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Understanding the Landscape of X-linked Variants Causing Intellectual Disability in Females Through Extreme X Chromosome Inactivation Skewing

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Abstract

Intellectual disability (ID) affects 30% more males than females. This sex bias can be attributed to the enrichment of genes on the X chromosome playing essential roles in the central nervous system and their hemizygous state on males. Moreover, as a result of X chromosome inactivation (XCI), most genes on one of the X chromosomes in female somatic cells are epigenetically silenced, so that females carrying X-linked variants are not expected to be so severely affected as males. Consequently, the knowledge about X-linked ID (XLID) in females is still scarce. Herein, we used extreme XCI skewing (≥ 90%) to predict X-linked variants in females with idiopathic ID. XCI profiles from 53 probands were estimated from blood and buccal mucosa through a methylation-sensitive AR/RP2 assay. DNA samples with extreme XCI skewing were then submitted to array-comparative genomic hybridization and whole-exome sequencing. Seven females (13.2%) exhibited extreme XCI skewing, a percentage significantly higher than expected for healthy females in our population. XLID-potentially related variants were identified in five patients with extreme XCI skewing, including one pathogenic rstructural rearrangement [der(X) chromosome from a t(X;2)] and four single nucleotide variants in NLGN4X, HDAC8, TAF1, and USP9X genes, two of which affecting XCI escape genes. XCI skewing showed to be an outstanding approach for the characterization of molecular mechanisms underlying XLID in females. Beyond expanding the spectrum of variants/phenotypes associated with ID, our results pointed to compensatory biological pathways underlying XCI and uncover new insights into the involvement of escape genes on XLID, impacting genetic counseling.

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Acknowledgments

The authors thank the studied families for their kind cooperation and Genome Facility Platform from the National Cancer Institute of Brazil.

Funding

This work was supported by funds from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Fundação de Amparo à Pesquisa do Estado de São Paulo (CEPID - FAPESP), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001, and Centro de Produção da Universidade do Estado do Rio de Janeiro (CEPUERJ).

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Authors and Affiliations

  1. Department of Genetics, Institute of Biology Roberto Alcantara Gomes, State University of Rio de Janeiro, Rua São Francisco Xavier, 524, PHLC – sala 501F, Maracanã, Rio de Janeiro, RJ, 20550-013, Brazil

    Evelyn Quintanilha Vianna, Rafael Mina Piergiorge, Andressa Pereira Gonçalves, Jussara Mendonça dos Santos, Veluma Calassara, Márcia Mattos Gonçalves Pimentel & Cíntia Barros Santos-Rebouças

  2. Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil

    Carla Rosenberg & Ana Cristina Victorino Krepischi

  3. Pedro Ernesto University Hospital, State University of Rio de Janeiro, Rio de Janeiro, Brazil

    Raquel Tavares Boy da Silva

  4. Gaffrée and Guinle University Hospital, Federal University of Rio de Janeiro State, Rio de Janeiro, Brazil

    Suely Rodrigues dos Santos

  5. Clinical Genetics Service, IPPMG, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

    Márcia Gonçalves Ribeiro

  6. Department of Biological Sciences, Minas Gerais State University, Belo Horizonte, Minas Gerais, Brazil

    Filipe Brum Machado

  7. Laboratory of Biotechnology, State University of Northern Rio de Janeiro Darcy Ribeiro, Rio de Janeiro, Brazil

    Enrique Medina-Acosta

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  1. Evelyn Quintanilha Vianna
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Contributions

Conception and design: C.B.S.R.

Acquisition of data: C.B.S.R, E.Q.V., R.M.P., A.P.G., J.M.S., V.C., A.C.V.K., C.R., F.B.M., E.M.A.

Clinical evaluation: R.T.B.S., S.R.S., M.G.R.

Analysis and interpretation: C.B.S.R, E.Q.V., R.M.P., A.C.V.K., C.R., M.M.G.P.

Manuscript drafting: C.B.S.R, E.Q.V., R.M.P, R.T.B.S., S.R.S., M.G.R.

Obtained funding: C.B.S.R, M.M.G.P., A.C.V.K., C.R.

Corresponding author

Correspondence to Cíntia Barros Santos-Rebouças.

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Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Web Resources

The URLs for data presented herein are as follows:

ClinVar, 2020, https://www.ncbi.nlm.nih.gov/clinvar/

Database of Genomic Variants - DGV, 2020, http://projects.tcag.ca/variation/

Decipher v9.28, 2020, https://decipher.sanger.ac.uk/

Ensembl Genome Browser, 2020, http://www.ensembl.org/index.html

ExAC Browser, 2020, http://exac.broadinstitute.org/

Geneimprint, 2020, http://www.geneimprint.com/site/genes-by-species

GnomAD, 2020, https://gnomad.broadinstitute.org/

Mutation Taster, 2020, http://www.mutationtaster.org

OMIM, 2020, http://www.omim.org/

Pfam 32.0 platform, 2020, http://pfam.sanger.ac.uk/

RefSeq, 2020, http://www.ncbi.nlm.nih.gov/RefSeq

RepeatMasker program, 2020, http://repeatmasker.genome.washington.edu

UCSC Genome Browser (Hg19), 2020, http://genome.ucsc.edu

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Electronic Supplementary Material

ESM 1

(PPTX 24481 kb)

Supplemental Table 2

In silico pathogenicity predictions and conservation data for the sequence variants found in females with extreme XCI skewing subjected to WES (excel file). (XLSX 10 kb)

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Vianna, E.Q., Piergiorge, R.M., Gonçalves, A.P. et al. Understanding the Landscape of X-linked Variants Causing Intellectual Disability in Females Through Extreme X Chromosome Inactivation Skewing. Mol Neurobiol 57, 3671–3684 (2020). https://doi.org/10.1007/s12035-020-01981-8

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