title: Whole-Genome Sequencing of a Family with Hereditary Pulmonary Alveolar Proteinosis Identifies a Rare Structural Variant Involving CSF2RA/CRLF2/IL3RA Gene Disruption.
abstract: Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disease in which the abnormalities in alveolar surfactant accumulation are caused by impairments of GM-CSF pathway attributing to defects in a variety of genes. However, hereditary PAP is extremely uncommon and a detailed understanding in the genetic inheritance of PAP in a family may provide timely diagnosis, treatment and proper intervention including genetic consultation. Here, we described a comprehensive analysis of genome and gene expression for a family containing one affected child with a diagnosis of PAP and two other healthy siblings. Family-based whole-genome analysis revealed a homozygous deletion that disrupts CSF2RA, CRLF2, and IL3RA gene in the pseudoautosomal region of the X chromosome in the affected child and one of asymptomatic siblings. Further functional pathway analysis of differentially expressed genes in IL-1β-treated peripheral blood mononuclear cells highlighted the insufficiency of immune response in the child with PAP, especially the protection against bacterial infection. Collectively, our results reveal a novel allele as the genetic determinant of a family with PAP and provide insights into variable expressivity and incomplete penetrance of this rare disease, which will be helpful for proper genetic consultation and prompt treatment to avoid mortality and morbidity.
authors.affiliation: Department of Pediatrics, Chang Gung Memorial Hospital at Keelung, College of Medicine, Chang Gung University, Taoyuan, Taiwan.|Division of Pediatric Pulmonology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan.|Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chih-Yung
authors.initials: CY
authors.lastname: Chiu
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linkou and Keelung, Taiwan.|Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan.
authors.forename: Shih-Chi
authors.initials: SC
authors.lastname: Su
authors.affiliation: Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan.
authors.forename: Wen-Lang
authors.initials: WL
authors.lastname: Fan
authors.affiliation: Division of Pediatric Pulmonology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Shen-Hao
authors.initials: SH
authors.lastname: Lai
authors.affiliation: Department of Pediatrics, Chang Gung Memorial Hospital at Keelung, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ming-Han
authors.initials: MH
authors.lastname: Tsai
authors.affiliation: Division of Pediatric Hematology/Oncology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Shih-Hsiang
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Division of Pediatric Pulmonology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Kin-Sun
authors.initials: KS
authors.lastname: Wong
authors.affiliation: Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.|Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linkou and Keelung, Taiwan.|Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan.
authors.forename: Wen-Hung
authors.initials: WH
authors.lastname: Chung
mesh_terms: D058070:Asymptomatic Diseases; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000737:chemistry*; D005260:Female; D017353:Gene Deletion; D030342:Genetic Diseases, Inborn / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006720:Homozygote; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D053650:Interleukin-3 Receptor alpha Subunit / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000473:pathology; D008297:Male; D010375:Pedigree; D019683:Penetrance; D061251:Primary Cell Culture; D011649:Pulmonary Alveolar Proteinosis / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D018121:Receptors, Cytokine / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D012720:Severity of Illness Index; D035781:Siblings; D000073336:Whole Genome Sequencing
chemical_list: C498762:CRLF2 protein, human; C521678:CSF2RA protein, human; C508585:IL1B protein, human; C115022:IL3RA protein, human; D053583:Interleukin-1beta; D053650:Interleukin-3 Receptor alpha Subunit; D018121:Receptors, Cytokine; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor