University of Oulu

Elke de Boer, Carlo Marcelis, Kornelia Neveling, Ellen van Beusekom, Alexander Hoischen, Willemijn M. Klein, Nicole de Leeuw, Tuomo Mantere, Uirá S. Melo, Jeroen van Reeuwijk, Dominique Smeets, Malte Spielmann, Tjitske Kleefstra, Hans van Bokhoven, Lisenka E.L.M. Vissers, A complex structural variant near SOX3 causes X-linked split-hand/foot malformation, Human Genetics and Genomics Advances, Volume 4, Issue 3, 2023, 100200, ISSN 2666-2477,

A complex structural variant near SOX3 causes X-linked split-hand/foot malformation

Saved in:
Author: de Boer, Elke1,2; Marcelis, Carlo1; Neveling, Kornelia1,2;
Organizations: 1Department of Human Genetics, Radboudumc University Medical Center, Nijmegen, the Netherlands
2Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands
3Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands
4Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
5Department of Medical Imaging, Radiology, Radboud University Medical Center, Nijmegen, the Netherlands
6Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit and Biocenter Oulu, University of Oulu, Oulu, Finland
7Max Planck Institute for Molecular Genetics, RG Development & Disease, Berlin, Germany
8Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany
9Institute of Human Genetics, University Hospitals Schleswig-Holstein, University of Lübeck and Kiel University, 23562 Lübeck, Kiel, Germany
10DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, Lübeck, Germany
11Center of Excellence for Neuropsychiatry, Vincent van Gogh Institute for Psychiatry, Venray, the Netherlands
12Department of Cognitive Neuroscience, Radboudumc, Nijmegen, the Netherlands
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 4.2 MB)
Persistent link:
Language: English
Published: Elsevier, 2023
Publish Date: 2023-09-20


Split-hand/foot malformation (SHFM) is a congenital limb defect most typically presenting with median clefts in hands and/or feet, that can occur in a syndromic context as well as in isolated form. SHFM is caused by failure to maintain normal apical ectodermal ridge function during limb development. Although several genes and contiguous gene syndromes are implicated in the monogenic etiology of isolated SHFM, the disorder remains genetically unexplained for many families and associated genetic loci. We describe a family with isolated X-linked SHFM, for which the causative variant could be detected after a diagnostic journey of 20 years. We combined well-established approaches including microarray-based copy number variant analysis and fluorescence in situ hybridization coupled with optical genome mapping and whole genome sequencing. This strategy identified a complex structural variant (SV) comprising a 165-kb gain of 15q26.3 material ([GRCh37/hg19] chr15:99795320-99960362dup) inserted in inverted position at the site of a 38-kb deletion on Xq27.1 ([GRCh37/hg19] chrX:139481061-139518989del). In silico analysis suggested that the SV disrupts the regulatory framework on the X chromosome and may lead to SOX3 misexpression. We hypothesize that SOX3 dysregulation in the developing limb disturbed the fine balance between morphogens required for maintaining AER function, resulting in SHFM in this family.

see all

Series: HGG advances
ISSN: 2666-2477
ISSN-E: 2666-2477
ISSN-L: 2666-2477
Volume: 4
Issue: 3
Article number: 100200
DOI: 10.1016/j.xhgg.2023.100200
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: This work was financially supported by Aspasia grants of the Dutch Research Council (015.014.036 to T.K. and 015.014.066 to L.V.) and Netherlands Organization for Health Research and Development (91718310 to T.K.). The collaborations in this study were facilitated by ERN ITHACA, one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States, co-funded by the European Commission. The aims of this study contribute to the Solve-RD project (E.d.B., A.H., T.K., L.V.), which has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 779257.
Copyright information: © 2023 The Author(s). This is an open access article under the CC BY license (