GLI3 – Acrocallosal Syndrome

Acrocallosal syndrome (ACS) is characterized by postaxial polydactyly, macrocephaly, and complete agenesis of the corpus callosum often accompanied by severe developmental delay. Two unrelated individuals with ACS have been reported to harbour de novo heterozygous missense variants in GLI3 (NM_000168.6:c.2800G>C (p.Ala934Pro) and c.2786T>C (p.Leu929Pro)), consistent with an autosomal dominant inheritance and allelism with Greig cephalopolysyndactyly syndrome (GCPS) (PMID:12414818; PMID:23633388). No additional affected relatives have been documented, and segregation data are lacking.

Functional studies in Gli3 loss-of-function mouse models demonstrate that GLI3 haploinsufficiency disrupts dorsal forebrain development and limb mesenchymal patterning, recapitulating key ACS features including polydactyly and corpus callosum abnormalities (PMID:9073443). These data support a mechanism of GLI3 haploinsufficiency in ACS. Given this limited clinical series and concordant animal data, GLI3 should be included in diagnostic gene panels for ACS and related midline and limb anomalies.

Key Take-home: Heterozygous GLI3 missense variants account for a severe allelic form of ACS via haploinsufficiency, informing molecular diagnosis and family counselling.

References

• Journal of Medical Genetics • 2002 • De novo GLI3 mutation in acrocallosal syndrome: broadening the phenotypic spectrum of GLI3 defects and overlap with murine models PMID:12414818
• American Journal of Medical Genetics Part A • 2013 • A de novo GLI3 mutation in a patient with acrocallosal syndrome PMID:23633388
• 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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