High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency

Happy to share our study applying splicing MAVEs to hypopituitarism, out at @AJHGNews https://doi.org/10.1016/j.ajhg.2021.06.013 - a team effort w/former postdoc Peter Gergics in Sally Camper’s lab @UM_Genetics, PhD student in my lab @smithcat1661, and collaborators worldwide.

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.

The group found four patient missense variants at adjacent codons in the key pituitary TF POU1F1, a leading genetic cause of hypopituitarism. These turned out to shift splicing to favor the minor beta isoform, a transcriptional repressor.

We wondered how widespread this effect was, and developed a splicing MAVE to measure how each of the >1000 possible SNVs in and around this exon affected splicing.

Map in hand, we revisited patient sequencing results, and found two affected individuals carrying ultra-rare, splice-disruptive synonymous variants. In total we find ~9% the tested SNVs are splice disruptive, and nearly 1 in 7 of these are synonymous.

We hope this will be a useful resource, both for resolving future POU1F1 VUSs, and also for developing improved wet- and dry-lab methods for splice effect prediction. Congrats to everyone involved!

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