Article Text

Download PDFPDF

Original research
Variant type and position predict two distinct limb phenotypes in patients with GLI3-mediated polydactyly syndromes
  1. Martijn Baas1,
  2. Elise Bette Burger1,
  3. Ans MW van den Ouweland2,
  4. Steven ER Hovius3,4,
  5. Annelies de Klein2,
  6. Christianne A van Nieuwenhoven1,
  7. Robert Jan H Galjaard2
  1. 1Plastic, Reconstructive and Hand Surgery, Erasmus MC, Rotterdam, The Netherlands
  2. 2Clinical Genetics, Erasmus MC, Rotterdam, Zuid-Holland, The Netherlands
  3. 3Plastic, Reconstructive and Hand Surgery, Radboud University Nijmegen, Nijmegen, Gelderland, The Netherlands
  4. 4Hand and Wrist Centre, Xpert Clinic, Eindhoven, The Netherlands
  1. Correspondence to Martijn Baas, Plastic, Reconstructive and Hand Surgery, Erasmus MC, Rotterdam 3015CN, The Netherlands; m.baas{at}


Introduction Pathogenic DNA variants in the GLI-Kruppel family member 3 (GLI3) gene are known to cause multiple syndromes: for example, Greig syndrome, preaxial polydactyly-type 4 (PPD4) and Pallister-Hall syndrome. Out of these, Pallister-Hall is a different entity, but the distinction between Greig syndrome and PPD4 is less evident. Using latent class analysis (LCA), our study aimed to investigate the correlation between reported limb anomalies and the reported GLI3 variants in these GLI3-mediated polydactyly syndromes. We identified two subclasses of limb anomalies that relate to the underlying variant.

Methods Both local and published cases were included for analysis. The presence of individual limb phenotypes was dichotomised and an exploratory LCA was performed. Distribution of phenotypes and genotypes over the classes were explored and subsequently the key predictors of latent class membership were correlated to the different clustered genotypes.

Results 297 cases were identified with 127 different variants in the GLI3 gene. A two-class model was fitted revealing two subgroups of patients with anterior versus posterior anomalies. Posterior anomalies were observed in cases with truncating variants in the activator domain (postaxial polydactyly; hand, OR: 12.7; foot, OR: 33.9). Multivariate analysis supports these results (Beta: 1.467, p=0.013 and Beta: 2.548, p<0.001, respectively). Corpus callosum agenesis was significantly correlated to these variants (OR: 8.8, p<0.001).

Conclusion There are two distinct phenotypes within the GLI3-mediated polydactyly population: anteriorly and posteriorly orientated. Variants that likely produce haploinsufficiency are associated with anterior phenotypes. Posterior phenotypes are associated with truncating variants in the activator domain. Patients with these truncating variants have a greater risk for corpus callosum anomalies.

  • developmental
  • molecular genetics
  • clinical genetics
  • genetic screening/counselling

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

Statistics from


  • MB and EBB contributed equally.

  • Contributors MB and EBB contributed equally to this study. All authors were involved in the conception, design and acquisition of data and/or in the analysis and interpretation of the data. A detailed description of the contribution of all authors has been submitted to the journal. All authors reviewed and approved the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The research protocol was approved by the local ethics board of the Erasmus MC University Medical Center (MEC 2015-679).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.