GLI1 – Ellis-van Creveld syndrome

Biallelic loss-of-function variants in the transcription factor GLI1, a terminal effector of Hedgehog (Hh) signaling, have been implicated in a spectrum of developmental defects overlapping with Ellis-van Creveld syndrome. Ellis-van Creveld syndrome (EvC) is characterized by short ribs, polydactyly, and ectodermal dysplasia due to diminished Hh pathway activity. While GLI2 and GLI3 inactivation underlies several congenital malformation syndromes, GLI1’s role remained elusive until recently.

A multi-site study described eight patients from three independent families presenting with postaxial polydactyly and EvC-like features harboring homozygous truncating variants in GLI1. Two families carried C-terminal truncations, and one had an N-terminal stop gain; one representative allele is c.337C>T (p.Arg113Ter) (PMID:28973407). All cases segregated autosomal recessive inheritance, with each variant absent or extremely rare in control populations.

Segregation analysis across the three pedigrees confirmed co-segregation of biallelic GLI1 truncations with disease in affected siblings and consanguineous unions (PMID:28973407). No unaffected individuals carried two damaged alleles. The inheritance mode is consistent with loss-of-function requiring both alleles to be disrupted to manifest the phenotype.

The variant spectrum in EvC-like cases comprises three truncating alleles: c.337C>T (p.Arg113Ter), c.1930C>T (p.Gln644Ter), and c.2340G>A (p.Trp780Ter), all predicted to escape or trigger nonsense-mediated decay depending on exon location. There is no evidence yet for hypomorphic or missense variants in this context.

Functional assessment in patient fibroblasts demonstrated that the truncated GLI1 protein is expressed and upregulated by Hh pathway agonists but exhibits severely impaired transcriptional activity in vitro and in vivo. Induction of the GLI1 target PTCH1 was significantly reduced following chemical pathway activation, indicating disruption of the activator-repressor balance in affected cells (PMID:28973407).

Integrating genetic and experimental data supports a loss-of-function mechanism whereby GLI1 inactivation leads to an EvC-like syndrome and isolated polydactyly. While additional case reports could expand the phenotypic spectrum, current evidence meets criteria for a Strong gene–disease association under ClinGen standards. Key Take-home: Genetic testing for GLI1 truncations should be considered in patients with autosomal recessive postaxial polydactyly and EvC-like skeletal anomalies.

References

• Human molecular genetics • 2017 • GLI1 inactivation is associated with developmental phenotypes overlapping with Ellis-van Creveld syndrome PMID:28973407

Evidence Based Scoring (AI generated)