ALDH1A2‐related disorder: A new genetic syndrome due to alteration of the retinoic acid pathway

Abstract

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.

Integrative genomic analyses identify candidate causal genes for calcific aortic valve stenosis involving tissue-specific regulation

“…ALDH1A2 , aldehyde dehydrogenase 1 family member A2, encodes an enzyme that catalyzes the synthesis of retinoic acid from retinaldehyde. 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 ectasia 35 , 36 . In our study, we report a high expression specificity for the aortic valve and a positive relationship between genetically determined expression and CAVS supported by MR. Of note, a missense variant in high LD with the lead SNP was inversely associated with CAVS risk.…”

Identification and Expression Analysis of Long Noncoding RNAs in Response to Infection with VHSV in Rainbow Trout

“…ALDH1A2 is crucial for converting vitamin A into retinoic acid and plays a vital role in embryonic development, as shown in studies on model organisms. However, only a small number of genetic mutations in ALDH1A2 have been associated with birth defects in humans [46].…”