IDENTIFICATION OF LIKELY PATHOGENIC VARIANTS IN NOVEL CANDIDATE GENES FOR HYPOPITUITARISM IN ARGENTINIAN CHILDREN

CAMILLETTI, MARIA ANDREA; BRASLAVSKY, DÉBORA; MARINO, ROXANA; PATIÑO MEJÍA, HELEN; BELGOROSKY, ALICIA; CAMPER, SALLY; MERCOGLIANO, MARIA FLORENCIA; BERGADA, IGNACIO; PÉREZ GARRIDO, NATALIA; DI PALMA, MARIA ISABEL; KITZMAN, JACOB; VISHNOPOLSKA, SEBASTIAN; KESELMAN, ANA; RAMIREZ, PABLO; CIACCIO, MARTA; MARTI, MARCELO; PEREZ-MILLÁN, MARIA INES

Congreso; Reunion de Sociedades de Biociencias 2020; 2020

Congenital hypopituitarism(CH) comprises of a spectrum of disorders that range in severity from isolated growth hormone deficiency(IGHD) to combined pituitary hormone deficiency(CPHD) when two or more pituitary hormones are deficient. The clinical spectrum varies widely and can present in isolation or with other birth defects. We conducted target panel genetic screening using single-molecule molecular inversion probes sequencing to assess the frequency of mutations in known hypopituitarism genes and new candidates. We captured genomic DNA from 170 pediatric patients with CH, either alone or with other abnormalities. We identified novel pathogenic, likely pathogenic(LP) or variants with uncertain significance in 26 cases. Interestingly, we found that the prevalence of known variants in transcription factor genes involved in pituitary development like PROP1, and POU1F1 was quite low in our cohort. A significant number of disease-causing variants in known causative genes(LHX3, LHX4, GLI2, OTX2 and HESX1) were found, and for LHX3 and LHX4 variants, both in silico and functional in vitro testing using luciferase assays were performed. One important novelty from our study is the identification of pathogenic variants in novel genes recently discovered in the etiology of CPHD. We found two heterozygous variants in FOXA2(p.R228S and p.R229*) which may affect the DNA binding ability of the coding protein in patients with IGHD and CPHD, respectively, and a missense PNPLA6 variant(p.T1115P) in a patient with CPHD, retinitis pigmentosa and neurodevelopmental delay. In this work we were able to expand our knowledge of pituitary target genes for genetic diagnosis for CH. Identifying population-specific pathogenic variants will improve the capacity of genetic data to predict eventual clinical outcomes for better diagnosis and treatment for the patients.