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. 2025 Oct;60(10):e71324.
doi: 10.1002/ppul.71324.

Phenotype-Genotype Correlations in ABCA3 Patients-The RespiRare Cohort

Manon Fleury  1 , Céline Delestrain  2   3 , Alice Hadchouel  4 , Julie Mazenq  5 , Myriam Benhamida  6   7 , Anne-Sophie Bernard  8 , Raphaël Borie  9 , Jacques Brouard  10 , Harriet Corvol  1   11 , Pierrick Cros  12 , Christophe Delacourt  4 , Tifenn Desroziers  13 , Jean-Christophe Dubus  5 , Carole Egron  14 , Ralph Epaud  2   3 , Michael Fayon  15   16 , Aude Forgeron  17 , Lisa Giovannini-Chami  18 , Christophe Marguet  19 , Alexandra Masson-Rouchaud  20 , Hortense Petat  19 , Marie-Catherine Renoux  21 , Léa Roditis  22 , Caroline Thumerelle  23 , Clémentine Vigier  24 , Aurore Coulomb L'Herminé  25 , Hubert Ducou le Pointe  26 , Pascale Fanen  27   28 , Camille Fletcher  2 , Chiara Sileo  26 , Laureline Berteloot  29 , Camille Louvrier  13   30 , Alix de Becdelièvre  27   28 , Marie Legendre  13   30 , Nadia Nathan  1   13
Affiliations

Phenotype-Genotype Correlations in ABCA3 Patients-The RespiRare Cohort

Manon Fleury et al. Pediatr Pulmonol. 2025 Oct.

Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusion: 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.

Keywords: ABCA3; Childhood interstitial lung disease; Interstitial lung disease; surfactant.

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Conflict of interest statement

The authors have no conflict of interest to disclose in relation to this study. They have declared the following disclosures: Myriam Benhamida has declared Support for attending meetings and/or travel from the Société Francaise Mucoviscidose, Filière MUCO‐CFTR, VIATRIS. Raphaël Borie has declared consulting fees from Boerhinger Ingelheim, Ferrer, Sanofi; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boerhinger Ingelheim and support for attending meetings and/or travel from Boerhinger Ingelheim. Harriet Corvol has declared being the head of the Alice Hadchouel has declared being the head of the Société de Pneumologie pédiatrique et allergologie (SP2A), unpaid. Ralph Epaud has declared consulting fees from Astra Zeneca; Payment or honoraria for lectures from GSK, Astra Zeneca, Menarini, support for attending meetings and/or travel from GSK, Astra Zeneca and participation on an advisory Board of Astra Zeneca and Novartis. Michaël Fayon has declared being the president of the SPOI (Indian Ocean Lung Society). Alice Hadchouel has declared being the head of the Scientific committee of the Société de Pneumologie pédiatrique et allergologie (SP2A), unpaid. Julie Mazenq has declared a PhD grand from Astra‐Zeneca. Nadia Nathan has declared grants from French Ministry of health, Million Dollar Bike Ride, Chancellerie des Universités, RespiFIL; payment for manuscript writing from La lettre du Pneumologue; and support for attending meetings from the ERS.

Figures

Figure 1
Figure 1
Clinical and radiological presentations of subjects with ABCA3 pathogenic variants. (a) Age at onset of the symptoms. These data were compared by genotype groups using the chi‐square test (p = 0.8329). (b–f) Main patterns seen in axial high‐resolution CT (HRCT). (b–d) newborns subjects with null/null (SURF549), null/other (FR003SU660‐1159) and other/other (19GM00649) genotypes respectively. All of them presented dense and diffuse GGO (under mechanical ventilation). (e) Long‐term evolution of a subject (17GM00717) with an other/other genotype at 25 days, 4 years 10 months and 6 years 2 months, decrease of GGO intensity and extension over time; at 5 years, diffuse parenchymal destruction with emphysema. (f) Long‐term evolution of a subject (PPD507) with an other/other genotype at 8, 10 and 21‐year‐old subject with a chILD evolving since birth, multiple cystic images, diffuse mild GGO and intralobular septal thickening.
Figure 2
Figure 2
Kaplan‐Meier survival curve according to the ABCA3 genotype. The three survival curves according to genotype were compared using the log‐rank test (p‐value = 0.9417). [Color figure can be viewed at wileyonlinelibrary.com]
Figure 3
Figure 3
ABCA3 transporter domain organization and localization of the pathogenic variants identified in the cohort. The missense pathogenic variants were primarily identified in the two extracytosolic domains (ECD1 and 2), and in the two nucleotide‐binding domains (NBD1 and 2). The boundaries of the helical transmembrane domains (TMD) were determined based on the 3D structure of the human protein (7W02 PDB crystal) and on TMHMM predictions. ECL, extracellular loop; IH, intracellular transverse helix; EH, external helix; RD, regulatory domain. Null variants resulting in a premature Stop codon are in purple. Created with Biorender. [Color figure can be viewed at wileyonlinelibrary.com]
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