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Pleiotropy is the phenomenon in which a single gene impacts multiple, seemingly unrelated phenotypic traits. For example, defects in the SOX10 gene cause Waardenburg Syndrome Type 4, or WS4, which can cause defects in pigmentation, hearing impairments, and an absence of intestinal contractions necessary for elimination. This diversity of phenotypes results from the expression pattern of SOX10 in early embryonic and fetal development. SOX10 is found in neural crest cells that form melanocytes,...
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A complex structural variant near SOX3 causes X-linked split-hand/foot malformation.

Elke de Boer1,2, Carlo Marcelis1, Kornelia Neveling1,2

  • 1Department of Human Genetics, Radboudumc University Medical Center, Nijmegen, the Netherlands.

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|May 22, 2023
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Summary

Split-hand/foot malformation (SHFM) is a rare limb defect. A 20-year diagnostic journey identified a complex structural variant disrupting SOX3 regulation, explaining X-linked SHFM in one family.

Keywords:
Optical genome mappingSHFM2SOX3Structural variationWhole genome sequencingX-linked split-hand/foot malformation

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Area of Science:

  • Genetics
  • Developmental Biology
  • Human Malformations

Background:

  • Split-hand/foot malformation (SHFM) is a congenital limb defect characterized by median clefts.
  • SHFM results from impaired apical ectodermal ridge (AER) function during limb development.
  • While some genetic causes are known, many isolated SHFM cases remain genetically unexplained.

Purpose of the Study:

  • To identify the genetic cause of isolated X-linked SHFM in a family after a prolonged diagnostic period.
  • To characterize the complex structural variant (SV) responsible for the condition.

Main Methods:

  • Combined microarray-based copy number variant analysis, fluorescence in situ hybridization, optical genome mapping, and whole genome sequencing.
  • Performed in silico analysis to predict the functional impact of the identified SV.

Main Results:

  • Identified a complex SV involving a duplication on chromosome 15 inserted into a deletion on the X chromosome (Xq27.1).
  • The SV disrupts the X chromosome's regulatory landscape, potentially leading to SOX3 misexpression.
  • This genetic alteration is hypothesized to cause SHFM by disturbing AER function.

Conclusions:

  • A complex structural variant involving chr15 duplication and Xq27.1 deletion is the likely cause of isolated X-linked SHFM in this family.
  • SOX3 dysregulation due to the SV is proposed as the mechanism leading to limb malformation.
  • This finding expands the genetic understanding of SHFM and highlights the utility of advanced genomic techniques for complex structural variants.