GLI3 – Pallister-Hall Syndrome

Pallister–Hall syndrome (PHS) is a pleiotropic autosomal dominant disorder caused by truncating variants in the GLI3 zinc-finger transcription factor gene, characterized by hypothalamic hamartoma, central/postaxial polydactyly, imperforate anus, bifid epiglottis, and variable renal anomalies. The GLI3 protein mediates Sonic hedgehog (SHH) signaling by acting as a transcriptional activator or repressor; PHS‐associated mutations cluster in the middle third of GLI3 and generate truncated proteins with constitutive repressor function.

Multiple linkage and mutation studies in unrelated families totaling over 60 affected individuals provide definitive clinical validity for the GLI3–PHS association. A 22‐member kindred demonstrated linkage to 7p13 near GLI3 with a maximum lod score of 7.0, and subsequent sequencing identified frameshift and nonsense mutations in all families (PMID:9192261, PMID:9054938). Functional concordance of these truncating alleles across pedigrees and absence of recombination in multiple families support a definitive classification.

Genetically, PHS follows an autosomal dominant pattern with high penetrance and variable expressivity. Segregation analysis in the large kindred and at least four additional pedigrees confirms segregation of heterozygous truncating variants in GLI3 with disease (affected_relatives = 22). Case reports and series include de novo and inherited variants, with a predominance of frameshift and nonsense changes in the central gene region. A recurrent de novo nonsense mutation, c.2641C>T (p.Gln881Ter), has been described in a patient with total colonic aganglionosis and imperforate anus (PMID:25604768).

Functionally, PHS mutations produce truncated GLI3 repressor isoforms that mimic the processed GLI3R form, leading to aberrant repression of SHH target genes. Mouse Gli3(Delta699) mutants recapitulate key PHS features including central polydactyly, imperforate anus, renal dysplasia, and hypothalamic defects, providing a robust in vivo model (PMID:11978771). In vitro assays show GLI3-PHS proteins localize to the nucleus and repress GLI3-activated PTCH1 expression, demonstrating a dominant repressor mechanism (PMID:17588959).

No significant conflicting evidence has been reported disputing the GLI3–PHS relationship. Mosaic GLI3 variants in nonsyndromic hypothalamic hamartoma further extend the phenotypic spectrum but do not contradict the core association.

In summary, overwhelming genetic and experimental data establish a definitive gene–disease relationship between GLI3 and Pallister–Hall syndrome. Truncating variants in the middle third of GLI3 reliably predict PHS, enabling accurate molecular diagnosis, risk assessment, and counseling.

Key Take-home: Heterozygous truncating GLI3 variants in the central coding region cause autosomal dominant Pallister–Hall syndrome via constitutive repressor activity, with clear diagnostic, counseling, and prenatal screening utility.

References

• Journal of medical genetics • 1997 • Linkage mapping and phenotypic analysis of autosomal dominant Pallister-Hall syndrome PMID:9192261
• Nature Genetics • 1997 • GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome PMID:9054938
• American Journal of Medical Genetics Part A • 2015 • Total colonic aganglionosis and imperforate anus in a severely affected infant with Pallister-Hall syndrome PMID:25604768
• Human Molecular Genetics • 2007 • The molecular basis of Pallister Hall associated polydactyly PMID:17588959
• Human Molecular Genetics • 2002 • Pallister-Hall syndrome phenotype in mice mutant for Gli3 PMID:11978771

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