Longest surviving patient with a homozygous splice-altering <i>EGFR</i> pathogenic variant presenting with skin autoinflammation and a Bartter-like salt-losing tubulopathy.

Abstract

Bartter syndrome (BS) is a salt-losing renal tubulopathy classically characterised by hypokalaemic metabolic alkalosis and hyperreninaemic hyperaldosteronism. We investigated the genetic cause of a Bartter-like phenotype in an adolescent patient with progressive nephrocalcinosis, hypercalciuria, polyuria, metabolic alkalosis, hypokalaemia, significantly elevated urine chloride, failure to thrive, and a salt-losing tubulopathy. Additionally, the patient presented with hypergammaglobulinaemia, abnormal cerebral white matter signal changes, skin autoinflammation, and mild intellectual disability. No pathogenic variants were detected in known BS-related genes, and all recessive BS genes were outside regions of homozygosity (ROH) in this patient from a consanguineous family. Instead, exome sequencing and homozygosity mapping identified a homozygous splicing variant, c.2702-2A>G, in the epidermal growth factor receptor (<i>EGFR</i>) gene within an ~28 Mb ROH on chromosome 7p. RNA-Seq and RT-PCR analysis of the patient's RNA confirmed the pathogenicity of this variant, demonstrating aberrant splicing resulting in an in-frame retention of 27 nucleotides from intron 22 of <i>EGFR</i>. Immunofluorescence analysis of the proband's skin revealed a reduced <i>EGFR</i> protein level, rather than a complete absence, supporting a hypomorphic effect and likely explaining compatibility with survival into adolescence. Whereas previously reported <i>EGFR</i> variants have been associated with severe neonatal epithelial inflammation, bowel disease, and early mortality, our findings demonstrate that a hypomorphic variant can be compatible with survival into the second decade of life. These findings support an association between a syndromic Bartter-like salt-losing tubulopathy with epithelial autoinflammation and a homozygous splice-altering <i>EGFR</i> pathogenic variant, thereby expanding the phenotypic spectrum of <i>EGFR</i>-associated disorders.