Screening and identification of pathogenic genes in a family of idiopathic pulmonary fibrosis

<bold>Background:</bold> Genetic factors play a crucial part in the occurrence of idiopathic pulmonary fibrosis, and many related pathogenic genes have been reported. Although ZCCHC8 has been reported as a disease-causing gene related to idiopathic pulmonary fibrosis, its mutation is currently less reported. ZCCHC8, as a core component of nuclear exosome targeting complexes, plays an important role in RNA quality control systems. <bold>Methods:</bold> Applying whole exome sequencing combined with IPF known pathogenic gene screening, to analyze the pathogenic variants, and use bioinformatics tools to analyze mutation conservation and pathogenicity. Functional validation of mutations using cell biology methods. <bold>Results:</bold> In this study, a disease-causing gene was screened and identified in an IPF family line by whole exome sequencing technology and genetic analysis, ZCCHC8 p. Pro410Alawas confirmed as its pathogenic gene and main genetic factors, and the pathogenic mechanism of ZCCHC8 protein was preliminarily explored through bioinformatics analysis, protein 3D structure modeling, immunofluorescence, Western Blot and other related experiments. <bold>Conclusion:</bold> ZCCHC8 p. Pro410Ala affect the protein intracellular localization. ZCCHC8 pathogenic mutation downregulates the expression of DKC1 and RTEL1 in cells, which may be related to the pathogenic mechanism of this mutation. Our study expanded the mutation profile of ZCCHC8 and further clarified its correlation with the occurrence of IPF.