Yingfen Ying

and 7 more

Background: Severe congenital neutropenia (SCN) is an autoimmune disease clinically characterized by persistent and severe neutropenia. It is typically caused by a heterozygous mutation in the ELANE gene, which encodes neutrophil elastase. Procedure: Using one 3-year-old male diagnosed with severe congenital neutropenia, we aimed to assess the clinical and genetic characteristics of SCN caused by ELANE mutations and test whether the mutation can be corrected by CRISPR/Cas9-mediated gene editing. The proband underwent extensive clinical assessments, with exome sequencing and bioinformatics analysis to identify pathogenic genes. In addition, Sanger sequencing was used to verify the pedigrees. The cell line, 293-ELANE, harboring ELANE mutation was generated by lentiviral transduction and selection with puromycin from HEK-293. And the mutation was corrected by CRISPR/Cas9-mediated homology-directed repair (HDR). Results: The ELANE gene test in the proband unveiled a heterozygous de novo missense mutation: c. 248T>A (p.V83D), which is not detected in his asymptomatic parents with peripheral blood samples. Surprisingly, we found that 46.01% of his father’s sperm cells had the same mutation. These results demonstrated that the proband inherited the ELANE mutation from his father, who had a normal neutrophil count but was germline mosaic. In this study, the highest repair efficiency of CRISPR/Cas9-mediated HDR for 293-ELANE is 4.43%. Conclusions: We identified a missense mutation (p.V83D) in ELANE causing SCN, the first report on paternal semen mosaicism of an ELANE mutation. Our study also paves the way for preimplantation genetic diagnosis (PGD) based on ELANE mutation prevention and clinical treatment of congenital disabilities.