1. Academic Validation
  2. Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency

Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency

  • Hum Genet. 2017 Apr;136(4):399-408. doi: 10.1007/s00439-017-1765-z.
Joshi Stephen 1 Thierry Vilboux 1 2 Luhe Mian 3 Chulaluck Kuptanon 1 Courtney M Sinclair 1 Deniz Yildirimli 1 Dawn M Maynard 1 Joy Bryant 1 Roxanne Fischer 1 Meghana Vemulapalli 4 James C Mullikin 4 NISC Comparative Sequencing Program Marjan Huizing 1 William A Gahl 1 3 5 May Christine V Malicdan 6 7 8 Meral Gunay-Aygun 9 10 11
Affiliations

Affiliations

  • 1 Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
  • 2 Division of Medical Genomics, Inova Translational Medicine Institute, Falls Church, VA, USA.
  • 3 NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
  • 4 NIH Intramural Sequencing Center (NISC), National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
  • 5 Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
  • 6 Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. malicdanm@mail.nih.gov.
  • 7 NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA. malicdanm@mail.nih.gov.
  • 8 Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. malicdanm@mail.nih.gov.
  • 9 Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. mgaygun@mail.nih.gov.
  • 10 Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. mgaygun@mail.nih.gov.
  • 11 Department of Pediatrics and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. mgaygun@mail.nih.gov.
Abstract

Joubert syndrome and related disorders (JSRD) are a heterogeneous group of ciliopathies defined based on the mid-hindbrain abnormalities that result in the characteristic "molar tooth sign" on brain imaging. The core clinical findings of JSRD are hypotonia, developmental delay, abnormal eye movements and breathing abnormalities. To date, more than 30 JSRD genes that encode proteins important for structure and/or function of cilia have been identified. Here, we present 2 siblings with Joubert syndrome associated with growth hormone deficiency. Whole exome Sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C). The intronic mutation alters normal splicing by activating a cryptic acceptor splice site in exon 16. The novel acceptor site skips nine nucleotides, deleting three Amino acids from the protein coding frame. KIAA0753 (OFIP) is a centrosome and pericentriolar satellite protein, previously not known to cause Joubert syndrome. We present comprehensive clinical descriptions of the Joubert syndrome patients as well as the cellular phenotype of defective ciliogenesis in the patients' fibroblasts.

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