Dendritic Spine in Autism Genetics: Whole-Exome Sequencing Identifying De Novo Variant of CTTNBP2 in a Quad Family Affected by Autism Spectrum Disorder

Yingmei Xie; Hui Wang; Bing Hu; Xueli Zhang; Aiping Liu; Chunquan Cai; Shijun Li; Cheng Chen; Zhangxing Wang; Zhaoqing Yin; Mingbang Wang

doi:10.3390/children10010080

Dendritic Spine in Autism Genetics: Whole-Exome Sequencing Identifying De Novo Variant of CTTNBP2 in a Quad Family Affected by Autism Spectrum Disorder

Children (Basel). 2022 Dec 30;10(1):80. doi: 10.3390/children10010080.

Authors

Yingmei Xie¹, Hui Wang², Bing Hu¹, Xueli Zhang³, Aiping Liu⁴, Chunquan Cai⁵, Shijun Li⁶, Cheng Chen¹, Zhangxing Wang³, Zhaoqing Yin⁷, Mingbang Wang^{8

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Affiliations

¹ Division of Neonatology, Longgang District Maternal and Child Health Hospital, Shenzhen 518172, China.
² Division of Child Health Care, Xiamen Branch of Children's Hospital of Fudan University (Xiamen Children's Hospital), Xiamen 361006, China.
³ Division of Neonatology, Shenzhen Longhua People's Hospital, Shenzhen 518109, China.
⁴ The Department of Laboratory, Baoan Public Health Service Center of Shenzhen, Shenzhen 518108, China.
⁵ Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin Children's Hospital (Children's Hospital of Tianjin University), Tianjin Pediatric Research Institute, Tianjin 300134, China.
⁶ First Medical Center, Chinese PLA General Hospital, Department of Radiology, Beijing 100853, China.
⁷ The People's Hospital of Dehong Autonomous Prefecture, Division of Pediatrics, Dehong Hospital of Kun-ming Medical University, Mangshi 678400, China.
⁸ Microbiome Therapy Center, South China Hospital, Medical School, Shenzhen University, Shenzhen 518116, China.
⁹ Shanghai Key Laboratory of Birth Defects, Division of Neonatology, Children's Hospital of Fudan University, National Center for Children's Health, Shanghai 201102, China.

Abstract

Autism spectrum disorder (ASD) affects around 1% of children with no effective blood test or cure. Recent studies have suggested that these are neurological disorders with a strong genetic basis and that they are associated with the abnormal formation of dendritic spines. Chromosome microarray (CMA) together with high-throughput sequencing technology has been used as a powerful tool to identify new candidate genes for ASD. In the present study, CMA was first used to scan for genome-wide copy number variants in a proband, and no clinically significant copy number variants were found. Whole-exome sequencing (WES) was used further for genetic testing of the whole quad family affected by ASD, including the proband, his non-autistic sister, and his parents. Sanger sequencing and MassARRAY-based validation were used to identify and confirm variants associated with ASD. WES yielded a 151-fold coverage depth for each sample. A total of 98.65% of the targeted whole-exome region was covered at >20-fold depth. A de novo variant in CTTNBP2, p.M115T, was identified. The CTTNBP2 gene belongs to a family of ankyrin repeat domain-containing proteins associated with dendritic spine formation. Although CTTNBP2 has been associated with ASD, limited studies have been developed to identify clinically relevant de novo mutations of CTTNBP2 in children with ASD; family-based WES successfully identified a clinically relevant mutation in the CTTNBP2 gene in a quad family affected by ASD. Considering the neuron-specific expression of CTTNBP2 and its role in dendritic spine formation, our results suggest a correlation between the CTTNBP2 mutation and ASD, providing genetic evidence for ASD spine pathology. Although the present study is currently insufficient to support the assertion that the de novo mutation M115T in CTTNBP2 directly causes the autism phenotype, our study provides support for the assertion that this mutation is a candidate clinically relevant variant in autism.

Keywords: CTTNBP2; autism spectrum disorder; cortactin-binding protein 2; whole-exome sequencing.

Abstract

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