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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Asymptomatic Diseases
-
Child
-
Child, Preschool
-
Chromosomes, Human, X / chemistry*
-
Female
-
Gene Deletion
-
Genetic Diseases, Inborn / diagnosis
-
Genetic Diseases, Inborn / genetics*
-
Genetic Diseases, Inborn / immunology
-
Genetic Diseases, Inborn / pathology
-
Homozygote
-
Humans
-
Interleukin-1beta / pharmacology
-
Interleukin-3 Receptor alpha Subunit / deficiency*
-
Interleukin-3 Receptor alpha Subunit / genetics
-
Interleukin-3 Receptor alpha Subunit / immunology
-
Leukocytes, Mononuclear / drug effects
-
Leukocytes, Mononuclear / immunology
-
Leukocytes, Mononuclear / pathology
-
Macrophages, Alveolar / immunology
-
Macrophages, Alveolar / pathology
-
Male
-
Pedigree
-
Penetrance
-
Primary Cell Culture
-
Pulmonary Alveolar Proteinosis / diagnosis
-
Pulmonary Alveolar Proteinosis / genetics*
-
Pulmonary Alveolar Proteinosis / immunology
-
Pulmonary Alveolar Proteinosis / pathology
-
Receptors, Cytokine / deficiency*
-
Receptors, Cytokine / genetics
-
Receptors, Cytokine / immunology
-
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / deficiency*
-
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / genetics
-
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / immunology
-
Severity of Illness Index
-
Siblings
-
Whole Genome Sequencing
Substances
-
CRLF2 protein, human
-
CSF2RA protein, human
-
IL1B protein, human
-
IL3RA protein, human
-
Interleukin-1beta
-
Interleukin-3 Receptor alpha Subunit
-
Receptors, Cytokine
-
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor