Mitochondrial DNA insert into CD40 ligand gene-associated X-linked hyper-IgM syndrome

Background: X-linked hyper-IgM (X-HIGM), which results from mutations in the CD4OLG gene located on chromosome Xq26.3, is the most common form of HIGM. To date, more than 130 variants of the CD40L gene have been reported. We described a patient with novel de novo nuclear mitochondria) DNA sequences (NUMTs) in the CD40LG gene that have resulted in X-HIGM. Methods: Whole-exome sequencing (WES) analysis was used to screen for causal variants in the genome, and the candidate breakpoint was confirmed by Sanger sequencing. Results: A new mutation of CD40LG, which deletes A at position 17 followed by a 147-nucleotide from mitochondrial DNA copies insertion in exon 1, was detected in a 20-month-old boy harbouring an X-HIGM combined with immunodeficiency syndrome. Conclusion: This is one of the few cases of a human genetic disease caused by nuclear mitochondrial DNA sequences (NUMTs). The presented data serve to demonstrate that de novo NUMT transfer of nucleic acid is a novel mechanism of X-HIGM.

Automated summary

A new mutation in the CD40LG gene was found in a X-HIGM patient, caused by de novo nuclear mitochondrial DNA sequences (NUMTs), highlighting a novel mechanism for X-HIGM.