A complex structural variant near SOX3 causes X-linked split-hand/foot malformation
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
Affiliations
Elke de Boer
Department of Human Genetics, Radboudumc University Medical Center, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands
Carlo Marcelis
Department of Human Genetics, Radboudumc University Medical Center, Nijmegen, the Netherlands
Kornelia Neveling
Department of Human Genetics, Radboudumc University Medical Center, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands
Ellen van Beusekom
Department of Human Genetics, Radboudumc University Medical Center, Nijmegen, the Netherlands
Alexander Hoischen
Department of Human Genetics, Radboudumc University Medical Center, Nijmegen, the Netherlands; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
Willemijn M. Klein
Department of Medical Imaging, Radiology, Radboud University Medical Center, Nijmegen, the Netherlands
Nicole de Leeuw
Department of Human Genetics, Radboudumc University Medical Center, Nijmegen, the Netherlands
Tuomo Mantere
Department of Human Genetics, Radboudumc University Medical Center, Nijmegen, the Netherlands; Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit and Biocenter Oulu, University of Oulu, Oulu, Finland
Uirá S. Melo
Max Planck Institute for Molecular Genetics, RG Development & Disease, Berlin, Germany; Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany
Jeroen van Reeuwijk
Department of Human Genetics, Radboudumc University Medical Center, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands
Dominique Smeets
Department of Human Genetics, Radboudumc University Medical Center, Nijmegen, the Netherlands
Malte Spielmann
Max Planck Institute for Molecular Genetics, RG Development & Disease, Berlin, Germany; Institute of Human Genetics, University Hospitals Schleswig-Holstein, University of Lübeck and Kiel University, 23562 Lübeck, Kiel, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, Lübeck, Germany
Tjitske Kleefstra
Department of Human Genetics, Radboudumc University Medical Center, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands; Center of Excellence for Neuropsychiatry, Vincent van Gogh Institute for Psychiatry, Venray, the Netherlands
Hans van Bokhoven
Department of Human Genetics, Radboudumc University Medical Center, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands; Department of Cognitive Neuroscience, Radboudumc, Nijmegen, the Netherlands
Lisenka E.L.M. Vissers
Department of Human Genetics, Radboudumc University Medical Center, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands; Corresponding author
Summary: 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.
