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

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 co...

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Published in:	American journal of human genetics Vol. 107; no. 6; pp. 1157 - 1169
Main Authors:	Palmer, Elizabeth E., Carroll, Renee, Shaw, Marie, Kumar, Raman, Minoche, Andre E., Leffler, Melanie, Murray, Lucinda, Macintosh, Rebecca, Wright, Dale, Troedson, Chris, McKenzie, Fiona, Townshend, Sharron, Ward, Michelle, Nawaz, Urwah, Ravine, Anja, Runke, Cassandra K., Thorland, Erik C., Hummel, Marybeth, Foulds, Nicola, Pichon, Olivier, Isidor, Bertrand, Le Caignec, Cédric, Demeer, Bénédicte, Andrieux, Joris, Albarazi, Salam Hadah, Bye, Ann, Sachdev, Rani, Kirk, Edwin P., Cowley, Mark J., Field, Mike, Gecz, Jozef
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 03-12-2020 Elsevier (Cell Press) Elsevier
Subjects:	Adolescent Australia autism Child Child, Preschool chromosomal duplication chromosomal microarray Chromosome Duplication dosage sensitive gene Face Female Gene Dosage Hemizygote Heterozygote Humans intellectual disability Intellectual Disability - genetics Life Sciences Male Middle Aged Monocarboxylic Acid Transporters - genetics Mothers Mutation, Missense Nerve Tissue Proteins - genetics NEXMIF Pedigree Phenotype RLIM Symporters - genetics Tonne-Kalscheuer syndrome Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism whole genome sequencing X Chromosome Inactivation Xq13 Young Adult Australia whole genome sequencing Xq13 chromosomal microarray dosage sensitive gene NEXMIF RLIM Tonne-Kalscheuer syndrome chromosomal duplication intellectual disability autism
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC7820564 These authors contributed equally to this work
ISSN:	0002-9297 1537-6605 1537-6605
DOI:	10.1016/j.ajhg.2020.10.005