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Mutations in gene regulatory elements linked to human limb malformations
  1. Karol Nowosad1,2,
  2. Ewa Hordyjewska-Kowalczyk1,2,
  3. Przemko Tylzanowski1,3
  1. 1Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland
  2. 2The Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
  3. 3Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, University of Leuven, Leuven, Belgium
  1. Correspondence to Dr Przemko Tylzanowski, Department of Development and Regeneration, Skeletal Biology and Engineering Research Centre, University of Leuven, Leuven 3000, Belgium; przemko{at}


Most of the human genome has a regulatory function in gene expression. The technological progress made in recent years permitted the revision of old and discovery of new mutations outside of the protein-coding regions that do affect human limb morphology. Steadily increasing discovery rate of such mutations suggests that until now the largely neglected part of the genome rises to its well-deserved prominence. In this review, we describe the recent technological advances permitting this unprecedented advance in identifying non-coding mutations. We especially focus on the mutations in cis-regulatory elements such as enhancers, and trans-regulatory elements such as miRNA and long non-coding RNA, linked to hereditary or inborn limb defects. We also discuss the role of chromatin organisation and enhancer–promoter interactions in the aetiology of limb malformations.

  • non-coding DNA
  • limb defects
  • enhancers
  • lncRNA
  • miRNA
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  • Contributors KN was responsible for drafting, writing of the manuscript, preparing the figures and corrections. EH-K was responsible for drafting, writing, preparing the table and corrections. PT was responsible for drafting, writing and corrections.

  • Funding This work was supported by the Polish National Science Centre (PRO-2013/11/B/NZ4/03660 to PT, UMO-2015/19/B/NZ4/03184 to PT, and PRO-2017/27/N/NZ5/02940 to EH-K).

  • Competing interests None declared.

  • Patient consent for publication Not required.

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

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