Molecular analysis expands the spectrum of phenotypes associated with GLI3 mutations

Abstract

A range of phenotypes including Greig cephalopolysyndactyly and Pallister-Hall syndromes (GCPS, PHS) are caused by pathogenic mutation of the GLI3 gene. To characterize the clinical variability of GLI3 mutations, we present a subset of a cohort of 174 probands referred for GLI3 analysis. Eighty-one probands with typical GCPS or PHS were previously reported, and we report the remaining ninety-three probands here. This includes nineteen probands (twelve mutations) who fulfilled clinical criteria for GCPS or PHS, forty-eight probands (sixteen mutations) with features of GCPS or PHS but who did not meet the clinical criteria (sub-GCPS and sub-PHS), twenty-one probands (six mutations) with features of PHS or GCPS and oral-facial-digital syndrome and five probands (one mutation) with non-syndromic polydactyly. These data support previously identified genotype-phenotype correlations and demonstrate a more variable degree of severity than previously recognized. The finding of GLI3 mutations in patients with features of oral-facial-digital syndrome supports the observation that GLI3 interacts with cilia. We conclude that the phenotypic spectrum of GLI3 mutations is broader than that encompassed by the clinical diagnostic criteria, but the phenotype-genotype correlation persists. Individuals with features of either GCPS or PHS should be screened for mutations in GLI3 even if they do not fulfill clinical criteria.

New insights into genotype–phenotype correlation for GLI3 mutations

“…22 Interestingly, corpus callosum anomalies were found in nine patients, including seven patients with a truncating mutation located in the third end of GLI3. In the two previous series reported by Johnston et al,9,10 four GCPS patients with corpus callosum dysgenesis were also carrying a GLI3 truncating mutation lying in the C-terminal domain of the protein further confirming our finding that corpus callosum dysgenesis is fully part of GCPS spectrum and is mainly caused by terminal truncating mutations. Overlapping features with acrocallosal syndrome (ACLS, MIM# 200990) associating callosal dysgenesis, hypertelorism, intellectual disability and PD 23 are explained by an impaired GLI3 processing in patients with KIF7 mutations.…”

“…24 Facial dysmorphism, as well as vermis dysgenesis with brainstem anomalies (molar tooth sign), strongly indicated the diagnosis of ACLS. Conversely, two GLI3 mutated cases with corpus callosum dysgenesis have been reported as ACLS 25,26 and a third similar patient has been reported by Johnston et al 10 All three mutations were missense and clustered in the same region between aa 903 and 934 suggesting a potential severe phenotype associated with alterations of this region. Whatever, mutation analysis in both genes is therefore essential as the distinction between these two syndromes is of obvious significance for genetic counseling considering the difference in heredity and neurodevelopmental outcome and patients with a GLI3 mutation may be diagnosed as GCPS.…”

“…8 Previous reports demonstrate a robust genotype-phenotype correlation of GLI3 mutations. 9,10 Truncating mutations in the middle third of the gene generally cause PHS, resulting in a constitutive repressor protein. By contrast, haploinsufficiency resulting from chromosomal rearrangements, but also missense, splicing or truncating mutations elsewhere in the gene cause GCPS by loss of the DNA-binding capacity 11 or activation of nonsense-mediated mRNA decay, 12 or by the formation of an unstable or mislocalized protein.…”

MED12 mutations link intellectual disability syndromes with dysregulated GLI3-dependent Sonic Hedgehog signaling

“…Our findings herein that the FG and Lujan mutations in MED12 also elicit aberrant GLI3-dependent SHH signaling not only suggests an additional basis for cognitive dysfunction through altered brain development (30,31), but may further explain a broad range of clinically diverse non-CNS phenotypes associated with these syndromal disorders. In this regard, many of the digit, craniofacial, corpus callosal, and anorectal malformations that typify FG and/or Lujan syndromes are similarly observed, to varying extents, in congenital anomaly syndromes (GCPS and PHS) arising from mutations in GLI3 (14,32,33). Thus, mutagenic impairment of two interacting components within a common signaling pathway could serve to explain the phenotypic overlap observed in these monogenic syndromes.…”

“…However, the underlying basis by which genetic disruption of MED12 elicits the broad spectrum of clinical phenotypes observed in FG and Lujan syndromes remains unknown. Notably, several phenotypes associated with FG and/or Lujan syndromes including macrocephaly, corpus callosal defects, hypertolerism, syndactyly, and cognitive impairment, overlap with a subset of those variously appearing in Greig cephalopolysyndactyly syndrome (GCPS) and/or Pallister-Hall syndrome (PHS) arising from mutations in GLI3, a Sonic Hedgehog (SHH) signaling effector and direct interaction target of MED12 (12,14).…”