Argentinian multicentric genetic study of pituitary hormonal deficiencies using a custom panel based on single molecule molecular inversion probes

VISHNOPOLSKA, SEBASTIAN ALEXIS; CAMILLETTI, MARIA ANDREA; MARTINEZ MAYER, JULIAN; CHAVES MURRIELLO AUGUSTO; CHIRINO FELKER GONZALO; BRASLAVSKY, DÉBORA; KESELMAN, ANA; BERGADA, IGNACIO; MARINO, ROXANA; RAMIREZ, PABLO; PEREZ GARRIDO, NATALIA; CIACCIO, MARTA; DI PALMA, MARIA ISABEL; BELGOROSKY, ALICIA; FORCLAZ, VERONICA; BENZHIREN, GABRIELA; D'AMATO SILVIA; MIRAS, MIRTA; ALONSO, G; MALLEA GIL, SUSANA; FIGUEROA, VERONICA; ARIAS CAU, CAROLINA; MARTÍ MARCELO, ADRIAN; KITZMAN, JACOB OTTO; CAMPER, SALLY ANN; PEREZ-MILLÁN, MARIA INES

Conferencia; ENDO 2022; 2022

Endocrine Society

Hypopituitarism with deficiency of one or more pituitary hormones (combined pituitary hormone deficiency or CPHD) can vary in severity and age at presentation. Additionally, the hormone abnormalities may evolve with time necessitating frequent evaluation. These hormonal deficits can also be present as part of a syndrome, with patients showing extrapituitary abnormalities such as eye or forebrain malformations. Over the past decade, there has been an explosion in the knowledge of the genetic cascade that orchestrates hypothalamic and pituitary development. Several transcription factors and signaling molecules are critical for cell differentiation and proliferation at a very early stage of gestation. However, more genes remain to be identified in order to provide patients with a definitive aetiology. We studied 95 children with congenital hypopituitarism from seven pediatric hospitals from Argentina. Children with non-endocrine, non-familial idiopathic short stature served as a control group (n=100). A custom exon capture panel based on single-molecule molecular inversion probes sequencing (MIPS) was performed in probands and parents. This panel tests 104 genes: including a selection of reported and candidate genes chosen from our knowledge of pituitary development in mice and PROP1 interacting proteins. We found at least 1 variant in 50 probands. The prevalence of known variants in the pituitary transcription factor genes PROP1 and PIT1 (frequently mutated in CPHD) was low in our cohort. A significant number of disease-causing variants were found in LHX3, LHX4, GLI2 and OTX2. An important advance of our study is the identification of pathogenic variants in recently discovered and novel genes. We found an heterozygous variant in the Roundabout (ROBO) receptor homolog 1 gene: ROBO1;p.Arg1504* in a patient with CPHD and septo-optic dysplasia (SOD); two variants in Steroid Receptor SRA1: p. Ile179Thr and p.Val110delinsArgLeu in a patient with CPHD and hypogonadism hypogonadotropic and a missense variant in Semaphorin 3A SEMA3A: p.Val588Leu in a case of CPHD and aortic coarctation. Our findings support evidence that the etiology of congenital hypopituitarism is highly heterogeneous and may be infrequently monogenic with full penetrance, underlying a more complex pathogenesis.