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Two distinct phenotypes in Snijders Blok-Campeau syndrome and characterization of the behavioral phenotype in a zebrafish model

European Journal of Human Genetics volume 33, pages 747–757 (2025)Cite this article

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Abstract

Chromatin remodeling is an important system controlling gene expression. CHD3, which is a causative gene of Snijders Blok-Campeau syndrome (SNIBCPS), is a member of the chromodomain helicase DNA-binding (CHD) family related to chromatin remodeling. SNIBCPS is characterized by developmental delay (DD), intellectual disability (ID), macrocephaly, and facial features including a prominent forehead and hypertelorism. Hypersociability/overfriendliness is a notable behavioral feature in patients. Here, we describe five SNIBCPS patients with CHD3 variants from four families, including a sibling pair caused by parental gonosomal mosaicism. We observed two distinct phenotypes in our patients in accordance with previous observations. Phenotype 1: macrocephaly, hypertelorism, overgrowth, DD, and ID; and Phenotype 2: microcephaly, growth retardation, DD, and ID. Phenotype 1 was consistent with the typical SNIBCPS phenotype, while Phenotype 2 was distinct. To understand further the features of the patients with SNIBCPS, we generated chd3-knockout (KO) zebrafish using CRISPR-Cas9 genome editing. No morphological changes were observed in chd3-KO zebrafish. However, behavioral tests showed that chd3-KO zebrafish had strong and sustained interest in others, and were less aggressive toward others, suggesting a recapitulation of the hypersociability/overfriendliness phenotype in patients with SNIBCPS. Metabolomic analysis using whole brains showed changes in metabolites processed by specific mitochondrial enzymes in chd3-KO zebrafish. The administration of metformin, which reportedly ameliorates mitochondrial dysfunction and behavioral abnormalities, attenuated the abnormal behavior of chd3-KO zebrafish. Our study helps delineate the phenotypes of patients with SNIBCPS, provides insights into a characteristic behavior of the disease, and suggests a potential treatment to improve the behavioral symptoms of patients.

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Fig. 1: Patient family pedigrees and location of the identified pathological variants in CHD3.
Fig. 2: Effects of chd3-knockout (KO) on social preference in zebrafish.
Fig. 3: Effects of chd3-knockout (KO) on mirror biting behavior of zebrafish.
Fig. 4: Differentially expressed metabolites between chd3-KO and WT zebrafish and the effect of metformin in the mirror biting test.

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The data are not available due to ethical restrictions.

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Acknowledgements

We thank patients and their families for their cooperation.

Funding

This research was supported by the Initiative on Rare and Undiagnosed Diseases (IRUD) (19ek0109301) from the Japan Agency for Medical Research and Development, a Grant-in-Aid for Research on rare and intractable diseases, Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan, MEXT KAKENHI (no. 221S0002 to KK), the Japan Society for the Promotion of Science, KAKENHI (grant nos. 20K08270 and 23K07283 to KK, 22K06882 to TS, and 23K06355 to YN), the Research Revitalization Program at Mie University Graduate School of Medicine (to YN), and Ikuura Mariko Foundation (to YN).

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Author notes

  1. These authors contributed equally: Yumi Enomoto, Takashi Shiromizu, Sakyo Yasojima.

Authors and Affiliations

  1. Clinical Research Institute, Kanagawa Children’s Medical Center, Yokohama, Japan

    Yumi Enomoto, Takuya Naruto & Kenji Kurosawa

  2. Department of Integrative Pharmacology, Graduate School of Medicine, Mie University, Tsu, Japan

    Takashi Shiromizu, Sakyo Yasojima, Junko Koiwa, Hiroaki Ito, Mizuki Yuge, Momoka Ohkawa, Ryohei Shibata & Yuhei Nishimura

  3. Mie University Research Center for Cilia and Diseases, Tsu, Japan

    Takashi Shiromizu, Yuhei Nishimura & Kenji Kurosawa

  4. Division of Medical Genetics, Kanagawa Children’s Medical Center, Yokohama, Japan

    Yukiko Kuroda, Hiroaki Murakami, Shizuka Shiiya, Naoko Omotani & Kenji Kurosawa

  5. Department of Clinical Dysmorphology, Graduate School of Medicine, Mie University, Tsu, Japan

    Kenji Kurosawa

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  1. Yumi Enomoto
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  2. Takashi Shiromizu
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Contributions

KK, YN, and YE designed the study, the main conceptual ideas, and the proof outline. YE analyzed the clinical and genomic data and wrote the manuscript with support from all members. KK, YK, and HM were involved in patients’ medical care and analysis of the clinical and genomic data. TN and YE provided the bioinformatics pipeline for genomic data analysis. SS and NO performed the laboratory experiments. TS generated the chd3-KO zebrafish and performed the metabolome analysis. JK maintained the zebrafish. SY, JK, MO, and HI performed the behavioral analysis of the zebrafish. RS and MY performed the histological analysis of the zebrafish.

Corresponding authors

Correspondence to Yuhei Nishimura or Kenji Kurosawa.

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The authors declare no competing interests.

Ethical approval and consent to participate

Written informed consent was obtained from the parents of the patients in accordance with the Kanagawa Children’s Medical Center Review Board and Ethics Committee. This study was approved by the Institutional Animal Care and Use Committee of Mie University (no. 2020-19).

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Enomoto, Y., Shiromizu, T., Yasojima, S. et al. Two distinct phenotypes in Snijders Blok-Campeau syndrome and characterization of the behavioral phenotype in a zebrafish model. Eur J Hum Genet 33, 747–757 (2025). https://doi.org/10.1038/s41431-025-01815-y

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