7389 Novel Candidate Genes for Congenital Hypopituitarism Revealed by Whole Exome Sequencing
Authors: Mayer Julián Jorge Martínez , Vishnopolska Sebastian , Catalina Perticarari , García Lucía Iglesias , Hackbartt Martina , Alvarado Andrea Jacome , Martinez Marcela , Zaiat Jonathan , Braslavsky Debora Giselle , Keselman Ana Claudia , Bergada Ignacio , Marino Roxana Marcela , Garrido Natacia Perez , Ciaccio Marta , Di Palma María Isabel , Belgorosky Alicia , Forclaz Maria Veronica , Benzrihen Maria Gabriela , D’Amato Silvia , Rojas Gabriela Patricia , Miras Mirta , Alonso Guillermo Francisco , Nuñez Alejandra Paez , Castro Laura Cecilia , Gil Susana Mallea , Ballarino Carolina , Villacorta Laura Viviana Latorre , Figueroa Verónica , Morin Analia , Guntsche Zelmira , Lee Hane , Lee Eugene , Song Yongjun , Marti Marcelo , Perez-Millan Maria Ines 
Published: October 2024

Disclosure: J.J. Martínez Mayer: None. S. Vishnopolska: None. P. Catalina: None. L. Iglesias García: None. M. Hackbartt: None. A. Jacome Alvarado: None. M. Martinez: None. J. Zaiat: None. D.G. Braslavsky: None. A.C. Keselman: None. I. Bergada: None. R.M. Marino: None. N. Perez Garrido: None. M. Ciaccio: None. M.I. Di Palma: None. A. Belgorosky: None. M.V. Forclaz: None. M.G. Benzrihen: None. S. D'Amato: None. G.P. Rojas: None. M. Miras: None. G.F. Alonso: None. A. Paez Nuñez: None. L.C. Castro: None. S. Mallea Gil: None. C. Ballarino: None. L. Latorre Villacorta: None. V. Figueroa: None. A. Morin: None. Z. Guntsche: None. H. Lee: Employee; Self; 3Billion. E. Lee: Employee; Self; 3Billion. Y. Song: Employee; Self; 3Billion. M. Marti: None. M.I. Perez-Millan: None.

Normal pituitary gland function is key for the correct development of children, controlling growth, puberty, and general homeostasis. Pituitary dysfunction is associated with many different disorders, congenital hypopituitarism (CH) being the most reported pediatric endocrine dysfunction. Despite CH relatively high frequency, around 90% of pediatric patients lack a definitive genetic diagnosis. Increasing sequencing efforts in the last decade have been slowly improving this diagnostic rate. However, the use of gene panel sequencing and small cohort sizes for whole exome sequencing has not allowed for a full exploration of the CH genetic etiology yet. Here we present whole exome sequencing results of 137 unrelated cases of hypopituitarism patients, the largest cohort examined with this method to date. Pathogenic (P) variants were present in 14.6% of cases, while 27% presented with likely pathogenic (LP) variants and 23% carried variants of uncertain significance (VUS). Interestingly, less than half of cases with a definitive genetic diagnosis had variants in genes traditionally associated with CH (13/30). Many cases carried variants in genes were associated with complex syndromes (CHD7, KDM6A, PTPN11, ALG1, MORC2), or genes that have, only recently, been associated with CH, where our research adds more evidence of pathogenicity (ROBO1, PIBF1, ACAN, GNAS). However, even these genes accounted only for a fraction of the P/LP variants found, since new candidate genes also harbored many P/LP variants. These novel candidate genes present low tolerance to loss of function and belong to diverse protein families. Some highlights are cell signaling involving the mTOR and PTPN pathways, cilia, RNA processing, DNA methylation and extracellular matrix and cytoskeleton components. Overall, our results provide unprecedented insight into the genetic etiology of hypopituitarism.

Presentation: 6/3/2024