Whole-Genome Sequencing of a Family with Hereditary Pulmonary Alveolar Proteinosis Identifies a Rare Structural Variant Involving CSF2RA/CRLF2/IL3RA Gene Disruption

Chih Yung Chiu, Shih Chi Su, Wen Lang Fan, Shen Hao Lai, Ming Han Tsai, Shih Hsiang Chen, Kin Sun Wong, Wen Hung Chung*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

10 Scopus citations

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.

Original languageEnglish
Article number43469
JournalScientific Reports
Volume7
DOIs
StatePublished - 24 02 2017

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© 2017 The Author(s).

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