Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression and a severe phenotype. Contrastingly, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay and encode truncated proteins, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

中文翻译：

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特定于突变的病理生理机制定义了与SATB1功能障碍相关的不同神经发育障碍

尽管大规模统计分析可以可靠地识别疾病与基因的关系，但它们不能准确地捕获基因型与表型的相关性或疾病机制。我们使用多行独立证据显示，单个基因SATB1中的不同变异类型会导致临床上重叠但又不同的神经发育障碍。42例携带SATB1的个体的临床评估通过功能测定确定了与不同病理生理机制相关的明显的基因型-表型关系。CUT1和CUT2 DNA结合域中的错义变体导致更强的染色质结合，增加的转录抑制和严重的表型。相反，预测会导致单倍功能不足的变体与较温和的临床表现有关。对于具有过早的蛋白质截断变体的个体观察到类似的轻度表型，所述变体逃避无意义的介导的衰变并编码截短的蛋白质，所述截短的蛋白质具有转录活性但在细胞中定位错误。我们的结果表明，深入的突变特异性基因型-表型研究对于捕获完整的疾病复杂性和解释表型变异性至关重要。