Background: GLI2 is a zinc-finger transcription factor of the SHH signaling pathway, expressed during ventral forebrain and pituitary development. GLI2 mutations account for microforms of dominant holoprosencephaly. So far, only 15 unambiguous mutations were found in hypopituitarism essentially combined pituitary hormone deficiency (CPHD) frequently associated with holoprosencephaly-like malformations and/or polydactyly.
Objective and hypotheses: To i) assess the prevalence of GLI2 mutations in patients with CPHD, isolated GH deficiency (IGHD) or isolated diabetes insipidus, associated with a personal or family history of midline defects and/or polydactyly/syndactyly, ii) provide a most complete description of GLI2-associated phenotypes.
Method: Sequencing of GLI2 coding exons in 206 independent probands.
Results: Twenty rare heterozygous variations (allele frequency <0.05 in ExAC) were identified in 23 probands. Nine are non-ambiguously deleterious: 3 nonsense mutations [p.(Arg264*), p.(Tyr893*) and p.(Gln1145*)], 5 frameshifts [p.(Asp129Glyfs*159), p.(Gly198Argfs*153), p.(Leu788Argfs*16), p.(His959Profs*72) and p.(*1587Tyrext*46)] and 1 missense variation in the first zinc finger (p.Tyr435Cys). Five missense variations [p.Pro63Leu, p.Arg473His, p.Ser831del, p.Ser941Arg and p.Arg1382His], located in functional domains, are probably deleterious (charge/steric change and involvement of residues invariant throughout evolution). Six other missense variations [p.Ala117Thr, p.Gly619Ser, p.Arg720His, p.Ala1077Val, p.Pro1228Leu, p.Asp1435Glu] would require functional studies. The 14 patients with a deleterious/probably deleterious mutation had IGHD (n=8) or CPHD (n=6). The extra-pituitary defects were: bilateral cleft lip/palate (n=3), unique central median incisor (n=2), choanal atresia/hypoplasia (n=3), corpus callosum anomaly (n=2), polydactyly (n=2), 23 foot syndactyly (n=3) and septum pellucidum agenesis (n=1). Among the seven relatives carrying a deleterious mutation, one had isolated polydactyly, and six were asymptomatic, thereby underlining the difficult aspects of genetic counseling.
Conclusion: In this large series of patients with hypopituitarism and a personal or family history of midline defects and/or digit anomalies, GLI2 mutations, which are associated with a wide range of extra-pituitary defects, are responsible for at least 7% (14/206) of independent cases.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology