ClinVar

In 2 male infants, born of unrelated Australian parents (family AUS1), with diaphragmatic hernia-4 with cardiovascular defects (DIH4; 620025), Beecroft et al. (2021) identified compound heterozygous missense variants in the ALDH1A2 gene: a c.544C-A transversion (c.544C-A, NM_003888), resulting in a gln182-to-lys (Q182K) substitution, and a c.1382C-A transversion, resulting in a ser461-to-tyr (S461Y; 603687.0002) substitution in the catalytic domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both mutations occurred at highly conserved residues and were absent from the gnomAD database. In a subsequent pregnancy in this family, a 12-week fetal morphology scan showed nuchal translucency and a cystic hygroma; the pregnancy was terminated. This fetus also carried the compound heterozygous missense mutations in the ALDH1A2 gene. In vitro functional expression studies in F9 cells transfected with the mutations showed that both reduced ALDH1A2 activity, as measured by decreased RA production. When expressed together, the Q182K and S461Y mutations decreased ALDH1A2 activity to about 54% that of controls. These findings were consistent with the mutations resulting in hypomorphic alleles. In addition to diaphragmatic hernia, the patients had variable cardiac abnormalities and dysmorphic features. They died in the first days or weeks of life.