Clinical findings in patients with GLI2 mutations – phenotypic variability

Abstract

Mutations in the human GLI2 gene were first reported in association with defective anterior pituitary formation, pan-hypopituitarism, and forebrain anomalies represented by typical holoprosencephaly (HPE) and holoprosencephaly-like (HPE-L) phenotypes and postaxial polydactyly. Subsequent, anophthalmia plus orbital anomalies, heminasal aplasia, branchial arch anomalies and polydactyly have also been incorporated into the general phenotype. Here we described six Brazilian patients with phenotypic manifestations that range from isolated cleft lip/palate with polydactyly, branchial arch anomalies to semi lobar holoprosencephaly. Novel sequence variants were found in the GLI2 gene in patients with marked involvement of the temporomandibular joint (TMJ), a new clinical finding observed with mutations of this gene. Clinical, molecular and genetic aspects are discussed.

Diagnostic exome sequencing identifies GLI2 haploinsufficiency and chromosome 20 uniparental disomy in a patient with developmental anomalies

“…The variant was confirmed by Sanger sequencing (Figure S1) and was deemed to explain the patient's growth delay, microcephaly, developmental delay, and dysmorphic features including hypotelorism, midface hypoplasia, and small nose, as well as the father's similar facial features. Heterozygous pathogenic alterations in this gene are known to cause a highly variable condition with incomplete penetrance characterized by hypopituitarism, growth hormone deficiency, postaxial polydactyly, and also holoprosencephaly 12. There were additional variants in 51 other genes that survived our filtering but were considered irrelevant to the patient's phenotype (Table S1).…”

From Normal Development to Disease: The Biochemistry and Regulation of GLI2

“…Additionally, given the role GLI2 in regulating limb bud patterning, variable polydactyly was also identified [52] . Various other reported mutations in GLI2 have resulted in a spectrum of phenotypes that ranged from cleft palate, polydactyly, branchial arch abnormalities, various degrees of HPE, and temporomandibular joint anomalies [53] . These examples highlight the need for GLI2 to be tightly regulated and function normally to ensure proper fetal development.…”

Human Malformation Syndromes of Defective <b><i>GLI</i></b>: Opposite Phenotypes of 2q14.2 (<b><i>GLI2</i></b>) and 7p14.2 (<b><i>GLI3</i></b>) Microdeletions and a GLIA/R Balance Model

“…It usually includes midline craniofacial anomalies involving the first branchial arch and/or orbits, pituitary hypoplasia with panhypopituitarism, and PAP. The disorder also shows incomplete penetrance and variable expressivity [Roessler et al, 2003;Bertolacini et al, 2012]. In fact, these 2 disorders belong to a continuous phenotypic spectrum, with the relatively mild forms referred to as CJS and severe cases known as HPE9 ( Table 1 ).…”