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<p>Oro-Facial-Digital Syndrome (OFDS) and Joubert syndrome are ciliary disorders. Fifteen individuals of consanguineous Bedouin kindred presented with global developmental delay with no speech, and a clear OFDS phenotype, combined with Joubert syndrome, with MRI showing hypoplastic corpus callosum and molar tooth sign. Renal and liver function tests and ultrasound were unremarkable. Within a 0.5 Mb disease-associated locus (LOD score 6.2), whole genome sequencing identified a single variant: <i>CEP83</i> NG_051825.2:g.5774dupG, (NM_016122.3):c.-278dupG. Patient fibroblasts showed aberrantly long cilia, and alternative splicing of <i>CEP83</i> 5’UTR, skipping most of exon 1 of the canonical transcript, and frameshift, abrogating CEP83 mRNA and protein expression. CEP83 acts in primary cilium assembly. <i>CEP83</i> biallelic missense or in-frame deletions, with presumed residual function, were previously associated with early-onset nephronophthisis culminating in end-stage renal disease. We now demonstrate that a biallelic complete loss-of-function <i>CEP83</i> variant culminates in elongated primary cilia, causing OFDS with Joubert-like features without evident renal involvement.</p>

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A ciliopathy combining Joubert syndrome and Oro-Facial-Digital syndrome caused by bi-allelic 5’-UTR loss-of-function CEP83 variant

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月10日

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  • Matan M. Jean,
  • Anan Yunis,
  • Tzofit Elbaz-Biton,
  • Vadim Dolgin,
  • Ginat Narkis,
  • Analia Michaelovsky,
  • Marina Eskin-Schwartz,
  • Alexandra A. Tsitrina,
  • Nadav Agam,
  • Tomer Poleg,
  • Amit Safran,
  • Ofek Freund,
  • Noam Hadar,
  • Dan Levy,
  • Ilan Shelef,
  • Khalil El Amour,
  • Hagit Flusser,
  • Ohad S. Birk

摘要

Oro-Facial-Digital Syndrome (OFDS) and Joubert syndrome are ciliary disorders. Fifteen individuals of consanguineous Bedouin kindred presented with global developmental delay with no speech, and a clear OFDS phenotype, combined with Joubert syndrome, with MRI showing hypoplastic corpus callosum and molar tooth sign. Renal and liver function tests and ultrasound were unremarkable. Within a 0.5 Mb disease-associated locus (LOD score 6.2), whole genome sequencing identified a single variant: CEP83 NG_051825.2:g.5774dupG, (NM_016122.3):c.-278dupG. Patient fibroblasts showed aberrantly long cilia, and alternative splicing of CEP83 5’UTR, skipping most of exon 1 of the canonical transcript, and frameshift, abrogating CEP83 mRNA and protein expression. CEP83 acts in primary cilium assembly. CEP83 biallelic missense or in-frame deletions, with presumed residual function, were previously associated with early-onset nephronophthisis culminating in end-stage renal disease. We now demonstrate that a biallelic complete loss-of-function CEP83 variant culminates in elongated primary cilia, causing OFDS with Joubert-like features without evident renal involvement.