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Homozygosity for the c.428delG variant in KIAA0586 in a healthy individual: implications for molecular testing in patients with Joubert syndrome
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  • Published on:
    Additional evidence for the c.428del variant in KIAA0586 as hypomorphic allele that is only disease causing in compound heterozygosity with strong mutations.
    • Matias Wagner, Geneticist Institute of Human Genetics, Technical University Munich, Munich, Germany
    • Other Contributors:
      • Dominik S Westphal, Geneticist
      • Iris Hannibal, Pediatrician
      • Johannes A Mayr, Biologist
      • Tim M Strom, Bioinformatician
      • Thomas Meitinger, Geneticist
      • Holger Prokisch, Biologist
      • Saskia B Wortmann, Pediatrician

    Matias Wagner1,2,3, Dominik S Westphal1,2, Iris Hannibal4, Johannes A. Mayr5, Tim M. Strom1,2, Thomas Meitinger1,2, Holger Prokisch1,2, Saskia B. Wortmann1,2,5
    1. Institute of Human Genetics, Technical University Munich, Munich, Germany;
    2. Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany;
    3. Institute of Neurogenomics, Helmholtz Zentrum Munich, Neuherberg, Germany
    4. Dr. von Hauner Children’s Hospital, Ludwig-Maximilians University, Munich, Germany
    5. Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria

    Biallelic mutations in KIAA0586 have been related to Joubert syndrome (JBTS) 23 and as the most frequent disease causing variant c.428del (p.Arg143Lysfs*4) was identified.1 However, the allele frequency of 0.003117 and two homozygotes in the gnomAD dataset as well as additional reports of healthy carriers have questioned the variant’s pathogenicity.2, 3 Pauli et al. have recently hypothesized that c.428del is a hypomorphic allele which is only causing JBTS in compound heterozygosity with other mutations.

    In 15,000 in-house exome data sets, we have identified three individuals harboring c.428del in a homozygous state. In two, we identified other variants sufficiently explaining the phenotype: In a 6 year old girl with global developmental delay and progressive myoclonic astatic epilepsy, we identified a de novo variant c.2683del, p.Ser895Le...

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    Conflict of Interest:
    None declared.