IMPE Abstracts

Congenital hypopituitarism occurs in approximately 1/4000 births. Affected children have either isolated growth hormone deficiency or multiple pituitary hormone deficiencies. 65% of these individuals have syndromic features, such as abnormalities in craniofacial, gonadal, eye, and/or central nervous system development. 57% of the cases are dominant with incomplete penetrance, and the presentation is highly variable, even among related individuals. 67 different genes have been implicated in the disorder, and many cases remain with no molecular diagnosis. We screened 170 Argentinean patients for mutations in these genes using an economical gene capture system and identified pathogenic variants in 12% of the cases. We found rare variants in POU1F1 that alter splicing, converting the transcriptional activator into a repressor. Using a high throughput splicing assay we tested 1070 variants in POU1F1 and found 9% were splice disruptive, including 17 synonymous variants. Using this information, we identified two families with hypopituitarism that had synonymous, splice disruptive variants in POU1F1. Mouse mutants offer the opportunity to uncover novel genes that cause hypopituitarism, as several of the known genes were first discovered in mice. We identified 51 novel embryonic lethal mouse strains with pituitary defects, and 4 were implicated in the current patient cohort. These mouse mutants will also be valuable for understanding novel mechanisms of congenital hypopituitarism. In sum, identification of genetic causes of hypopituitarism provides the opportunity for a molecular diagnosis, which is valuable for predicting the course of disease and familial risk.