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The chromatin remodeler CHD1L controls human cortical neurogenesis and contributes to distal 1q21.1 deletion/duplication syndrome [RNA-seq]

ABSTRACT: Background/objectives: Deletions and duplications of the distal 1q21.1 region are associated with syndromic forms of autism (MIM612474, 612475). Variable phenotypes have been reported, including congenital heart defects, autism, schizophrenia, head circumference and height defects. Methods: To elucidate which gene(s) are responsible for the 1q21.1 duplication/deletion- associated phenotypes, we performed gene manipulation in zebrafish and mice. We deciphered the function of candidate driver(s) by multi-omics approaches on human iPSC- derived neural progenitor cells (NPC) and cerebral organoids (CO). Results: We modeled duplication of the 1q21.1 region by overexpressing the 8 genes in the region in zebrafish. We found that only overexpression of CHD1L led to macrocephaly and increased larval body length. Conversely, deletion of the CHD1L zebrafish ortholog resulted in microcephaly and decreased larval body length. These mirror phenotypes are also observed when Chd1l expression is modulated in a mammalian model, notably with a variation in the number of mature Tbr1-positive neurons in the mouse embryo. NPCs derived from control and CHD1L Knock-out isogenic hiPSCs were subjected to transcriptomic and chromatin accessibility analyses. These approaches revealed that CHD1L regulates the expression levels and accessibility of genes involved in neuronal differentiation and synaptogenesis, including autism susceptibility genes such as UNC5D and DPP6. Strikingly, absence of CHD1L shifts the cellular identity from forebrain to retinal fate in CO. Finally, pathogenic missense and truncating variants of CHD1L were found in individuals with autism and/or height defects. Conclusion: CHD1L is a major contributor of the 1q21.1 duplication/deletion-associated microcephaly and growth defects. CHD1L dosage is required during human brain regionalization.

ORGANISM(S): Homo sapiens

PROVIDER: GSE266030 | GEO | 2025/09/25

REPOSITORIES: GEO

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Project description:Objective: Chromosomal 1q21.1 deletions and duplications are genomic disorders which are usually diagnosed postnatally. However, the genotype-phenotype correlations of 1q21.1 copy number variants (CNVs) during prenatal period are still not clear. This study aimed to provide a systematical summary of prenatal phenotypes for such genomic disorders. Methods: Twenty-six prenatal amniotic fluid samples diagnosed with 1q21.1 microdeletions/microduplications were obtained from pregnant women who opted for invasive prenatal testing. Karyotypic analysis and chromosomal microarray analysis (CMA) were performed for all cases simultaneously. The pregnancy outcomes and health conditions after birth for all cases were followed up. Meanwhile, prenatal cases with 1q21.1 microdeletions or microduplications in the literature were retrospectively collected. Results: Eleven pregnancies (11/8252, 0.13%) with 1q21.1 microdeletions and fifteen (15/8252, 0.18%) with 1q21.1 microduplications were identified. Among these 1q21.1 CNVs, four cases covered thrombocytopenia-absent radius (TAR) region, sixteen cases covered 1q21.1 recurrent microdeletion/microduplication region, and six cases covered all regions mentioned above. The prenatal abnormal ultrasound findings were recorded in four participants with 1q21.1 deletions and seven participants with 1q21.1 duplications. Finally, three cases with 1q21.1 deletions and five with 1q21.1 duplications terminated their pregnancies. Conclusion: 1q21.1 microdeletions were associated with increased nuchal translucency (NT), anomalies of urinary system and cardiovascular abnormalities, and 1q21.1 microduplications were correlated with cardiovascular malformations, nasal bone dysplasia and increased NT in prenatal setting. In addition, cerebral ventriculomegaly might be correlated with 1q21.1 microduplications. Considering the variable expressivity and incomplete penetrance of 1q21.1 CNVs, long term follow up after birth should be carried out for these cases. We identified 26 fetuses carrying the 1q21.1 microdeletions and microduplications using chromosomal microarray analysis. And diverse prenatal phenotypes and the critical genes involved in the deleted/duplicated regions were described in this study.

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The chromatin remodeler CHD1L controls human cortical neurogenesis and contributes to distal 1q21.1 deletion/duplication syndrome [RNA-seq]

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