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

Adolescent Australia Child Child, Preschool Chromosome Duplication Face Female Gene Dosage Hemizygote Heterozygote Humans Intellectual Disability / genetics Male Middle Aged Monocarboxylic Acid Transporters / genetics Mothers Mutation, Missense Nerve Tissue Proteins / genetics Pedigree Phenotype Symporters / genetics Ubiquitin-Protein Ligases / genetics X Chromosome Inactivation Young Adult

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

Journal

American journal of human genetics

ISSN: 1537-6605

Titre abrégé: Am J Hum Genet

Pays: United States

ID NLM: 0370475

Informations de publication

Date de publication:
03 12 2020

Historique:

received: 22 05 2020

accepted: 13 10 2020

pubmed: 8 11 2020

medline: 13 1 2021

entrez: 7 11 2020

Statut: ppublish

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.

Identifiants

DOI: 10.1016/j.ajhg.2020.10.005 PMID: 33159883 PMC: PMC7820564

pubmed: 33159883

pii: S0002-9297(20)30363-3

doi: 10.1016/j.ajhg.2020.10.005

pmc: PMC7820564

pii:

doi:

Substances chimiques

Monocarboxylic Acid Transporters 0

NEXMIF protein, human 0

Nerve Tissue Proteins 0

SLC16A2 protein, human 0

Symporters 0

RLIM protein, human EC 2.3.2.27

Ubiquitin-Protein Ligases EC 2.3.2.27

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1157-1169

Subventions

Organisme : Wellcome Trust

Pays : United Kingdom

Informations de copyright

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