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

CAMILLETTI MA; VISHNOPOLSKA SA; MERCOGLIANO FLORENCIA; BRASLAVSKY D; KESELMAN A; BERGADA I; KITZMAN JO; CAMPER SA; PÉREZ MILLÁN, MARIA I.

Congreso; SAIC; 2020

Congenital hypopituitarism (CH) occurs in 1 in 4000 live births. Patients with CH are born without normal production of at least one pituitary hormone. The most common single hormone deficiency is isolated growth hormone deficiency (IGHD) whereas if two or more pituitary hormones are involved it is called combined pituitary hormone deficiency (CPHD). The clinical spectrum of CH 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 (VUS) in 26 cases. Interestingly, we found that the prevalence of known variants in transcription factor genes involved in pituitary development like PROP1, and PIT1 was in fact quite low in our cohort. A significant number of disease-causing variants in known causative genes (LHX3, LHX4, GLI2, OTX2, HESX1) were found, and for LHX3 and LHX4 variants, both in silico and functional in vitro testing using luciferase reporter 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 conclusion, 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.