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

doi:10.1016/j.xhgg.2023.100200

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^*

^*Corresponding author for this work

Institute of Human Genetics

3 Citations (Scopus)

Abstract

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.

Original language	English
Article number	100200
Journal	Human Genetics and Genomics Advances
Volume	4
Issue number	3
Pages (from-to)	100200
DOIs	https://doi.org/10.1016/j.xhgg.2023.100200
Publication status	Published - 13.07.2023

Funding

We are very grateful to all individuals from the family for their participation in this study. We would like to thank Joost Kummeling, Guillaume van de Zande, Martina Ruiterkamp-Versteeg, Ronald van Beek, Michael Kwint, Michiel Oorsprong, Ellen Kater-Baats, Jordi Corominas Galbany, Christian Gilissen, the Radboudumc Technology Center Genomics, and the Radboudumc Cell Culture Facility for their technical and bioinformatic support, and Musa M. Mhlanga and Lucas L. Boer for the fruitful discussions. 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 . We are very grateful to all individuals from the family for their participation in this study. We would like to thank Joost Kummeling, Guillaume van de Zande, Martina Ruiterkamp-Versteeg, Ronald van Beek, Michael Kwint, Michiel Oorsprong, Ellen Kater-Baats, Jordi Corominas Galbany, Christian Gilissen, the Radboudumc Technology Center Genomics, and the Radboudumc Cell Culture Facility for their technical and bioinformatic support, and Musa M. Mhlanga and Lucas L. Boer for the fruitful discussions. 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. The authors declare no competing interests.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being
SDG 10 Reduced Inequalities

Research Areas and Centers

Research Area: Medical Genetics

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de Boer, E., Marcelis, C., Neveling, K., van Beusekom, E., Hoischen, A., Klein, W. M., de Leeuw, N., Mantere, T., Melo, U. S., van Reeuwijk, J., Smeets, D., Spielmann, M., Kleefstra, T., van Bokhoven, H., & Vissers, L. E. L. M. (2023). A complex structural variant near SOX3 causes X-linked split-hand/foot malformation. Human Genetics and Genomics Advances, 4(3), 100200. Article 100200. https://doi.org/10.1016/j.xhgg.2023.100200

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title = "A complex structural variant near SOX3 causes X-linked split-hand/foot malformation",

abstract = "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.",

author = "\{de Boer\}, Elke and Carlo Marcelis and Kornelia Neveling and \{van Beusekom\}, Ellen and Alexander Hoischen and Klein, \{Willemijn M.\} and \{de Leeuw\}, Nicole and Tuomo Mantere and Melo, \{Uir{\'a} S.\} and \{van Reeuwijk\}, Jeroen and Dominique Smeets and Malte Spielmann and Tjitske Kleefstra and \{van Bokhoven\}, Hans and Vissers, \{Lisenka E.L.M.\}",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = jul,

day = "13",

doi = "10.1016/j.xhgg.2023.100200",

language = "English",

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de Boer, E, Marcelis, C, Neveling, K, van Beusekom, E, Hoischen, A, Klein, WM, de Leeuw, N, Mantere, T, Melo, US, van Reeuwijk, J, Smeets, D, Spielmann, M, Kleefstra, T, van Bokhoven, H & Vissers, LELM 2023, 'A complex structural variant near SOX3 causes X-linked split-hand/foot malformation', Human Genetics and Genomics Advances, vol. 4, no. 3, 100200, pp. 100200. https://doi.org/10.1016/j.xhgg.2023.100200

TY - JOUR

T1 - A complex structural variant near SOX3 causes X-linked split-hand/foot malformation

AU - de Boer, Elke

AU - Marcelis, Carlo

AU - Neveling, Kornelia

AU - van Beusekom, Ellen

AU - Hoischen, Alexander

AU - Klein, Willemijn M.

AU - de Leeuw, Nicole

AU - Mantere, Tuomo

AU - Melo, Uirá S.

AU - van Reeuwijk, Jeroen

AU - Smeets, Dominique

AU - Spielmann, Malte

AU - Kleefstra, Tjitske

AU - van Bokhoven, Hans

AU - Vissers, Lisenka E.L.M.

PY - 2023/7/13

Y1 - 2023/7/13

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85158817883

UR - https://www.mendeley.com/catalogue/b77f34b9-91bf-3fdc-aca4-22753e481035/

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DO - 10.1016/j.xhgg.2023.100200

M3 - Journal articles

C2 - 37216008

AN - SCOPUS:85158817883

SN - 2666-2477

VL - 4

SP - 100200

JO - Human Genetics and Genomics Advances

JF - Human Genetics and Genomics Advances

IS - 3

M1 - 100200

ER -

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

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