{
  "abstract": "Background Bartter syndrome (BS) is a salt-losing renal tubulopathy classically characterised by hypokalaemic metabolic alkalosis and hyperreninaemic hyperaldosteronism.Methods 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.Results 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 ( EGFR) 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 EGFR. Immunofluorescence analysis of the proband’s skin revealed a reduced EGFR protein level, rather than a complete absence, supporting a hypomorphic effect and likely explaining compatibility with survival into adolescence. Whereas previously reported EGFR 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.Conclusion These findings support an association between a syndromic Bartter-like salt-losing tubulopathy with epithelial autoinflammation and a homozygous splice-altering EGFR pathogenic variant, thereby expanding the phenotypic spectrum of EGFR-associated disorders.",
  "authors": [
    {
      "affiliations": [
        "Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Department of Pathology, Cytogenetics Laboratory, City of Hope National Medical Center, Duarte, CA, USA"
      ],
      "name": "Leila Youssefian"
    },
    {
      "affiliations": [
        "Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran"
      ],
      "name": "Sajjad Biglari"
    },
    {
      "affiliations": [
        "Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Department of Computer Science and Engineering Technology, University of Maryland Eastern Shore, Princess Anne, Maryland, USA",
        "Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA"
      ],
      "name": "Fatemeh Vahidnezhad"
    },
    {
      "affiliations": [
        "Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA",
        "Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA"
      ],
      "name": "Amir Hossein Saeidian"
    },
    {
      "affiliations": [
        "Department of Dermatology, Razi Hospital, Tehran, Iran"
      ],
      "name": "Rana Samii"
    },
    {
      "affiliations": [
        "Department of Neurology, Barrow Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ, USA",
        "Pediatric Neurology Division, Children's Medical Center, Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran"
      ],
      "name": "Ali Reza Tavasoli"
    },
    {
      "affiliations": [
        "Department of Obstetrics and Gynecology, Mashhad University of Medical Sciences, Mashhad, Iran"
      ],
      "name": "Elnaz Kalamati"
    },
    {
      "affiliations": [
        "Children's Medical Center, Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran"
      ],
      "name": "Soheila Sotoudeh"
    },
    {
      "affiliations": [
        "Pediatric Chronic Kidney Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran",
        "Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran"
      ],
      "name": "Behnaz Bazargani"
    },
    {
      "affiliations": [
        "Children's Medical Center, Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran"
      ],
      "name": "Sareh Hosseinpour"
    },
    {
      "affiliations": [
        "Children's Medical Center, Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran"
      ],
      "name": "Neda Pak"
    },
    {
      "affiliations": [
        "Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran"
      ],
      "name": "Mohammad Amin Tabatabaiefar"
    },
    {
      "affiliations": [
        "Children's Medical Center, Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran"
      ],
      "name": "Elaheh Malekan Rad"
    },
    {
      "affiliations": [
        "Department of Allergy and Clinical Immunology, Shahid Beheshti University of Medical Sciences, Tehran, Iran"
      ],
      "name": "Mehrnaz Mesdaghi"
    },
    {
      "affiliations": [
        "Department of Dermatology, Razi Hospital, Tehran, Iran",
        "Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran"
      ],
      "name": "Zahra Saffarian"
    },
    {
      "affiliations": [
        "Department of Cardiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran"
      ],
      "name": "Fatemeh Saffarian"
    },
    {
      "affiliations": [
        "Viapath, St Thomas’ Hospital, London, UK"
      ],
      "name": "Alyson Guy"
    },
    {
      "affiliations": [
        "Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran"
      ],
      "name": "Ariana Kariminejad"
    },
    {
      "affiliations": [
        "St. John's Institute of Dermatology, King’s College London, London, UK"
      ],
      "name": "John McGrath"
    },
    {
      "affiliations": [
        "Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA"
      ],
      "name": "Johann E Gudjonsson"
    },
    {
      "affiliations": [
        "Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA",
        "Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "Hakon Hakonarson"
    },
    {
      "affiliations": [
        "Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA",
        "Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA",
        "Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"
      ],
      "name": "Hassan Vahidnezhad"
    }
  ],
  "title": "Longest surviving patient with a homozygous splice-altering EGFR pathogenic variant presenting with skin autoinflammation and a Bartter-like salt-losing tubulopathy",
  "uid": "ae868279-8579-58fa-aa7f-0badcb41ae35"
}