A Novel Intronic Deletion Causing “Deficiency in ELF4, X-Linked”

Deficiency in ELF4, X-linked (DEX) is a monogenic autoinflammatory disorder caused by loss-of-function (LOF) mutations in the ETS transcription factor ELF4. This rare disorder primarily affects young, male patients due to its X-linked expression. To date, the genetic aberrations causing disease in these patients have been (1) nonsense mutations leading to premature stop codons and a loss of ELF4 protein expression, and (2) missense mutations abrogating DNA-binding activity of ELF4. Here, we describe the case of an 11-year-old male harboring a de novo four-nucleotide deletion in the splice donor region following exon 5 (NM_001421.3:c.532+3_532+6del), which was discovered via trio whole-exome sequencing. The patient presented with characteristic DEX symptoms, including periodic fevers, oral ulcers, arthritis, and Crohn’s disease. The mutation was confirmed at the DNA level via nanopore sequencing of the genomic region surrounding exon 5 of ELF4, and subsequent analyses of patient-derived peripheral blood mononuclear cells (PBMCs) revealed a loss of ELF4 protein expression, confirming that this patient suffers from DEX. Predictions of splicing outcomes caused by this variant suggested the possibility of partial intronic retention causing a frameshift and ultimately leading to a premature stop codon. RNA sequencing on patient-derived CD4+ and CD8+ T cell blasts confirmed the predicted splicing outcome, as well as a significant decrease in ELF4 transcript expression, likely due to nonsense-mediated decay. Here, we describe the first DEX patient with a de novo deletion in an intronic region of ELF4 that leads to a loss of ELF4 protein expression and autoinflammatory disease.