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Published on: August 15, 2019
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Non-coding structural variants disrupting conserved PITX2 enhancer loci in Axenfeld-Rieger syndrome
Lucas A Mitchell1,2, Joshua Schmidt1,3, Emmanuelle Souzeau3
1Garvan Institute of Medical Research, Sydney, NSW, Australia.
European Journal of Human Genetics : EJHG
|March 27, 2026
Summary
Axenfeld-Rieger Syndrome (ARS) is often caused by gene variants. This study found new non-coding structural variants affecting PITX2 gene regulation, offering insights into undiagnosed ARS cases.
Area of Science:
- Genetics
- Developmental Biology
- Ophthalmology
Background:
- Axenfeld-Rieger Syndrome (ARS) is an autosomal dominant disorder with ocular and non-ocular features.
- Primary genetic causes are coding variants in PITX2 or FOXC1, but many cases remain undiagnosed.
Purpose of the Study:
- To identify the genetic basis of ARS in families with undiagnosed cases.
- To investigate non-coding variants affecting PITX2 gene regulation.
Main Methods:
- Whole-genome sequencing was employed to analyze DNA from affected families.
- Structural variants, including deletions and inversions, were identified and characterized.
Main Results:
- Two families presented with typical PITX2-associated ARS due to non-coding structural variants.
- One family had a deletion of distal enhancer elements, and the other had an inversion displacing PITX2 from these enhancers.
- These variants disrupt PITX2 expression by altering enhancer accessibility, not by direct gene mutation.
Conclusions:
- Non-coding structural variants, particularly PITX2 enhancer-disrupting inversions, represent an emerging genetic mechanism for ARS.
- These findings expand the known genetic causes of ARS and highlight the importance of considering non-coding regions in genetic diagnostics.
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