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Abstract: SA-PO572

Detection of X-Linked Variations in SHROOM4 in Four Families With Syndromic Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)

Session Information

  • Genetic Diseases: Diagnosis
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic


  • Kolvenbach, Caroline Maria, Rheinische Friedrich-Wilhelms-Universitat Bonn, Bonn, Nordrhein-Westfalen, Germany
  • Felger, Tim, Rheinische Friedrich-Wilhelms-Universitat Bonn, Bonn, Nordrhein-Westfalen, Germany
  • Schierbaum, Luca M., Rheinische Friedrich-Wilhelms-Universitat Bonn, Bonn, Nordrhein-Westfalen, Germany
  • Thiffault, Isabelle, Children's Mercy Hospitals and Clinics, Kansas City, Missouri, United States
  • Zaniew, Marcin, Uniwersytet Zielonogorski, Zielona Gora, Lubuskie, Poland
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
  • Grote, Phillip, Institut fur Tumorbiologie und experimentelle Therapie, Frankfurt am Main, Hessen, Germany
  • Odermatt, Benjamin, Rheinische Friedrich-Wilhelms-Universitat Bonn, Bonn, Nordrhein-Westfalen, Germany
  • Reutter, Heiko M., Universitatsklinikum Erlangen, Erlangen, Bayern, Germany
  • Dworschak, Gabriel C., Rheinische Friedrich-Wilhelms-Universitat Bonn, Bonn, Nordrhein-Westfalen, Germany

SHROOM4 plays an important role in cytoskeletal modification and development of the early nervous system. Previously, single nucleotide variants (SNVs) or copy number variations (CNVs) in SHROOM4 were shown to cause the X-linked neurodevelopmental disorder Stocco dos Santos syndrome (MIM 300434). However, no congenital anomalies of the kidney and the urinary tract (CAKUT), the intestinal, or cardiovascular system have been described in Stocco dos Santos syndrome.


Here, we performed exome sequencing (ES) and CNV analyses to detect further variants, and expression studies and gene knockdown experiments in zebrafish to study the role of SHROOM4 during embryonic development.


In a family with two affected individuals with CAKUT, anorectal, cardiovascular, and central nervous system anomalies, we identified by ES a putative disease-causing SNV in SHROOM4 (c.940G>A; p.Glu314Lys). Analysis of 666 CAKUT ES samples revealed no further allele carriers. Through GeneMatcher, one family with a SNV (c.3942+1G>A; p.?) and two families with two different CNVs (chrX:g.49,369,600-50,447,320 and chrX:g.49,375,617-52,838,206) in SHROOM4 were contributed with a matching syndromic CAKUT phenotype. Upon embryonic mouse and zebrafish in situ mRNA expression studies we showed Shroom4 expression in the urinary tract, cloaca, heart, and cerebral central nervous system. Knockdown studies in zebrafish larvae using a splice blocking Morpholino revealed pronephric cysts, anomalies of the cloaca and the heart, decreased eye-to-head size ratio, and higher mortality compared to controls. These findings replicate the phenotypic spectrum of the affected individuals with genetic variations in SHROOM4 reported here. Co-injection of human wild-type SHROOM4 mRNA and Morpholino rescued the observed phenotypes.


The identified SNVs and CNVs in four families with syndromic CAKUT and embryonic mouse and zebrafish studies suggest functional deleteriousness of SHROOM4. We therefore propose that SHROOM4 plays an important role in the development of several principal organ structures.


  • Government Support – Non-U.S.