ArticleAmerican journal of human genetics2019
Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway.
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Article in American journal of human genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers, 2 of them syntheses that pooled it.
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70citing papers in PubMed, 2 pooled it
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Who cites it
70 citing papers in PubMed, 2 syntheses or guidelines pooled it, 176 citations in OpenAlex.
- Sequencing individual genomes with recurrent genomic disorder deletions: an approach to characterize genes for autosomal recessive rare disease traits.Genome medicine · 2022Pooled it
- Phenotypic spectrum ofPeerJ · 2022Pooled it
- Variant Class-Specific Phenotypes and Outcomes in Pediatric TBX4-Associated Pulmonary Hypertension.Pediatric pulmonology · 2026Article
- Review
- Alveolar capillary dysplasia: an example of health system data to understand rare conditions.Pediatric research · 2026Article
- Excessive postnatal smooth muscle differentiation in a lung-specific model of TBX4-related pulmonary hypertension.JCI insight · 2026Article
- Evaluation and Management of Genetic Respiratory Disorders Presenting as Hypoxemic Respiratory Failure in the Newborn Infant.Clinics in perinatology · 2026Review
- Rare T-box variants in adult pulmonary arterial hypertension with congenital heart disease.Journal of applied genetics · 2026Article
- Inherited TBX4 frameshifting variants predicted to escape nonsense mediated decay in two families with variable phenotypes, including lethal lung developmental disorders.Human genomics · 2026Article
- Chromosome 17q23.1-q23.2 deletion syndrome with severe pulmonary hypertension in neonates: two case reports and literature review.BMC pediatrics · 2026Review
- FGF family in health and disease.Molecular biomedicine · 2026Review
- Multifaceted role of T-box transcription factor 4: From embryonic development to disease pathogenesis.Genes & diseases · 2026Review
- Postnatally induced TBX4 insufficiency confers pulmonary hypertension and impairs lung development in infant mice.Pediatric research · 2026Article
- Complex Genomic Rearrangement Involving theHuman mutation · 2026Article
- Highly Variable Expressivity of a CNV Deletion Involving TBX4 in Three Deceased Siblings With Lung Developmental Disorder and Their Mildly Affected Mother and Grandfather.Clinical genetics · 2026Article
- Why some and not others? Understanding vascular phenotypes in genetic developmental lung diseases.Current opinion in pediatrics · 2025Review
- Pathology and Therapeutic Significance of Fibroblast Growth Factors.Targets (Basel) · 2025Article
- Implementing pulmonary arterial hypertension screening amongERJ open research · 2025Article
- The Glu86 Residue in TBX4 Proves Critical for Human Lung Development.American journal of medical genetics. Part A · 2025Article
- Interstitial lung disease in the newborn.Journal of perinatology : official journal of the California Perinatal Association · 2025Review
10 more citing papers are in PubMed but not listed here.
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Authors and funding
72 authors at 20 institutions in 11 countries.
Justyna A KarolakDepartment of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Genetics and Pharmaceutical Microbiology, Poznan University of Medical Sciences, 60-781 Poznan, Poland.
Marie VincentService de Génétique Médicale, CHU de Nantes, 44000 Nantes, France; Inserm, CNRS, Univ Nantes, l'institut du thorax, 44000 Nantes, France.
Gail DeutschDepartment of Pathology, Seattle Children's Hospital, Seattle, WA 98105, USA.
Tomasz GambinDepartment of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, Poland; Institute of Computer Science, Warsaw University of Technology, 00-665 Warsaw, Poland.
Benjamin CognéService de Génétique Médicale, CHU de Nantes, 44000 Nantes, France; Inserm, CNRS, Univ Nantes, l'institut du thorax, 44000 Nantes, France.
Olivier PichonService de Génétique Médicale, CHU de Nantes, 44000 Nantes, France.
Francesco VetriniBaylor Genetics, Houston, TX 77021, USA.
Heather C MeffordDepartment of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA.
Jennifer N DinesDepartment of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA; Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA.
Katie Golden-GrantDivision of Genetic Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA.
Katrina DippleDepartment of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA; Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA.
Amanda S FreedDepartment of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA; Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA.
Kathleen A LeppigGenetic Services Kaiser Permanente of Washington, Seattle, WA 98112, USA.
Megan DishopPathology and Laboratory Medicine, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.
David MowatCentre for Clinical Genetics, Sydney Children's Hospital, Randwick Sydney, NSW 2031 Australia; School of Women's and Children's Health, The University of New South Wales, Sydney, NSW 2052, Australia.
Bruce BennettsDiscipline of Child & Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Molecular Genetics Department, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia; Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia.
Andrew J GiffordSchool of Women's and Children's Health, The University of New South Wales, Sydney, NSW 2052, Australia; Department of Anatomical Pathology, Prince of Wales Hospital, Randwick, NSW 2031, Australia.
Martin A WeberDepartment of Anatomical Pathology, Prince of Wales Hospital, Randwick, NSW 2031, Australia; School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
Anna F LeeDepartment of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
Cornelius F BoerkoelDepartment of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
Tina M BartellDepartment of Genetics, Kaiser Permanente Sacramento Medical Center, Sacramento, CA 95815, USA.
Catherine Ward-MelverDivision of Medical Genetics, Akron Children's Hospital, Akron, OH 44302, USA.
Thomas BesnardService de Génétique Médicale, CHU de Nantes, 44000 Nantes, France; Inserm, CNRS, Univ Nantes, l'institut du thorax, 44000 Nantes, France.
Florence PetitService de Génétique Clinique, CHU Lille, 59000 Lille, France.
Iben BacheDepartment of Cellular and Molecular Medicine, University of Copenhagen, 2200 N Copenhagen, Denmark; Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, 2100 Ø Copenhagen, Denmark.
Zeynep TümerKennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, 2600 Glostrup, Copenhagen, Denmark; Deparment of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 N, Copenhagen, Denmark.
Marie Denis-MusquerService d'anatomo-pathologie, CHU Nantes, 44093 Nantes, France.
Madeleine JoubertService d'anatomo-pathologie, CHU Nantes, 44093 Nantes, France.
Jelena MartinovicUnit of Fetal Pathology, AP-HP, Antoine Beclere Hospital, 75000 Paris, France.
Claire BénéteauService de Génétique Médicale, CHU de Nantes, 44000 Nantes, France; Inserm, CNRS, Univ Nantes, l'institut du thorax, 44000 Nantes, France.
Arnaud MolinService de Génétique Médicale, CHU Caen, 14000 Caen, France.
Dominique CarlesService d'anatomo-pathologie, CHU Bordeaux, 33000 Bordeaux, France.
Gwenaelle AndréService d'anatomo-pathologie, CHU Bordeaux, 33000 Bordeaux, France.
Eric BiethService de génétique médicale, CHU Toulouse, France and UDEAR, UMR 1056 Inserm - Université de Toulouse, 31000 Toulouse, France.
Nicolas ChassaingService de génétique médicale, CHU Toulouse, France and UDEAR, UMR 1056 Inserm - Université de Toulouse, 31000 Toulouse, France.
Louise DevismeInstitut de Pathologie, CHU Lille, 59000 Lille, France.
Lara ChalabreysseService d'anatomo-pathologie, CHU Lyon, 69000 Lyon, France.
Laurent PasquierService de génétique médicale, CHU Rennes, 35000 Rennes, France.
Véronique SecqAix Marseille Univ, APHM, Hôpital Nord, Service d'anatomo-pathologie, 13000 Marseille, France.
Massimiliano DonSant'Antonio General Hospital, Pediatric Care Unit, San Daniele del Friuli, 33100 Udine, Italy.
Maria OrsariaDepartment of Medical and Biological Sciences, Pathology Unit, University of Udine, Udine, Italy.
Chantal MissirianAix Marseille Univ, APHM, INSERM, MMG, Marseille, Timone Hospital, 13000 Marseille, France.
Jérémie MortreuxAix Marseille Univ, APHM, INSERM, MMG, Marseille, Timone Hospital, 13000 Marseille, France.
Damien SanlavilleHospices Civils de Lyon, GHE, Genetics department, and Lyon University, 69000 Lyon, France.
Linda PonsHospices Civils de Lyon, GHE, Genetics department, and Lyon University, 69000 Lyon, France.
Sébastien KüryService de Génétique Médicale, CHU de Nantes, 44000 Nantes, France; Inserm, CNRS, Univ Nantes, l'institut du thorax, 44000 Nantes, France.
Stéphane BézieauService de Génétique Médicale, CHU de Nantes, 44000 Nantes, France; Inserm, CNRS, Univ Nantes, l'institut du thorax, 44000 Nantes, France.
Jean-Michel LietService de réanimation pédiatrique, CHU Nantes, 44000 Nantes, France.
Nicolas JoramService de réanimation pédiatrique, CHU Nantes, 44000 Nantes, France.
Tiphaine BihouéeService de pédiatrie, CHU Nantes, 44000 Nantes, France.
Daryl A ScottDepartment of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
Chester W BrownDepartment of Pediatrics, Genetics Division, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Fernando ScagliaDepartment of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Joint BCM-CUHK Center of Medical Genetics, Prince of Wales Hospital, ShaTin, New Territories, Hong Kong SAR.
Anne Chun-Hui TsaiDepartment of Pediatrics, The Children's Hospital, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Dorothy K GrangeDepartment of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA.
John A PhillipsDepartment of Pediatrics, Division of Medical Genetics and Genomic Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Jean P PfotenhauerDepartment of Pediatrics, Division of Medical Genetics and Genomic Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Shalini N JhangianiHuman Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Claudia G Gonzaga-JaureguiRegeneron Genetics Center, Regeneron Pharmaceuticals Inc. Tarrytown, NY 10599, USA.
Wendy K ChungDepartments of Pediatrics and Medicine, Columbia University, New York, NY 10032, USA.
Galen M SchauerDepartment of Pathology, Kaiser Permanente Oakland Medical Center, Oakland, CA 94611, USA.
Mark H LipsonDepartment of Genetics, Kaiser Permanente Sacramento Medical Center, Sacramento, CA 95815, USA.
Catherine L MercerWessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Princess Anne Hospital, Southampton SO16 5YA, UK.
Arie van HaeringenDepartment of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
Qian LiuDepartment of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Edwina PopekDepartment of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
Zeynep H Coban AkdemirDepartment of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
James R LupskiDepartment of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Przemyslaw SzafranskiDepartment of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Bertrand IsidorService de Génétique Médicale, CHU de Nantes, 44000 Nantes, France; Inserm, CNRS, Univ Nantes, l'institut du thorax, 44000 Nantes, France.
Cedric Le CaignecService de Génétique Médicale, CHU de Nantes, 44000 Nantes, France. Electronic address: cedric.lecaignec@chu-nantes.fr.
Paweł StankiewiczDepartment of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA; Institute of Mother and Child, 01-211 Warsaw, Poland. Electronic address: pawels@bcm.edu.
Baylor College of Medicine · USCentre Hospitalier Universitaire de Nantes · FRGénétique Médicale & Génomique Fonctionelle · FRInserm · FRUniversity of Washington · USCentre Hospitalier Universitaire de Bordeaux · FRCentre Hospitalier Universitaire de Lille · FRHospices Civils de Lyon · FRKaiser Permanente Sacramento Medical Center · USSeattle Children's Hospital · USUniversity of British Columbia · CAUniversity of Copenhagen · DKUNSW Sydney · AUVanderbilt University Medical Center · USAix-Marseille Université · FRAkron Children's Hospital · USBaylor Genetics · USCentre Hospitalier Universitaire de Rennes · FRChildren's Hospital Colorado · USColumbia University · US
Funding
Baylor-Johns Hopkins Center for Mendelian GeneticsUM1HG006542 · NHGRI · JOHNS HOPKINS UNIVERSITY · PI VALLE, DAVID · 2016 to 2020
$14.5MMedical Genetics Training GrantT32GM007454 · NIGMS · UNIVERSITY OF WASHINGTON · PI Gail Pairitz Jarvik, Andrew Ben Stergachis · 1985 to 2026
$6.9MSTRUCTURAL VARIATION IN NEUROLOGICAL DISEASER35NS105078 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI LUPSKI, JAMES R. · 2018 to 2025
$6.0MEpigenomic dysfunction at 16q24.1 vascular defects and perinatal consequencesR01HL137203 · NHLBI · BAYLOR COLLEGE OF MEDICINE · PI STANKIEWICZ, PAWEL · 2017 to 2020
$2.0MNHGRI NIH HHS UM1 HG006542NHLBI NIH HHS R01 HL137203NIGMS NIH HHS T32 GM007454NINDS NIH HHS R35 NS105078Wellcome Trust
Abstract
Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.
Indexed as
DNA Copy Number VariationsFemaleFibroblast Growth Factor 10Gene Expression RegulationGestational AgeHumansInfant, NewbornInfant, Newborn, DiseasesLungLung DiseasesMaleMaternal InheritanceOrganogenesisPaternal InheritancePedigreePolymorphism, Single NucleotideFGF10 protein, humanFGFR2 protein, humanFibroblast Growth Factor 10Receptor, Fibroblast Growth Factor, Type 2T-Box Domain ProteinsTBX4 protein, human17q23.1q23.2 recurrent deletion5p12 deletionaplasia of lacrimal and salivary glandsfibroblast growth factor 10lacrimoauriculodentodigital (LAAD) syndromelung hypoplasianeonatal lung diseaseT-box transcription factor 4
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