GLI3 – Preaxial Polydactyly Type 4

Heterozygous truncating variants in the zinc-finger transcription factor GLI3 have been linked to autosomal dominant polysyndactyly 4. A single family segregating the nonsense variant c.1927C>T (p.Arg643Ter) in two heterozygous individuals exhibited isolated preaxial polydactyly type 4 (PMID:32112393). Functional studies in a mouse loss-of-function Gli3 model demonstrate complementary expression of Gli3 to the zone of polarizing activity and ectopic Shh activation in anterior limb buds, resulting in digit duplications consistent with haploinsufficiency (PMID:9073443). No additional unrelated cases or extended segregation data have been reported, and no conflicting evidence has emerged. The concordance of human truncating variants with murine phenotypes supports a mechanism of GLI3 haploinsufficiency in digit patterning. Further case series are needed to confirm penetrance and recurrence risk. Key take-home: GLI3 loss-of-function variants should be considered in diagnostic panels for dominant preaxial polydactyly type 4.

References

• Clinical Genetics • 2020 • A GLI3 variant leading to polydactyly in heterozygotes and Pallister-Hall-like syndrome in a homozygote. PMID:32112393
• Developmental Biology • 1997 • Multigenic control of the localization of the zone of polarizing activity in limb morphogenesis in the mouse. PMID:9073443

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