Phenotype-Genotype Correlations in ABCA3 Patients-The RespiRare Cohort

ATP-binding cassette transporter A3 (ABCA3) deficiency is one of the most severe causes of childhood interstitial lung diseases (chILD). This study aims to report the RespiRare ABCA3 cohort and to establish phenotype-genotype correlations.

Phenotypic and genotypic data of patients under 18 years were retrospectively included (1995-2023) in the RespiRare centers. The initial presentation and evolution of the subjects was analyzed depending on their genotype.

The ABCA3 cohort comprised 36 children (30 families), including 5.5%, 22%, and 72% of null/null (no protein), null/other (potential residual function) and other/other genotypes respectively. A neonatal respiratory distress syndrome was observed in 31 (86%) subjects and 27 (75%) died at a median age of 3 months. The 5-year overall survival was 25% with an overall median survival of 0.33 year (IQR 0.09-4.43). A neonatal onset (p = 0.009) and the presence of pulmonary hypertension (p = 0.037) impaired the prognosis. At the last follow-up, the survival rates were 0/2 (0%), 4/8 (50%) and 6/26 (23%) in the null/null, null/other and other/other groups respectively. Eight of the 12 subjects who survived beyond 1 year carried at least one missense variant outside the nucleotide-binding domains (NBD) (n = 9) or the hypomorphic p.(Glu292Val) variant (n = 1).

The variable presentation and outcome of chILD due to ABCA3 pathogenic variants are linked to the underlying genotype. Neonatal onset, null variants, and variants involving the NBD are of peculiar severity.