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De novo variants in the Helicase-C domain of CHD8 are associated with severe phenotypes including autism, language disability and overgrowth

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Abstract

CHD8, which encodes Chromodomain helicase DNA-binding protein 8, is one of a few well-established Autism Spectrum Disorder (ASD) genes. Over 60 mutations have been reported in subjects with variable phenotypes, but little is known concerning genotype–phenotype correlations. We have identified four novel de novo mutations in Chinese subjects: two nonsense variants (c.3562C>T/p.Arg1188X, c.2065C>A/p.Glu689X), a splice site variant (c.4818-1G>A) and a missense variant (c.3502T>A/p.Tyr1168Asn). Three of these were identified from a 445-member ASD cohort by ASD gene panel sequencing of the 96 subjects who remained negative after molecular testing for copy number variation, Rett syndrome, FragileX and tuberous sclerosis complex (TSC). The fourth (p.Glu689X) was detected separately by diagnostic trio exome sequencing. We used diagnostic instruments and a comprehensive review of phenotypes, including prenatal and postnatal growth parameters, developmental milestones, and dysmorphic features to compare these four subjects. In addition to autism, they also presented with prenatal onset macrocephaly, intellectual disability, overgrowth during puberty, sleep disorder, and dysmorphic features, including broad forehead with prominent supraorbital ridges, flat nasal bridge, telecanthus and large ears. For further comparison, we compiled a comprehensive list of CHD8 variants from the literature and databases, which revealed constitutive and somatic truncating variants in the HELIC (Helicase-C) domain in ASD and in cancer patients, respectively, but not in the general population. Furthermore, HELIC domain mutations were associated with a severe phenotype defined by a greater number of clinical features, lower verbal IQ, and a prominent, consistent pattern of overgrowth as measured by weight, height and head circumference. Overall, this study adds to the ASD-associated loss-of-function mutations in CHD8 and highlights the clinical importance of the HELIC domain of CHD8.

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Data availability

gnomAD, gnomad.broadinstitute.org/;ExAC Browse, https://Exac.broadinstitute.org/; Mutation Taster, https://mutationtaster.org/, Polyphen-2, https://genetics.bwh.harvard.edu/pph2/; SIFT, https://sif.jcvi.org, UCSC human Genome Browser, https://genome-euro.ucsc.edu/index.html; Exome Variant Server, https://evs.gs.washington.edu/EVS/;1K Genomes Project: https://www.1000genomes.org/; BioMuta v2.0 (https://hive.biochemistry.gwu.edu/cgi-bin/prd/biomuta/servlet.cgi); Conserved Domain Database (CDD) https://www.ncbi.nlm.nih.gov/Structure/cdd/.

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Acknowledgements

We appreciate the ASD participants and their families and also the physicians who took part in collection of samples. We also thank students (Yanhua Lv and Qing Ji) for their efforts on validation of CHD8 variants by Sanger sequencing in Yu An’s lab. We much appreciated Dr.Kai Wang from University of Pennsylvania who contributed to the annotation of frameshift variants of CHD8.

Funding

This work was supported by Grants from the Shanghai Municipal Science and Technology Major Project (Grant No. 2017SHZDZX01), National Natural Science Foundation of China (No. 31671386 and No. 91430112).

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Author notes

  1. Yu An, Yasong Du and Yiping Shen contributed equally to this work.

Authors and Affiliations

  1. Human Phenome Institute, Fudan University, 825 Zhangheng Road, Shanghai, 201203, China

    Yu An

  2. Huangpu District Mental Health Center, 1162 Qu Xi Road, Shanghai, 200023, China

    Linna Zhang

  3. Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, 600 Wan ping Nan Road, Shanghai, 200013, China

    Wenwen Liu & Yasong Du

  4. Maternal and Child Health Hospital, Children’s Hospital and Birth Defect Prevention Research Institute of Guangxi Zhuang Autonomous Region, 59 Xiangzhu Avenue, Nanning, 530002, Guangxi, China

    Yunyun Jiang, Xue Chen & Yiping Shen

  5. Children’s Hospital of Shanghai, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Xiaoping Lan

  6. State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China

    Gan Li & Qiang Hang

  7. Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Jian Wang & Yiping Shen

  8. Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    James F. Gusella & Yiping Shen

  9. Department of Genetics, Harvard Medical School, Boston, MA, USA

    James F. Gusella & Yiping Shen

  10. Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA

    Yiping Shen

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  1. Yu An
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Contributions

YA, YSD, and YPS conceived the project and designed the experiments. LNZ, WWL and YSD collected ASD patients, performed autism behavior evaluation and clinical diagnosis as well as summarized the clinical information. YYJ and XC contributed one Autism patient. XPL also contributed one patient with mild intellectual disability with a CHD8 variant. QH and GL performed protein model analysis. JW and YA performed NGS analysis and variant calling. YA and her lab performed confirmation for the variants. YA and YPS did further analysis based on comprehensive database assessment (SSC and gnomAD). YA, JFG and YPS wrote and edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yu An.

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This study was approved by the Ethics Committee of Fudan University and informed consent was obtained from all families.

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An, Y., Zhang, L., Liu, W. et al. De novo variants in the Helicase-C domain of CHD8 are associated with severe phenotypes including autism, language disability and overgrowth. Hum Genet 139, 499–512 (2020). https://doi.org/10.1007/s00439-020-02115-9

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