Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway.,American Journal of Human Genetics

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Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway.
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2019-01-10 , DOI: 10.1016/j.ajhg.2018.12.010
Justyna A Karolak ₁ , Marie Vincent ₂ , Gail Deutsch ₃ , Tomasz Gambin ₄ , Benjamin Cogné ₂ , Olivier Pichon ₅ , Francesco Vetrini ₆ , Heather C Mefford ₇ , Jennifer N Dines ₈ , Katie Golden-Grant ₉ , Katrina Dipple ₁₀ , Amanda S Freed ₈ , Kathleen A Leppig ₁₁ , Megan Dishop ₁₂ , David Mowat ₁₃ , Bruce Bennetts ₁₄ , Andrew J Gifford ₁₅ , Martin A Weber ₁₆ , Anna F Lee ₁₇ , Cornelius F Boerkoel ₁₈ , Tina M Bartell ₁₉ , Catherine Ward-Melver ₂₀ , Thomas Besnard ₂ , Florence Petit ₂₁ , Iben Bache ₂₂ , Zeynep Tümer ₂₃ , Marie Denis-Musquer ₂₄ , Madeleine Joubert ₂₄ , Jelena Martinovic ₂₅ , Claire Bénéteau ₂ , Arnaud Molin ₂₆ , Dominique Carles ₂₇ , Gwenaelle André ₂₇ , Eric Bieth ₂₈ , Nicolas Chassaing ₂₈ , Louise Devisme ₂₉ , Lara Chalabreysse ₃₀ , Laurent Pasquier ₃₁ , Véronique Secq ₃₂ , Massimiliano Don ₃₃ , Maria Orsaria ₃₄ , Chantal Missirian ₃₅ , Jérémie Mortreux ₃₅ , Damien Sanlaville ₃₆ , Linda Pons ₃₆ , Sébastien Küry ₂ , Stéphane Bézieau ₂ , Jean-Michel Liet ₃₇ , Nicolas Joram ₃₇ , Tiphaine Bihouée ₃₈ , Daryl A Scott ₃₉ , Chester W Brown ₄₀ , Fernando Scaglia ₄₁ , Anne Chun-Hui Tsai ₄₂ , Dorothy K Grange ₄₃ , John A Phillips ₄₄ , Jean P Pfotenhauer ₄₄ , Shalini N Jhangiani ₄₅ , Claudia G Gonzaga-Jauregui ₄₆ , Wendy K Chung ₄₇ , Galen M Schauer ₄₈ , Mark H Lipson ₁₉ , Catherine L Mercer ₄₉ , Arie van Haeringen ₅₀ , Qian Liu ₅₁ , Edwina Popek ₅₂ , Zeynep H Coban Akdemir ₅₁ , James R Lupski ₅₃ , Przemyslaw Szafranski ₅₁ , Bertrand Isidor ₂ , Cedric Le Caignec ₅ , Paweł Stankiewicz ₅₄

Affiliation

Department 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.
Service de Génétique Médicale, CHU de Nantes, 44000 Nantes, France; Inserm, CNRS, Univ Nantes, l'institut du thorax, 44000 Nantes, France.
Department of Pathology, Seattle Children's Hospital, Seattle, WA 98105, USA.
Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, Poland; Institute of Computer Science, Warsaw University of Technology, 00-665 Warsaw, Poland.
Service de Génétique Médicale, CHU de Nantes, 44000 Nantes, France.
Baylor Genetics, Houston, TX 77021, USA.
Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA.
Department 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.
Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA.
Department 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.
Genetic Services Kaiser Permanente of Washington, Seattle, WA 98112, USA.
Pathology and Laboratory Medicine, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.
Centre 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.
Discipline 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.
School 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.
Department of Anatomical Pathology, Prince of Wales Hospital, Randwick, NSW 2031, Australia; School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
Department of Genetics, Kaiser Permanente Sacramento Medical Center, Sacramento, CA 95815, USA.
Division of Medical Genetics, Akron Children's Hospital, Akron, OH 44302, USA.
Service de Génétique Clinique, CHU Lille, 59000 Lille, France.
Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 N Copenhagen, Denmark; Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, 2100 Ø Copenhagen, Denmark.
Kennedy 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.
Service d'anatomo-pathologie, CHU Nantes, 44093 Nantes, France.
Unit of Fetal Pathology, AP-HP, Antoine Beclere Hospital, 75000 Paris, France.
Service de Génétique Médicale, CHU Caen, 14000 Caen, France.
Service d'anatomo-pathologie, CHU Bordeaux, 33000 Bordeaux, France.
Service de génétique médicale, CHU Toulouse, France and UDEAR, UMR 1056 Inserm - Université de Toulouse, 31000 Toulouse, France.
Institut de Pathologie, CHU Lille, 59000 Lille, France.
Service d'anatomo-pathologie, CHU Lyon, 69000 Lyon, France.
Service de génétique médicale, CHU Rennes, 35000 Rennes, France.
Aix Marseille Univ, APHM, Hôpital Nord, Service d'anatomo-pathologie, 13000 Marseille, France.
Sant'Antonio General Hospital, Pediatric Care Unit, San Daniele del Friuli, 33100 Udine, Italy.
Department of Medical and Biological Sciences, Pathology Unit, University of Udine, Udine, Italy.
Aix Marseille Univ, APHM, INSERM, MMG, Marseille, Timone Hospital, 13000 Marseille, France.
Hospices Civils de Lyon, GHE, Genetics department, and Lyon University, 69000 Lyon, France.
Service de réanimation pédiatrique, CHU Nantes, 44000 Nantes, France.
Service de pédiatrie, CHU Nantes, 44000 Nantes, France.
Department 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.
Department of Pediatrics, Genetics Division, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Department 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.
Department of Pediatrics, The Children's Hospital, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA.
Department of Pediatrics, Division of Medical Genetics and Genomic Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Regeneron Genetics Center, Regeneron Pharmaceuticals Inc. Tarrytown, NY 10599, USA.
Departments of Pediatrics and Medicine, Columbia University, New York, NY 10032, USA.
Department of Pathology, Kaiser Permanente Oakland Medical Center, Oakland, CA 94611, USA.
Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Princess Anne Hospital, Southampton SO16 5YA, UK.
Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
Department 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.
Department 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.

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) involvingTBX4(n = 8 and n = 2, respectively) orFGF10(n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition toTBX4, 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 eitherTBX4orFGF10also 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 involvingTBX4orFGF10with 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.

中文翻译：

TBX-FGF途径中断导致致死性肺发育障碍的复杂复合遗传。

肺分支形态发生的主要缺陷，导致新生儿致命性肺发育不全，目前尚不完全清楚。为了阐明人肺发育的病原学，我们研究了一组从临床和组织病理学诊断为间质性新生儿肺部疾病的已故个体中收集的独特样本：腺泡发育不良（n = 14），先天性肺泡发育不良（n = 2）和其他致命性疾病肺发育不全（n = 10）。我们在16/26（61％）的个体中发现了涉及TBX4（分别为n = 8和n = 2）或FGF10（分别为n = 2和n = 2）的罕见杂合拷贝数变异或单核苷酸变异（SNV）。。除TBX4外，在17q23.1q23处重叠的〜2 Mb重复和非重复删除。在七个肺发育不全的个体中鉴定出的2个也去除了肺特异性增强子区域。具有涉及TBX4或FGF10的编码变体的个体在预测的肺特异性增强子区域中也包含至少一个非编码SNV，在缺失重叠但没有任何结构性肺异常的13个对照个体中不存在。涉及TBX4或FGF10并伴有假定的亚型非编码SNV的罕见编码变体的出现暗示了这些肺发育不全的复杂化合物遗传。此外，它们支持TBX4-FGF10-FGFR2上皮间质信号传导在人肺器官发生中的重要性，并有助于解释在这些罕见的致命性肺发育疾病中观察到的组织病理学连续性。具有涉及TBX4或FGF10的编码变体的个体在预测的肺特异性增强子区域中也包含至少一个非编码SNV，在缺失重叠但没有任何结构性肺异常的13个对照个体中不存在。涉及TBX4或FGF10并伴有假定的亚型非编码SNV的罕见编码变体的出现暗示了这些肺发育不全的复杂化合物遗传。此外，它们支持TBX4-FGF10-FGFR2上皮间质信号传导在人肺器官发生中的重要性，并有助于解释在这些罕见的致命性肺发育疾病中观察到的组织病理学连续性。具有涉及TBX4或FGF10的编码变体的个体在预测的肺特异性增强子区域中也包含至少一个非编码SNV，在缺失重叠但没有任何结构性肺异常的13个对照个体中不存在。涉及TBX4或FGF10并伴有假定的亚型非编码SNV的罕见编码变体的出现暗示了这些肺发育不全的复杂化合物遗传。此外，它们支持TBX4-FGF10-FGFR2上皮间质信号传导在人肺器官发生中的重要性，并有助于解释在这些罕见的致命性肺发育疾病中观察到的组织病理学连续性。在缺失重叠但没有任何结构性肺部异常的13个对照个体中，这是缺失的。涉及TBX4或FGF10并伴有假定的亚型非编码SNV的罕见编码变体的出现暗示了这些肺发育不全的复杂化合物遗传。此外，它们支持TBX4-FGF10-FGFR2上皮间质信号传导在人肺器官发生中的重要性，并有助于解释在这些罕见的致命性肺发育疾病中观察到的组织病理学连续性。在缺失重叠但没有任何结构性肺部异常的13个对照个体中，这是缺失的。涉及TBX4或FGF10并伴有假定的亚型非编码SNV的罕见编码变体的出现暗示了这些肺发育不全的复杂化合物遗传。此外，它们支持TBX4-FGF10-FGFR2上皮间质信号传导在人肺器官发生中的重要性，并有助于解释在这些罕见的致命性肺发育疾病中观察到的组织病理学连续性。

更新日期：2019-01-11

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