Pituitary hormone deficiency occurs in ∼1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We found four separate heterozygous missense variants in unrelated individuals with hypopituitarism that were predicted to affect a minor isoform, POU1F1 beta, which can act as a transcriptional repressor. These variants retain repressor activity, but they shift splicing to favor the expression of the beta isoform, resulting in dominant-negative loss of function. Using a high-throughput splicing reporter assay, we tested 1,070 single-nucleotide variants in POU1F1. We identified 96 splice-disruptive variants, including 14 synonymous variants. In separate cohorts, we found two additional synonymous variants nominated by this screen that co-segregate with hypopituitarism. This study underlines the importance of evaluating the impact of variants on splicing and provides a catalog for interpretation of variants of unknown significance in POU1F1.

垂体激素缺乏发生在 1:4,000 左右的活产儿中。大约 3% 的病例是由于 POU1F1（一种垂体特异性转录激活因子）的 α 亚型突变所致。我们在患有垂体功能减退症的无关个体中发现了四种不同的杂合错义变体，这些变体预计会影响一种次要同种型 POU1F1 β，它可以作为转录抑制因子。这些变体保留了阻遏物活性，但它们会改变剪接以有利于 β 同种型的表达，从而导致显性负功能丧失。使用高通量剪接报告基因检测，我们测试了POU1F1 中的1,070 个单核苷酸变体. 我们确定了 96 个剪接破坏变体，包括 14 个同义变体。在不同的队列中，我们发现了此筛选指定的另外两个同义变体，它们与垂体功能减退症共同分离。该研究强调了评估变体对剪接影响的重要性，并为解释POU1F1中未知意义的变体提供了目录。