You are here

  • Home
  • Archive
  • Volume 57, Issue 10
  • Variable expression of subclinical phenotypes instead of reduced penetrance in families with mild triphalangeal thumb phenotypes

Article Text

Article menu
Phenotypes
Short report
Variable expression of subclinical phenotypes instead of reduced penetrance in families with mild triphalangeal thumb phenotypes
  1. Jacob W P Potuijt1,
  2. Jeannette Hoogeboom2,
  3. Esther de Graaff3,
  4. Christianne A van Nieuwenhoven4,
  5. Robert Jan H Galjaard2
  1. 1 Plastic, Reconstructive and Hand Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
  2. 2 Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
  3. 3 Division of Cell Biology, Neurobiology and Biophysics, Utrecht University, Utrecht, Utrecht, The Netherlands
  4. 4 Plastic, Reconstructive and Hand Surgery, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands
  1. Correspondence to Mr Jacob W P Potuijt, Plastic, Reconstructive and Hand Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands; j.potuijt{at}erasmusmc.nl

Abstract

Background The of zone of polarizing activity regulatory sequence (ZRS) is a regulatory element residing in intron 5 of LMBR1 and regulates Sonic Hedgehog expression in the limb bud. Variants in the ZRS are generally fully penetrant and can cause triphalangeal thumb (TPT) and polydactyly in affected families.

Objective In this report, we describe two families with mild phenotypical presentation.

Methods We performed a field study for clinical evaluation and sequenced the ZRS for variantsusing Sanger sequencing.

Results In family I, a novel 165A>G variant in the ZRS (g.156584405A>G, GRCh37/Hg19) was found. In family II, we identified a 295T>C variant in the ZRS (g.156584535T>C, GRCh37/Hg19). Family members of both families who were presumed to be unaffected shared the variant in the ZRS with affected family members, suggesting reduced penetrance of the genotype. However, clinical examination of these unaffected family members revealed minor anomalies like broad thumbs and lack of thumb opposition. As the phenotype in affected patients is remarkably mild, we suggest that these ZRS variants are minimally disruptive for Sonic Hedgehog expression and therefore can result in subclinical phenotypes.

Conclusion Our study underlines the importance of accurate clinical examination and appropriate genetic counselling in families with mild cases of TPT.

  • polydactyly
  • genetic enhancer elements
  • congenital abnormalities
https://creativecommons.org/licenses/by/4.0/

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: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/jmedgenet-2019-106685

Statistics from Altmetric.com

    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.

    View Full Text

    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • Correction notice This article has been corrected since it was published Online First. Typesetting errors in the abstract have been corrected, and the name of author Esther de Graaff has been amended, too.

    • Contributors JWPP planned the study, performed laboratory work on family I and II and drafted the manuscript. JH and EdG conducted the field study of family II and revised the manuscript. RJHG and CAvN evaluated and examined family I, supervised JWPP and revised 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 This study was approved by the Dutch Medical Ethical Research Committee in Rotterdam (MEC-2015–12).

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