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ALDH1A2‐related disorder: A new genetic syndrome due to alteration of the retinoic acid pathway
Open accessAbstract
Aldehyde Dehydrogenase 1, Family Member A2 (ALDH1A2) is essential for the synthesis of retinoic acid from vitamin A. Studies in model organisms demonstrate a critical role for ALDH1A2 in embryonic development, yet few pathogenic variants are linked to congenital anomalies in humans. We present three siblings with multiple congenital anomaly syndrome linked to biallelic sequence variants in ALDH1A2. The major congenital malformations affecting these children include tetralogy of Fallot, absent thymus, diaphragmatic eventration, and talipes equinovarus. Upper airway anomalies, hypocalcemia, and dysmorphic features are newly reported in this manuscript. In vitro functional validation of variants indicated that substitutions reduced the expression of the enzyme. Our clinical and functional data adds to a recent report of biallelic ALDH1A2 pathogenic variants in two families with a similar constellation of congenital malformations. These findings provide further evidence for an autosomal recessive ALDH1A2‐deficient recognizable malformation syndrome involving the diaphragm, cardiac and musculoskeletal systems.
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Loss-of-function mutations in ALDH1A2 lead to an autosomal recessive condition presenting with diaphragmatic hernia and cardiovascular defects, including atrial and ventricular septal defects and aortic root ectasia.
“Loss-of-function mutations in this gene lead to an autosomal recessive condition presenting with diaphragmatic hernia and cardiovascular defects, including atrial as well as ventricular septal defects and aortic root ectasia35,36.”
From Integrative genomic analyses identify candidate causal genes for calcific aortic valve stenosis involving tissue-specific regulation (2024) · cites this paper as [36]
The Abstract describes an autosomal recessive ALDH1A2-related syndrome affecting the diaphragm and heart, and the Subject 2 case report documents both atrial and ventricular septal defects. The paper’s own cases describe diaphragmatic eventration rather than hernia, although the Introduction links ALDH1A2 variants to congenital diaphragmatic hernia. No passage found supports aortic root ectasia (searched: ectasia, aortic root dilation). Page numbers were unavailable in our copy. (LLM, conf=0.86)
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Metadata
- Authors
- Leon, E., Nde, C., Ray, R. S., Preciado, D., & Zohn, I. E.
- Affiliations
- Children's National (US)
- Corresponding author
- Leon, Eyby
- Venue
- American Journal of Medical Genetics Part A
- Publisher
- Wiley
- Published
- 2022-10-19
- Volume
- 191
- Issue
- 1
- Pages
- 90-99
- ISSN
- 1552-4825 (ISSN-L)
- 1552-4833
- PMC
- PMC9805811
- OpenAlex
- W4306912952
- Cited by
- 13
- References
- 31
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 2 · 2023: 3
- FWCI
- 2.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Medical Genetics Part A (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD098861, U54HD090257, P50HD105328, R01HD113214)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- ALDH1A2, retinoic acid pathway, congenital malformation syndrome, autosomal recessive inheritance, biallelic pathogenic variants, tetralogy of Fallot, diaphragmatic eventration, clubfoot, hypocalcemia, dysmorphic features, vitamin A metabolism
- MeSH terms
- Aldehyde Dehydrogenase 1 Family, Child, Humans, Tretinoin, Retinal Dehydrogenase
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