Abstract
Yin and Yang 1 gene (YY1; MIM#600,013) is recognized as a dual transcriptional activating and repressing factor, RNA-binding protein, and 3D chromatin regulator, with multi roles in neurodevelopmental and maintenance pathways. YY1 haploinsufficiency caused either by heterozygous sequence variants or deletions involving the whole gene has been recently associated with Gabriele-de Vries syndrome (GADEVS), a rare congenital autosomal dominant condition, leading to intellectual disability (ID) and multiple physical/behavioural abnormalities. Herein, we describe clinical and molecular findings from a Brazilian female harbouring a de novo missense pathogenic variant in YY1 gene (NM_003403.5:c.1106A > G; p.Asn369Ser) found by whole exome sequencing with potential implications for protein structure and function. Undescribed or uncommon clinical features in this patient included non-febrile seizures, severe scoliosis, hearing impairment, and chorioretinitis. Further bioinformatics analyses using YY1-other protein interaction networks reinforced the involvement of YY1 interactors in such phenotypes, in exception of chorioretinitis. Moreover, X-chromosome inactivation (XCI) skewing was evidenced in the patient and attributed to the haploinsufficiency of YY1, which direct and indirectly interacts with numerous XCI key regulators. Besides expanding the mutational and phenotype spectrum of GADEVS, our results highlight the role of YY1 as an essential autosomal regulator of XCI epigenetic process.
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Data availability
The variant described in this study is available at ClinVar repository (accession number SCV002505686).
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Web Resources
The URLs for data presented herein are as follows:
ClinVar (2022) https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV001321254.1. Accessed 24 March 2022
DisGeNET (2022) https://www.disgenet.org/
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GeneCards (2022) https://www.genecards.org/
Mutation Taster (2021) http://www.mutationtaster.org
OMIM (2022) http://www.omim.org/
Pfam 32.0 platform (2022) http://pfam.sanger.ac.uk/
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Acknowledgements
The authors thank the family members for their kind cooperation. This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq/Brazil; 302263/2019-5), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ/Brazil; E-26/010.001888/2019), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/BRAZIL; Finance Code 001) and Centro de Produção da Universidade do Estado do Rio de Janeiro (CEPUERJ).
Funding
This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq/Brazil; 302263/2019–5), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ/Brazil; E-26/010.001888/2019), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/BRAZIL; Finance Code 001), Departamento de Inovação (InovUerj/UERJ/Brazil), and Centro de Produção da Universidade do Estado do Rio de Janeiro (CEPUERJ/Brazil).
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Cíntia Barros Santos-Rebouças contributed to the study conception and design. Data collection were performed by Cíntia Barros Santos-Rebouças, Suely Rodrigues dos Santos, Rafael Mina Piergiorge, Jady Rocha, Bianca Barbosa Abdala, Andressa Pereira Gonçalves, and Márcia Mattos Gonçalves Pimentel. Clinical evaluation was done by Suely Rodrigues dos Santos. Analysis and interpretation of data were performed by Cíntia Barros Santos-Rebouças, Suely Rodrigues dos Santos, and Rafael Mina Piergiorge. The first draft of the manuscript was written by Cíntia Barros Santos-Rebouças, Suely Rodrigues dos Santos, and Rafael Mina Piergiorge. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding was obtained by Cíntia Barros Santos-Rebouças.
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dos Santos, S.R., Piergiorge, R.M., Rocha, J. et al. A de novo YY1 missense variant expanding the Gabriele-de Vries syndrome phenotype and affecting X-chromosome inactivation. Metab Brain Dis 37, 2431–2440 (2022). https://doi.org/10.1007/s11011-022-01024-2
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DOI: https://doi.org/10.1007/s11011-022-01024-2