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.