Paternal germline mosaicism of a missense mutation in ELANE in a Chinese
male with severe congenital neutropenia
Abstract
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.