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A recurrent ITGA9 missense mutation in human fetuses with severe chylothorax: possible correlation with poor response
Gwo-Chin Ma1, Chin-San Liu, Shun-Ping Chang
1Department of Genomic Medicine and Center for Medical Genetics, Changhua Christian Hospital, Changhua, Taiwan.
Objectives:
To assess the possible correlations between the reported candidate genes (VEGFR3, FOXC2, ITGA9 and ITGB1) and the clinical response in fetuses with severe congenital chylothorax (CC) treated by prenatal OK-432 pleurodesis.
Methods:
We studied 12 unrelated fetuses with severe CC, receiving fetal therapy by OK-432 pleurodesis. Genotyping of the candidate genes and the clinical parameters of these 12 fetuses were investigated. Additional 96 control individuals were enrolled to evaluate the possible polymorphisms at these candidate genes in population.
Results:
A recurrent heterozygous missense mutation (c.1210G>A, p.G404S) was identified in the beta-propeller domain of integrin alpha(9) (ITGA9), a cell adhesion receptor, in four of the five fetuses who failed to respond to the OK-432 treatment. Computer modeling of the p.G404S substitution supported the deleterious nature of this mutation. Family analyses in three affected fetuses demonstrated that the heterozygous mutant allele is of parental origin, suggesting an autosomal recessive inheritance of this genetic defect.
Conclusions:
To the best of our knowledge, this is the first insight into the possible link between ITGA9 and CC in human fetuses. The identification of pathogenetic mutations and their possible link to the clinical responses of particular treatments may contribute to better pregnancy counseling and management.
Insights
A specific mutation in the ITGA9 gene was found in fetuses with congenital chylothorax (CC) that did not respond to OK-432 treatment. This finding may improve pregnancy counseling for this condition.
Area of Science:
- Medical Genetics
- Fetal Medicine
- Molecular Biology
Background:
- Congenital chylothorax (CC) is a serious fetal condition.
- Prenatal OK-432 pleurodesis is a treatment option for severe CC.
- Genetic factors may influence treatment response in CC.
Purpose of the Study:
- To investigate correlations between candidate genes (VEGFR3, FOXC2, ITGA9, ITGB1) and clinical response to prenatal OK-432 pleurodesis in fetuses with severe CC.
- To identify potential genetic markers for treatment outcomes.
Main Methods:
- Genotyping of candidate genes in 12 fetuses with severe CC undergoing OK-432 pleurodesis.
- Analysis of clinical parameters and treatment response.
- Population-based polymorphism evaluation in 96 controls.
Main Results:
- A recurrent heterozygous missense mutation (c.1210G>A, p.G404S) in the ITGA9 gene was identified in 4 out of 5 non-responding fetuses.
- Computer modeling indicated the p.G404S mutation is deleterious.
- Family analyses suggested autosomal recessive inheritance of the ITGA9 defect.
Conclusions:
- This study provides the first evidence linking ITGA9 mutations to congenital chylothorax in human fetuses.
- Identifying pathogenetic mutations and their impact on treatment response can enhance pregnancy counseling and management strategies.
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