{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T17:09:27Z","timestamp":1790010567015,"version":"4.0.1"},"reference-count":49,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T00:00:00Z","timestamp":1748131200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Clin. Med.","JCM"],"abstract":"<jats:p>Background: Children\u2019s interstitial and diffuse lung diseases, commonly referred to as \u201cchILDs\u201d, include around 200 rare conditions that disrupt normal lung function. They are classified, based on etiopathogenesis, into several subgroups, having a varied and multifaceted clinical presentation depending on the type of genetic mutation present. Methods and Results: We describe the case of a late preterm newborn presenting soon after birth with respiratory distress syndrome poorly responsive to surfactant administration, in whom a targeted gene panel analysis for pulmonary congenital diseases, performed using next-generation sequencing (NGS), revealed a novel compound heterozygous variant of the ATP-Binding-Cassette-Subfamily-A-Member-3 (ABCA3) gene. A review of the literature on the subject completes our work. Conclusions: Molecular genetic analysis has become crucial for a more targeted therapeutic treatment, along with the only current curative treatment option that is lung transplantation.<\/jats:p>","DOI":"10.3390\/jcm14113704","type":"journal-article","created":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T20:26:50Z","timestamp":1748204810000},"page":"3704","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Novel Compound Heterozygous Mutation of the ABCA3 Gene in a Patient with Neonatal-Onset Interstitial Lung Disease"],"prefix":"10.3390","volume":"14","author":[{"given":"Gregorio","family":"Serra","sequence":"first","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties \u201cG. D\u2019Alessandro\u201d, University of Palermo, 90133 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Notarbartolo","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties \u201cG. D\u2019Alessandro\u201d, University of Palermo, 90133 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Antona","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties \u201cG. D\u2019Alessandro\u201d, University of Palermo, 90133 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8128-9670","authenticated-orcid":false,"given":"Caterina","family":"Cacace","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, \u201cBarone Ignazio Romeo\u201d Hospital, 98066 Patti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Rita","family":"Di Pace","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties \u201cG. D\u2019Alessandro\u201d, University of Palermo, 90133 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela Mariarosa","family":"Morreale","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties \u201cG. D\u2019Alessandro\u201d, University of Palermo, 90133 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3187-1901","authenticated-orcid":false,"given":"Marco","family":"Pensabene","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties \u201cG. D\u2019Alessandro\u201d, University of Palermo, 90133 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4727-1628","authenticated-orcid":false,"given":"Ettore","family":"Piro","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties \u201cG. D\u2019Alessandro\u201d, University of Palermo, 90133 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid Anne Mandy","family":"Schierz","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties \u201cG. D\u2019Alessandro\u201d, University of Palermo, 90133 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Sergio","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties \u201cG. D\u2019Alessandro\u201d, University of Palermo, 90133 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppina","family":"Valenti","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties \u201cG. D\u2019Alessandro\u201d, University of Palermo, 90133 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9576-1635","authenticated-orcid":false,"given":"Mario","family":"Giuffr\u00e8","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties \u201cG. D\u2019Alessandro\u201d, University of Palermo, 90133 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Corsello","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties \u201cG. D\u2019Alessandro\u201d, University of Palermo, 90133 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/S2352-4642(19)30117-8","article-title":"Children\u2019s interstitial and diffuse lung disease","volume":"3","author":"Cunningham","year":"2019","journal-title":"Lancet Child. Adolesc. Health"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1164\/rccm.201305-0923ST","article-title":"American Thoracic Society Committee on Childhood Interstitial Lung Disease (chILD) and the chILD Research Network. An official American Thoracic Society clinical practice guideline: Classification, evaluation, and management of childhood interstitial lung disease in infancy","volume":"188","author":"Kurland","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1186\/s13052-022-01336-0","article-title":"Novel mutations of the ABCA12, KRT1 and ST14 genes in three unrelated newborns showing congenital ichthyosis","volume":"48","author":"Serra","year":"2022","journal-title":"Ital. J. Pediatr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1186\/s13052-022-01329-z","article-title":"Distal Arthrogryposis type 5 in an Italian family due to an autosomal dominant gain-of-function mutation of the PIEZO2 gene","volume":"48","author":"Serra","year":"2022","journal-title":"Ital. J. Pediatr."},{"key":"ref_5","unstructured":"Valutazione Antropometrica Neonatale (2025, May 12). Riferimento Carte INeS. Available online: http:\/\/www.inescharts.com."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1136\/thoraxjnl-2015-207349","article-title":"chILD-EU Collaboration. European protocols for the diagnosis and initial treatment of interstitial lung disease in children","volume":"70","author":"Bush","year":"2015","journal-title":"Thorax"},{"key":"ref_7","unstructured":"World Health Organization (2025, May 12). Child Growth Standards. Available online: https:\/\/www.who.int\/tools\/child-growth-standards\/standards."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1016\/j.jpeds.2009.06.006","article-title":"Inherited surfactant deficiency caused by uniparental disomy of rare mutations in the surfactant protein-B and ATP binding cassette, subfamily a, member 3 genes","volume":"155","author":"Hamvas","year":"2009","journal-title":"J. Pediatr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/jp.2010.122","article-title":"Fatal respiratory failure in a full-term newborn with two ABCA3 gene mutations: A case report","volume":"31","author":"Ciantelli","year":"2011","journal-title":"J. Perinatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1038\/s41436-021-01139-4","article-title":"Next-generation sequencing for constitutional variants in the clinical laboratory, 2021 revision: A technical standard of the American College of Medical Genetics and Genomics (ACMG)","volume":"23","author":"Rehder","year":"2021","journal-title":"Genet. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/ejhg.2015.226","article-title":"EuroGentest; European Society of Human Genetics. Guidelines for diagnostic next-generation sequencing","volume":"24","author":"Matthijs","year":"2016","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_13","unstructured":"(2015). Standard Title: Quality Management Systems (Standard No. ISO 9001:2015)."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/nprot.2015.123","article-title":"SIFT missense predictions for genomes","volume":"11","author":"Vaser","year":"2016","journal-title":"Nat. Protoc."},{"key":"ref_15","first-page":"Unit7.20","article-title":"Predicting functional effect of human missense mutations using PolyPhen-2","volume":"7","author":"Adzhubei","year":"2013","journal-title":"Curr. Protoc. Hum. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"W446","DOI":"10.1093\/nar\/gkab266","article-title":"MutationTaster2021","volume":"49","author":"Steinhaus","year":"2021","journal-title":"Nucleic. Acids Res."},{"key":"ref_17","unstructured":"Panther Classification System (2023, September 17). PANTHER\u2122 Website News. Available online: https:\/\/www.pantherdb.org."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/s00441-016-2554-z","article-title":"The biology of the ABCA3 lipid transporter in lung health and disease","volume":"367","author":"Beers","year":"2017","journal-title":"Cell Tissue Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s12931-017-0526-9","article-title":"Examining the role of ABC lipid transporters in pulmonary lipid homeostasis and inflammation","volume":"18","author":"Chai","year":"2017","journal-title":"Respir. Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Tirelli, C., Pesenti, C., Miozzo, M., Mondoni, M., Fontana, L., and Centanni, S. (2022). The Genetic and Epigenetic Footprint in Idiopathic Pulmonary Fibrosis and Familial Pulmonary Fibrosis: A State-of-the-Art Review. Diagnostics, 12.","DOI":"10.3390\/diagnostics12123107"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.jpeds.2007.05.054","article-title":"ABCA3 deficiency presenting as persistent pulmonary hypertension of the newborn","volume":"151","author":"Kuning","year":"2007","journal-title":"J. Pediatr."},{"key":"ref_22","first-page":"51","article-title":"ABCA3 Deficiency: An unusual cause of respiratory distress in the newborn","volume":"78","author":"Anandarajan","year":"2009","journal-title":"Ulster Med. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1007\/s00431-013-2087-3","article-title":"Different course of lung disease in two siblings with novel ABCA3 mutations","volume":"173","author":"Hallik","year":"2014","journal-title":"Eur. J. Pediatr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.gene.2013.11.015","article-title":"Novel ABCA3 mutations as a cause of respiratory distress in a term newborn","volume":"534","author":"Pinheiro","year":"2014","journal-title":"Gene"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1038\/jp.2014.132","article-title":"Respiratory failure in a term newborn due to compound heterozygous ABCA3 mutation: The case report of another lethal variant","volume":"34","author":"Looman","year":"2014","journal-title":"J. Perinatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1164\/rccm.201312-2225LE","article-title":"Novel mutation in ABCA3 resulting in fatal congenital surfactant deficiency in two siblings","volume":"189","author":"Moore","year":"2014","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/jp.2014.236","article-title":"Respiratory failure in a term infant with cis and trans mutations in ABCA3","volume":"35","author":"Jackson","year":"2015","journal-title":"J. Perinatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1111\/ped.12673","article-title":"New ATP-binding cassette A3 mutation causing surfactant metabolism dysfunction pulmonary type 3","volume":"57","author":"Piersigilli","year":"2015","journal-title":"Pediatr. Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1186\/s13256-016-1027-z","article-title":"Fatal respiratory disease due to a homozygous intronic ABCA3 mutation: A case report","volume":"10","author":"Pachajoa","year":"2016","journal-title":"J. Med. Case Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.1002\/ppul.23260","article-title":"ABCA3 lung disease in an ex 27 week preterm infant responsive to systemic glucocorticosteroids","volume":"51","author":"Tan","year":"2016","journal-title":"Pediatr. Pulmonol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"E21","DOI":"10.1002\/ppul.23379","article-title":"ABCA3 mutations led to pulmonary fibrosis and emphysema with pulmonary hypertension in an 8-year-old girl","volume":"51","author":"Ota","year":"2016","journal-title":"Pediatr. Pulmonol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e1347","DOI":"10.1542\/peds.2010-1477","article-title":"Pulmonary nodules in a newborn with ATP-binding cassette transporter A3 (ABCA3) mutations","volume":"127","author":"Uchida","year":"2011","journal-title":"Pediatrics"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"E12","DOI":"10.1002\/ppul.23994","article-title":"Surfactant deficiency syndrome in an infant with a C-terminal frame shift in ABCA3: A case report","volume":"53","author":"Akil","year":"2018","journal-title":"Pediatr. Pulmonol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Mitsiakos, G., Tsakalidis, C., Karagianni, P., Gialamprinou, D., Chatziioannidis, I., Papoulidis, I., Tsanakas, I., and Soubasi, V. (2019). A New ABCA3 Gene Mutation c.3445G > A (p.Asp1149Asn) as a Causative Agent of Newborn Lethal Respiratory Distress Syndrome. Medicina, 55.","DOI":"10.3390\/medicina55070389"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"a005074","DOI":"10.1101\/mcs.a005074","article-title":"Neonatal respiratory failure due to novel compound heterozygous mutations in the ABCA3 lipid transporter","volume":"6","author":"Oltvai","year":"2020","journal-title":"Cold Spring Harb. Mol. Case Stud."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e235520","DOI":"10.1136\/bcr-2020-235520","article-title":"Novel homozygous missense mutation in ABCA3 protein leading to severe respiratory distress in term infant","volume":"13","author":"Gupta","year":"2020","journal-title":"BMJ Case Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s13256-020-02604-5","article-title":"Hydroxychloroquine, a successful treatment for lung disease in ABCA3 deficiency gene mutation: A case report","volume":"15","author":"Shaaban","year":"2021","journal-title":"J. Med. Case Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"703","DOI":"10.24953\/turkjped.2021.04.019","article-title":"Whole exome sequencing identifies a novel variant in ABCA3 in an individual with fatal congenital surfactant protein deficiency","volume":"63","author":"Bozkurt","year":"2021","journal-title":"Turk. J. Pediatr."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Zhang, W., Liu, Z., Lin, Y., Wang, R., Xu, J., He, Y., Zhang, F., Wu, L., and Chen, D. (2021). A novel synonymous ABCA3 variant identified in a Chinese family with lethal neonatal respiratory failure. BMC Med. Genom., 14.","DOI":"10.1186\/s12920-021-01098-4"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.jpeds.2020.12.055","article-title":"Three Infants with Pathogenic Variants in the ABCA3 Gene: Presentation, Treatment, and Clinical Course","volume":"231","author":"Si","year":"2021","journal-title":"J. Pediatr."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Chen, F., Xie, Z., Zhang, V.W., Chen, C., Fan, H., Zhang, D., Jiang, W., Wang, C., and Wu, P. (2022). Case Report: Report of Two Cases of Interstitial Lung Disease Caused by Novel Compound Heterozygous Variants in the ABCA3 Gene. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.875015"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1056\/NEJMoa032178","article-title":"ABCA3 gene mutations in newborns with fatal surfactant deficiency","volume":"350","author":"Shulenin","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1002\/humu.23416","article-title":"ABCA3 missense mutations causing surfactant dysfunction disorders have distinct cellular phenotypes","volume":"39","author":"Schindlbeck","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/1465-9921-15-43","article-title":"A large kindred of pulmonary fibrosis associated with a novel ABCA3 gene variant","volume":"15","author":"Campo","year":"2014","journal-title":"Respir. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e97381","DOI":"10.1172\/jci.insight.97381","article-title":"Alveolar injury and regeneration following deletion of ABCA3","volume":"2","author":"Rindler","year":"2017","journal-title":"JCI Insight"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"101500","DOI":"10.1016\/j.siny.2023.101500","article-title":"Towards personalized therapies for genetic disorders of surfactant dysfunction","volume":"28","author":"Wambach","year":"2023","journal-title":"Semin. Fetal Neonatal Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1186\/s13052-022-01365-9","article-title":"Congenital hypopituitarism and multiple midline defect sin a new born with non-familial Cat Eye syndrome","volume":"48","author":"Serra","year":"2022","journal-title":"Ital. J. Pediatr."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Presti, S., Parisi, G.F., Papale, M., Gitto, E., Manti, S., and Leonardi, S. (2022). Interstitial Lung Disease in Children: \u201cSpecific Conditions of Undefined Etiology\u201d Becoming Clearer. Children, 9.","DOI":"10.3390\/children9111744"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Drob\u0148akov\u00e1, S., Vargov\u00e1, V., and Barkai, L. (2024). The Clinical Approach to Interstitial Lung Disease in Childhood: A Narrative Review Article. Children, 11.","DOI":"10.3390\/children11080904"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/11\/3704\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T16:25:34Z","timestamp":1790007934000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/11\/3704"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,25]]},"references-count":49,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["jcm14113704"],"URL":"https:\/\/doi.org\/10.3390\/jcm14113704","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,25]]}}}