ABCA3 gene mutations shape the clinical profiles of severe unexplained respiratory distress syndrome in late preterm and term infants

BACKGROUND: The majority of unexplained respiratory distress syndrome (URDS) cases in late preterm and term infants are caused by genetic abnormalities, with the most common of these being ABCA3 gene mutation. At present, it is unclear to neonatologists whether URDS patients with ABCA3 mutation have similar or more challenging clinical profiles to those without any defined genetic abnormalities. Our study aimed to answer this question by comparing the clinical characteristics of severe URDS patients with homozygous or compound heterozygous ABCA3 mutations, a single ABCA3 mutation, or no defined genetic abnormalities. METHODS: This retrospective cohort study involved 39 late preterm and term infants with URDS underwent a clinical exome sequencing at a tertiary neonatal intensive care unit between January 2013 and December 2019. Based on the sequencing result, the study subjects were classified into the homozygous or compound heterozygous mutations, single ABCA3 mutation, or no defined genetic abnormalities groups. The major outcomes, including mortality, the age of symptom onset and development of severe RDS, and the radiological score, were compared between the groups. RESULTS: A novel splicing site (c.3862+1G>C) was identified in one twin with homozygous expression. Patients with homozygous or compound heterozygous ABCA3 mutations exhibited symptom onset and development of severe respiratory distress syndrome (RDS) earlier than those with a single mutation or no genetic abnormalities (P<0.05). These patients also had higher mortality rates than those without genetic abnormalities (P=0.029). The total radiological scores were 51.14±4.91, 44.20±6.54, 35.91±4.42 for patients with homozygous or compound heterozygous mutations, a single mutation, and a wild-type gene, respectively, with significant differences between the groups observed by pairwise comparison (all P<0.05). CONCLUSIONS: Late preterm or term infants with URDS due to homozygous or compound heterozygous ABCA3 mutations exhibited more challenging clinical profiles than those without genetic abnormalities. However, whether this relationship exists between patients with a single ABCA3 mutation and those without genetic abnormalities warrants further study.