RLIM Is a Candidate Dosage-Sensitive Gene for Individuals with Varying Duplications of Xq13, Intellectual Disability, and Distinct Facial Features - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue American Journal of Human Genetics Année : 2020

RLIM Is a Candidate Dosage-Sensitive Gene for Individuals with Varying Duplications of Xq13, Intellectual Disability, and Distinct Facial Features

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Elizabeth E. Palmer
  • Fonction : Auteur
Renee Carroll
  • Fonction : Auteur
Marie Shaw
  • Fonction : Auteur
Raman Kumar
  • Fonction : Auteur
Andre E. Minoche
  • Fonction : Auteur
Melanie Leffler
  • Fonction : Auteur
Lucinda Murray
  • Fonction : Auteur
Rebecca Macintosh
  • Fonction : Auteur
Dale Wright
  • Fonction : Auteur
Chris Troedson
  • Fonction : Auteur
Fiona Mckenzie
  • Fonction : Auteur
Sharron Townshend
  • Fonction : Auteur
Michelle Ward
  • Fonction : Auteur
Urwah Nawaz
  • Fonction : Auteur
Anja Ravine
  • Fonction : Auteur
Cassandra K. Runke
  • Fonction : Auteur
Erik C. Thorland
  • Fonction : Auteur
Marybeth Hummel
  • Fonction : Auteur
Nicola Foulds
  • Fonction : Auteur
Olivier Pichon
  • Fonction : Auteur
Bertrand Isidor
  • Fonction : Auteur
Cedric Le Caignec
  • Fonction : Auteur
Joris Andrieux
  • Fonction : Auteur
Salam Hadah Albarazi
  • Fonction : Auteur
Ann Bye
  • Fonction : Auteur
Rani Sachdev
  • Fonction : Auteur
Edwin P. Kirk
  • Fonction : Auteur
Mark J. Cowley
  • Fonction : Auteur
Mike Field
  • Fonction : Auteur
Jozef Gecz

Résumé

Interpretation of the significance of maternally inherited X chromosome variants in males with neurocognitive phenotypes continues to present a challenge to clinical geneticists and diagnostic laboratories. Here we report 14 males from 9 families with duplications at the Xq13.2-q13.3 locus with a common facial phenotype, intellectual disability (ID), distinctive behavioral features, and a seizure disorder in two cases. All tested carrier mothers had normal intelligence. The duplication arose de novo in three mothers where grandparental testing was possible. In one family the duplication segregated with ID across three generations. RLIM is the only gene common to our duplications. However, flanking genes duplicated in some but not all the affected individuals included the brain-expressed genes NEXMIF, SLC16A2, and the long non-coding RNA gene FTX. The contribution of the RLIM-flanking genes to the phenotypes of individuals with different size duplications has not been fully resolved. Missense variants in RLIM have recently been identified to cause X-linked ID in males, with heterozygous females typically having normal intelligence and highly skewed X chromosome inactivation. We detected consistent and significant increase of RLIM mRNA and protein levels in cells derived from seven affected males from five families with the duplication. Subsequent analysis of MDM2, one of the targets of the RLIM E3 ligase activity, showed consistent downregulation in cells from the affected males. All the carrier mothers displayed normal RLIM mRNA levels and had highly skewed X chromosome inactivation. We propose that duplications at Xq13.2-13.3 including RLIM cause a recognizable but mild neurocognitive phenotype in hemizygous males.

Dates et versions

hal-03600548 , version 1 (07-03-2022)

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Citer

Elizabeth E. Palmer, Renee Carroll, Marie Shaw, Raman Kumar, Andre E. Minoche, et al.. RLIM Is a Candidate Dosage-Sensitive Gene for Individuals with Varying Duplications of Xq13, Intellectual Disability, and Distinct Facial Features. American Journal of Human Genetics, 2020, 107 (6), pp.1157-1169. ⟨10.1016/j.ajhg.2020.10.005⟩. ⟨hal-03600548⟩

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