Hypotonia, Ataxia, and Delayed Development syndrome is a neurodevelopmental disorder caused by heterozygous Early B-Cell Factor 3 (EBF3) loss-of-function variants. Identified in 2016, the full spectrum of clinical findings and the relationship between the EBF3 genotype and clinical outcomes has not been determined beyond its namesake features. We combined a phenotypic assessment of 33 individuals molecularly diagnosed with EBF3 pathogenic variants with a meta-analysis of 34 previously reported individuals. The combined 62 unique individuals enabled comparative cross-sectional phenotype and genotype analysis in the largest cohort to date of affected individuals. Cardinal distinguishing features were identified that facilitate phenotypic stratification for clinical diagnosis. We developed assessment scales to ascertain individuals at risk for pathogenic EBF3 variants, stratify the clinical severity, and connect variant-specific molecular phenotypes to clinical outcomes. Our findings show that a specific class of EBF3 variants affecting the evolutionarily conserved Zinc Finger (ZNF) motif, which is critical for stabilizing the protein interaction with the DNA target sequence, is associated with an increased risk of persistent motor and language impairments. These findings highlight the impact of combining variant-specific molecular phenotypes with comprehensive clinical data to predict neurodevelopmental outcomes and potentially guide personalized decisions for therapeutic interventions.

中文翻译：

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综合的表型和突变方法定义了与EBF3相关的HADD综合征的基因型-表型关系

低钾，共济失调和延迟发育综合征是由杂合的早期B细胞因子3（EBF3）功能丧失的变异体引起的神经发育障碍。在2016年确定，除了其同名特征外，尚未确定全部临床发现以及EBF3基因型与临床结果之间的关系。我们将分子诊断为EBF3致病性变异的33个个体的表型评估与34个先前报道的个体的荟萃分析相结合。合并的62位独特的个体能够在迄今为止最大的受累个体队列中进行比较横断面表型和基因型分析。识别出有助于临床表型分层的主要区别特征。我们制定了评估量表，以确定有致病性EBF3变异风险的个体，对临床严重性进行分层，并将变异特异性分子表型与临床结果联系起来。我们的发现表明，影响进化保守的锌指（ZNF）基序的特定类别的EBF3变体对稳定蛋白质与DNA靶序列的相互作用至关重要，与持续性运动和语言障碍的风险增加有关。这些发现凸显了将变体特异性分子表型与全面的临床数据相结合来预测神经发育结果并可能指导个性化治疗干预决策的影响。我们的发现表明，影响进化保守的锌指（ZNF）基序的特定类别的EBF3变体对稳定蛋白质与DNA靶序列的相互作用至关重要，与持续性运动和语言障碍的风险增加有关。这些发现凸显了将变体特异性分子表型与全面的临床数据相结合来预测神经发育结果并可能指导个性化治疗干预决策的影响。我们的发现表明，影响进化保守的锌指（ZNF）基序的特定类别的EBF3变体对稳定蛋白质与DNA靶序列的相互作用至关重要，与持续性运动和语言障碍的风险增加有关。这些发现凸显了将变体特异性分子表型与全面的临床数据相结合来预测神经发育结果并可能指导个性化治疗干预决策的影响。