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SETBP1 variants outside the degron disrupt DNA-binding, transcription and neuronal differentiation capacity to cause a heterogeneous neurodevelopmental disorder [induced neurons]

ABSTRACT: Different types of germline de novo SETBP1 variants cause clinically distinct and heterogeneous neurodevelopmental disorders: Schinzel-Giedion syndrome (SGS, via missense variants at a critical degron region) and SETBP1-haploinsufficiency disorder. However, due to the lack of systematic investigation of genotype-phenotype associations of different types of SETBP1 variants, and limited understanding of its roles in neurodevelopment, the extent of clinical heterogeneity and how this relates to underlying pathophysiological mechanisms remain elusive. This imposes challenges for diagnosis. Here, we present a comprehensive investigation of the largest cohort to-date of individuals carrying SETBP1 missense variants outside the degron region (n=18). We performed thorough clinical and speech phenotyping with functional follow-up using cellular assays and transcriptomics. Our findings suggest that such variants cause a clinically and functionally variable developmental syndrome, showing only partial overlaps with classical SGS and SETBP1-haploinsufficiency disorder. We provide evidence of loss-of-function pathophysiological mechanisms impairing ubiquitination, DNA-binding, transcription, and neuronal differentiation capacity and morphologies. In contrast to SGS and SETBP1 haploinsufficiency, these effects are independent of protein abundance. Overall, our study provides important novel insights into diagnosis, patient care, and aetiology of SETBP1-related disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE301239 | GEO | 2025/09/08

REPOSITORIES: GEO

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Project description:Rationale: SMAD2 is a co-regulator that binds a variety of transcription factors and modulates activities during human development. Heterozygous SMAD2 loss-of-function (LoF) variants and missense variants are identified in patients with complex congenital heart disease (CHD), and in patients with arterial aneurysms and dissections. Mechanisms that account for distinct cardiovascular phenotypes caused by SMAD2 variants remain unknown. We aimed to define the transcriptional and epigenetic effects of heterozygous SMAD2 loss-of-function (LoF) and missense variants and identify the involvement of transcription factor networks and genes that contribute to CHD. Compared to LoF variants, we assessed the function of rare SMAD2 missense variants of uncertain significance. Methods: We constructed isogenic induced pluripotent stem cells (iPSCs) with heterozygous or homozygous LoF and rare (MAF ≤ 10-5) missense SMAD2 variants identified in CHD probands. Wildtype and mutant iPSCs were studied by bulk RNA sequencing (RNAseq) and chromatin accessibility (ATACseq). Datasets were integrated with published SMAD2/3 chromatin immunoprecipitation (ChIPseq) studies. Cardiomyocyte differentiation and contractility of mutant iPSCs was assessed. Results: SMAD2 haploinsufficiency reduced open chromatin across promoter regions and altered the expression of 385 direct SMAD regulated genes, including ten previously identified as dominant CHD genes. Motif analyses in regions with differential ATAC peaks predicted that SMAD2 haploinsufficiency disrupts interactions with at least five transcription factors, NANOG, ETS, TEAD3/4, CREB1 and AP1. Compared to SMAD2-haploinsufficient cells, iPSCs with heterozygous R114C or W274C variants exhibited shared and distinct patterns of altered chromatin accessibility, transcription factor binding motifs, and dysregulated genes. Conclusions: SMAD2 haploinsufficiency disrupts chromatin interactions and perturbs transcription factor binding, disrupting normal cardiovascular development. Differences in the molecular consequences of LoF and missense variants likely contribute to clinical phenotypic heterogeneity. Additionally, these data indicate opportunities for molecular functional analyses to improve re-classification of SMAD2 variants of uncertain clinical significance.

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SETBP1 variants outside the degron disrupt DNA-binding, transcription and neuronal differentiation capacity to cause a heterogeneous neurodevelopmental disorder [induced neurons]

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