Phenotype-Genotype Correlations in ABCA3 Patients-The RespiRare Cohort.

Area of Science:

• Genetics
• Pediatric Pulmonology
• Molecular Biology

Background:

• ATP-binding cassette transporter A3 (ABCA3) deficiency is a severe cause of childhood interstitial lung diseases (chILD).
• Understanding genotype-phenotype correlations is crucial for managing chILD.
• The RespiRare cohort provides valuable data on ABCA3 deficiency.

Purpose of the Study:

• To report the RespiRare ABCA3 cohort.
• To establish phenotype-genotype correlations in children with ABCA3 deficiency.
• To analyze the impact of genotype on the presentation and evolution of chILD.

Main Methods:

• Retrospective analysis of phenotypic and genotypic data from patients under 18 years (1995-2023).
• Inclusion of data from RespiRare centers.
• Analysis of initial presentation and disease evolution based on genotype.

Main Results:

• The ABCA3 cohort included 36 children; 86% presented with neonatal respiratory distress syndrome.
• Overall 5-year survival was 25%, with a median survival of 0.33 years.
• Neonatal onset and pulmonary hypertension significantly worsened prognosis; survival varied by genotype (0% for null/null, 50% for null/other, 23% for other/other).

Conclusions:

• The clinical presentation and outcomes of chILD due to ABCA3 variants are strongly linked to the specific genotype.
• Null variants and variants affecting nucleotide-binding domains (NBD) are associated with particularly severe disease.
• Genotype-guided understanding is essential for predicting disease course and managing ABCA3 deficiency.