Introduction: Bartter syndrome (BS) manifests as hypokalemic and hypochloremic metabolic alkalosis and hyperreninemic hyperaldosteronism. Loss-of-function (LoF) mutations in any of seven genes cause different subtypes of BS.
Case Description: We sought the genetic cause of BS in a 17-year-old patient who presented with progressive nephrocalcinosis, hypercalciuria, polyuria, metabolic alkalosis, hypokalemia, significantly high urine chloride, failure-to-thrive, hypergammaglobulinemia, abnormal cerebral white matter signal changes, autoinflammation, and moderate intellectual disability. No mutations were identified in previously BS-associated genes in this patient with consanguineous parents, and all seven genes resided outside of genomic regions of homozygosity (ROH). Instead, whole-exome sequencing and homozygosity mapping identified a homozygous intronic mutation, c.2702-2A >G, in the epidermal growth factor receptor (EGFR) gene within an ROH of ~28 Mb in chromosome 7p. Examination of the patient's RNA by RNA-Seq and RT-PCR confirmed the pathogenicity of this variant, causing aberrant splicing resulting in an in-frame retention of 27 nucleotides of intron 22 of EGFR. Immunofluorescence of proband's skin, with a monoclonal antibody, revealed reduced protein level of EGFR, instead of complete protein absence, presumably justifying the life compatibility of this mutation.
Discussion: Previously, three loss-of-function EGFR mutations have been reported in patients with neonatal lethal inflammatory skin lesions and bowel disease. Thus, these observations provide an association of an autosomal recessive BS with hypomorphic EGFR mutation, expanding the phenotypic spectrum of the EGFR-associated disorders.
.jpg)