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

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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)1157-1169
Number of pages13
JournalAmerican journal of human genetics
Issue number6
StatePublished - Dec 3 2020


  • RLIM
  • Tonne-Kalscheuer syndrome
  • Xq13
  • autism
  • chromosomal duplication
  • chromosomal microarray
  • dosage sensitive gene
  • intellectual disability
  • whole genome sequencing

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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