Purpose

Heterozygous pathogenic variants in various FOXP genes cause specific developmental disorders. The phenotype associated with heterozygous variants in FOXP4 has not been previously described.

Methods

We assembled a cohort of eight individuals with heterozygous and mostly de novo variants in FOXP4: seven individuals with six different missense variants and one individual with a frameshift variant. We collected clinical data to delineate the phenotypic spectrum, and used in silico analyses and functional cell-based assays to assess pathogenicity of the variants.

Results

We collected clinical data for six individuals: five individuals with a missense variant in the forkhead box DNA-binding domain of FOXP4, and one individual with a truncating variant. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia, cervical spine abnormalities, and ptosis. Luciferase assays showed loss-of-function effects for all these variants, and aberrant subcellular localization patterns were seen in a subset. The remaining two missense variants were located outside the functional domains of FOXP4, and showed transcriptional repressor capacities and localization patterns similar to the wild-type protein.

Conclusion

Collectively, our findings show that heterozygous loss-of-function variants in FOXP4 are associated with an autosomal dominant neurodevelopmental disorder with speech/language delays, growth defects, and variable congenital abnormalities.

中文翻译：

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扰乱 FOXP4 转录抑制活性的杂合变异会导致发育障碍，伴有言语/语言延迟和多种先天性异常

 目的

各种FOXP基因的杂合致病性变异会导致特定的发育障碍。先前尚未描述与FOXP4杂合变异体相关的表型。

 方法

我们组装了一个由FOXP4中具有杂合且大部分从头变异的 8 个人组成的队列：7 个人具有 6 种不同的错义变异，1 个人具有移码变异。我们收集了临床数据来描绘表型谱，并用于计算机分析和基于功能细胞的测定，以评估变异的致病性。

 结果

我们收集了 6 个人的临床数据：5 个人在 FOXP4 的叉头盒 DNA 结合域中具有错义变异，1 个人具有截短变异。重叠的特征包括言语和语言发育迟缓、生长异常、先天性膈疝、颈椎异常和上睑下垂。荧光素酶检测显示所有这些变体均出现功能丧失效应，并且在一个子集中观察到异常的亚细胞定位模式。其余两个错义变体位于 FOXP4 功能域之外，并表现出与野生型蛋白相似的转录抑制能力和定位模式。

 结论

总的来说，我们的研究结果表明， FOXP4杂合性功能丧失变异与常染色体显性神经发育障碍相关，伴有言语/语言延迟、生长缺陷和各种先天性异常。