Since 2008, FOXG1 haploinsufficiency has been linked to a severe neurodevelopmental phenotype resembling Rett syndrome but with earlier onset. Most patients are unable to sit, walk, or speak. For years, FOXG1 sequencing was only prescribed in such severe cases, limiting insight into the full clinical spectrum associated with this gene. Next‐generation sequencing (NGS) now enables unbiased diagnostics. Through the European Reference Network for Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders, we gathered data from patients with heterozygous FOXG1 variants presenting a mild phenotype, defined as able to speak and walk independently. We also reviewed data from three previously reported patients meeting our criteria. We identified five new patients with pathogenic FOXG1 missense variants, primarily in the forkhead domain, showing varying nonspecific intellectual disability and developmental delay. These features are not typical of congenital Rett syndrome and were rarely associated with microcephaly and epilepsy. Our findings are consistent with a previous genotype–phenotype analysis by Mitter et al. suggesting the delineation of five different FOXG1 genotype groups. Milder phenotypes were associated with missense variants in the forkhead domain. This information may facilitate prognostic assessments in children carrying a FOXG1 variant and improve the interpretation of new variants identified with genomic sequencing.

中文翻译：

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FOXG1 变异与先天性 Rett 综合征（无辅助行走和语言发育）相比，可能与更温和的表型相关

自2008年以来，福克斯G1单倍体不足与类似雷特综合征的严重神经发育表型有关，但发病较早。大多数患者无法坐下、行走或说话。多年，福克斯G1仅在此类严重病例中才进行测序，限制了对该基因相关的完整临床谱的了解。新一代测序 (NGS) 现在可以实现公正的诊断。通过欧洲罕见畸形综合征、智力和其他神经发育障碍参考网络，我们收集了杂合子患者的数据福克斯G1表现出温和表型的变体，被定义为能够独立说话和行走。我们还审查了之前报告的三名符合我们标准的患者的数据。我们发现了五名新的致病患者福克斯G1错义变异，主要发生在叉头区域，表现出不同的非特异性智力障碍和发育迟缓。这些特征不是先天性雷特综合征的典型特征，并且很少与小头畸形和癫痫相关。我们的研究结果与 Mitter 等人之前的基因型-表型分析一致。建议划定五种不同的福克斯G1基因型组。较温和的表型与叉头结构域中的错义变异相关。这些信息可能有助于对携带该疾病的儿童进行预后评估福克斯G1变体并改善对基因组测序发现的新变体的解释。