions and may confer risk for ASD and SCZ by disrupting protein–protein interactions. Our study supports the involvement of rare missense variants of BAF genes in ASD and SCZ susceptibility.

Keywords:

• Chromatin remodelling
• BAF complex
• autism spectrum disorder
• schizophrenia
• rare variant

Acknowledgments

The authors thank all the patients and families for participating in this study. We also thank Kiyori Monta, Mami Yoshida, Hiromi Noma and Yukari Mitsui for the technical support.

Disclosure statement

The authors declare that they have no competing interest.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request

Additional information

Funding

This study was supported by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) and the Ministry of Health, Labour and Welfare of Japan; the Japan Agency for Medical Research and Development (AMED) under Grant Nos. JP21dm0207075, JP21ak0101113, JP21dk030710, JP21ek0109488, JP21km0405216, JP21ek0109411, and JP 21wm0425007; the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Nos. 17H05090, 18H04040, 21K07543, 21H00194, 18K19511, 21H04815, 21H02848 and 15K19720; the Uehara Memorial Foundation; and the SENSHIN Medical Research Foundation.