Identifying causative genes for pituitary hormone deficiencies

MARTINEZ MAYER, JULIAN; LUCIA IGLESIAS GARCIA; VISHNOPOLSKA, SEBASTIAN; PÉREZ MILLÁN, MARIA I.

Congreso; ENDO; 2023

Hypopituitarism is the decreased (hypo) secretion of one or more of the eight hormones normally produced by the pituitary gland. When there is decreased secretion of one specific pituitary hormone, the condition is known as isolated hormone deficiency; when more than one hormone is affected it is called Combined pituitary hormone deficiency (CPHD). Congenital hypopituitarism is a rare disorder, with a frequency of 1 case in 4000 live births. More than 30 genes were linked to this disorder, most of them transcription factors expressed during the development of the head, hypothalamus and pituitary. However, the etiology of around 85% of the cases remains unknown. The aim of this study was to unveil the genetic etiology in a large cohort of patients with congenital hypopituitarism from Argentina, employing whole exome sequencing (WES). We sequenced 148 patients presenting hypopituitarism with and without other abnormalities. We found pathogenic variants in known genes (LHX4, GLI2, GH1 and PROP1) or in or less frequently affected genes in CPHD (FOXA2, ROBO1) or in novel genes (RPL5, CHD7, COL1A1, KDM6A, SOX2). Interestingly, frameshift variants in CHD7 found in this study were identified in 2 independent cases with CPHD (none of them met the full criteria for CHARGE syndrome), suggesting a new spectrum of phenotypes for this gene. Variants causing alternative-splicing defects were identified in 3 independent cases: GH1: c.291+1G>C was found in one IGHD case and RPL5: c.189+1G>C in a patient with IGHD combined with erythroblastopenia, megalocornea, palate fistula, chronic diarrhea and microcephaly. Lastly, a splicing variant PROP1: c.343-1G>A was found in compound heterozygous together with PROP1; p.Arg16* in a CPHD patient. Another interesting finding was the identification of microdeletions in 4 cases of CPHD, encompassing between 17 and 64 deleted genes, among them genes related to CPHD such as IGF1R, SOX2, LHX4 and TGIF1. Our results highlight the importance of an exhaustive analysis of candidate variants, which contemplates splicing variants as well as copy number variation (CNVs). Finally, these findings further support the hypothesis that CPHD is highly heterogeneous and may be frequently oligogenic, underlying a very complex pathogenesis for genetic diagnosis.