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Congenital heart defects in patients with deletions upstream of SOX9

Marta Sanchez-Castro1, Christopher T Gordon, Florence Petit

  • 1INSERM, UMR1087, l'institut du thorax, Nantes, France; Université de Nantes, Nantes, France.

Human Mutation
|October 12, 2013
PubMed

Insights

Genetic deletions upstream of the SOX9 gene can cause congenital heart defects (CHDs) and Pierre Robin sequence (PRS). These deletions disrupt cardiac enhancers, impacting SOX9 gene regulation and leading to developmental anomalies.

Area of Science:

  • Genetics
  • Developmental Biology
  • Molecular Biology

Background:

  • SOX9 is a crucial transcription factor involved in skeletal development and sex determination.
  • Mutations in SOX9 cause campomelic dysplasia, a severe skeletal disorder with multiple congenital anomalies.
  • The genetic and regulatory mechanisms underlying isolated congenital heart defects (CHDs) and Pierre Robin sequence (PRS) are not fully understood.

Purpose of the Study:

  • To investigate the genetic basis of isolated Pierre Robin sequence (PRS) and congenital heart defects (CHDs) in two unrelated families.
  • To identify the specific genetic alterations responsible for these phenotypes.
  • To explore the functional consequences of these alterations on SOX9 gene regulation and cardiac development.

Main Methods:

  • Whole-genome sequencing to identify deletions in patients with PRS and/or CHDs.
  • Comparative genomic hybridization (CGH) to confirm deletions.
  • Chromatin immunoprecipitation sequencing (ChIP-Seq) using H3K27ac in mouse cardiac tissue to identify active regulatory elements.
  • Bioinformatic analysis to identify cardiac enhancers within the deleted region and their potential interactions with known cardiac transcription factors.

Main Results:

  • Two unrelated families presented with isolated PRS, isolated CHDs, or both anomalies.
  • Patients in both families carried a similar large deletion (approximately 1 Mb) upstream of the SOX9 gene.
  • Analysis revealed several putative cardiac enhancers within the deleted region, including one known to interact with cardiac transcription factors Nkx2.5 and Gata4.

Conclusions:

  • Disruption of critical cardiac enhancers located upstream of SOX9 is a potential cause of CHDs in humans.
  • These findings expand the phenotypic spectrum associated with SOX9 regulatory element disruption beyond campomelic dysplasia.
  • This study highlights the importance of non-coding regulatory regions in human development and disease.
Keywords:
CNVSOX9congenital heart defectcopy number variantpierre robin sequence

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