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Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia

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  3. Contingent first-trimester screening for aneuploidies with cell-free DNA in a Danish clinical setting

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  • Claire Guissart
  • Xenia Latypova
  • Paul Rollier
  • Tahir N Khan
  • Hannah Stamberger
  • Kirsty McWalter
  • Megan T Cho
  • Susanne Kjaergaard
  • Sarah Weckhuysen
  • Gaetan Lesca
  • Thomas Besnard
  • Katrin Õunap
  • Lynn Schema
  • Andreas G Chiocchetti
  • Marie McDonald
  • Julitta de Bellescize
  • Marie Vincent
  • Hilde Van Esch
  • Shannon Sattler
  • Irman Forghani
  • Isabelle Thiffault
  • Christine M Freitag
  • Deborah Sara Barbouth
  • Maxime Cadieux-Dion
  • Rebecca Willaert
  • Maria J Guillen Sacoto
  • Nicole P Safina
  • Christèle Dubourg
  • Lauren Grote
  • Wilfrid Carré
  • Carol Saunders
  • Sander Pajusalu
  • Emily Farrow
  • Anne Boland
  • Danielle Hays Karlowicz
  • Jean-François Deleuze
  • Monica H Wojcik
  • Rena Pressman
  • Bertrand Isidor
  • Annick Vogels
  • Wim Van Paesschen
  • Lihadh Al-Gazali
  • Aisha Mohamed Al Shamsi
  • Mireille Claustres
  • Aurora Pujol
  • Stephan J Sanders
  • François Rivier
  • Nicolas Leboucq
  • Benjamin Cogné
  • Souphatta Sasorith
  • Damien Sanlaville
  • Kyle Retterer
  • Sylvie Odent
  • Nicholas Katsanis
  • Stéphane Bézieau
  • Michel Koenig
  • Erica E Davis
  • Laurent Pasquier
  • Sébastien Küry
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RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.

Original languageEnglish
JournalAmerican Journal of Human Genetics
Volume102
Issue number5
Pages (from-to)744-759
Number of pages16
ISSN0002-9297
DOIs
Publication statusPublished - 3 May 2018

    Research areas

  • Adolescent, Adult, Aged, 80 and over, Alleles, Animals, Autistic Disorder/complications, Brain/pathology, Cerebellar Ataxia/complications, Child, Child, Preschool, DNA Copy Number Variations/genetics, Disease Models, Animal, Female, Genes, Dominant, Genetic Complementation Test, Humans, Intellectual Disability/complications, Larva/genetics, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Missense/genetics, Nuclear Receptor Subfamily 1, Group F, Member 1/genetics, Purkinje Cells/metabolism, Syndrome, Zebrafish/genetics

ID: 56215910