ESPE Abstracts

Background: GL1I2 encodes a zinc-finger transcription factor expressed in the developing hypothalamus and in Rathke's pouch, the embryonic precursor of the pituitary gland. Pathogenic GL1I2 variants have been implicated in the etiology of the broad clinical spectrum of congenital hypopituitarism (CHY): holoprosencephaly, midline facial abnormalities, Culler-Jones syndrome, combined pituitary hormone-deficiency (CPHD) and isolated GH-deficiency (IGHD) with hypothalamic-pituitary anatomical abnormalities. However, GL1I2 variants show a highly variable expressivity and incomplete penetrance, suggesting the possibility of a complex multifactorial genetic component.

Aims: Characterization of genotype-phenotype correlations in a cohort of patients with CHY and deleterious GL1I2 variants.

Subjects and methods: 156 patients with CPHD (n=109), septo-optic dysplasia (SOD; n=35) or IGHD with pituitary abnormalities (n=12), were analyzed by targeted NGS with a custom gene panel, designed for the analysis of the coding sequences and intron/exon transitions (+/-50bp) of 310 genes implicated in the etiology of CHY and hypothalamic-pituitary development.

Results: Predicted deleterious GL1I2 variants were identified in 14/156 (9.0%) cases with a clinical diagnosis of CPHD. All (14/14) also presented with a burden of additional inherited, deleterious variants in multiple genes involved in the regulation of pituitary development signaling pathways (SHH, BMP/TGFb, FGF, WNT, NOTCH, NODAL). GL1I2 variants included 6 truncating [p.(Arg1226*), p.(Leu709Trpfs*15), p.(Ser267*), p.(Ser859Profs*53), p.(Gln1224*), and p.(Leu182Profs*169)], all classified as pathogenic (ACMG), and 9 missense variants (ACMG: VUS). All patients with GL1I2 variants had pituitary hypoplasia, 75% had also ectopic neurohypophysis, and those with truncating variants had both conditions. These presented GH and TSH deficiency and 3/6 also ACTH deficiency. Among the 9 probands with non-truncating variants, 7/9 were GH and TSH deficient and 2/9 were also ACTH deficient. Other intra-familiar associated traits observed included postaxial polydactyly, ogival palate, bulbous nose, nephrourological abnormalities, and holoprosencephaly, with midfacial hypoplasia and hypotelorism being the most penetrant among the studied relatives (n=25) of the 14 probands.

Conclusions: All probands with GL1I2 variants presented with additional predicted deleterious variants in other genes involved in pituitary development signaling and function. This may explain the highly variable intra-familiar expressivity and incomplete penetrance observed, which may be determined by the combination with additional inherited variants in other relevant genes. Pituitary hypoplasia and midline craniofacial abnormalities appear to segregate with complete penetrance and variable severity in patients with GL1I2 variants. No GL1I2 variants were observed in SOD patients, suggesting that GL1I2 is not implicated in the etiology of SOD.