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Expanding the genetics and phenotypic spectrum of Lysine-specific demethylase 5C (KDM5C): a report of 13 novel variants

Abstract

Lysine-specific demethylase 5C (KDM5C) has been identified as an important chromatin remodeling gene, contributing to X-linked neurodevelopmental disorders (NDDs). The KDM5C gene, located in the Xp22 chromosomal region, encodes the H3K4me3-me2 eraser involved in neuronal plasticity and dendritic growth. Here we report 30 individuals carrying 13 novel and one previously identified KDM5C variants. Our cohort includes the first reported case of somatic mosaicism in a male carrying a KDM5C nucleotide substitution, and a dual molecular finding in a female carrying a homozygous truncating FUCA1 alteration together with a de novo KDM5C variant. With the use of next generation sequencing strategies, we detected 1 frameshift, 1 stop codon, 2 splice-site and 10 missense variants, which pathogenic role was carefully investigated by a thorough bioinformatic analysis. The pattern of X-chromosome inactivation was found to have an impact on KDM5C phenotypic expression in females of our cohort. The affected individuals of our case series manifested a neurodevelopmental condition characterized by psychomotor delay, intellectual disability with speech disorders, and behavioral features with particular disturbed sleep pattern; other observed clinical manifestations were short stature, obesity and hypertrichosis. Collectively, these findings expand the current knowledge about the pathogenic mechanisms leading to dysfunction of this important chromatin remodeling gene and contribute to a refinement of the KDM5C phenotypic spectrum.

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Fig. 1: Pedigrees of the 14 reported families.
Fig. 2: Schematic representation of the KDM5C gene organization, protein domains, and localization of the fourteen variants described in this study.
Fig. 3: Structural effect of KDM5C missense variants mapping in structural domains.

Data availability

All data generated or analysed during this study are included in this published article and its Supplementary Information files. Genetic variants reported in this study have been submitted to the “Global Variome shared LOVD” and they can be accessed using the url databases.lovd.nl/shared/genes/KDM5C. (Individual IDs: 405782, 405784, 405804, 405805, 405807, 408280, 408281, 408282, 408285, 408297, 408298, 408300, 408317, 408318, 408319, 408320).

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Acknowledgements

We would like to thank all the families involved in this study for their generous participation. We are grateful to “SPECIALmente Noi Onlus Foundation” for promoting research in epilepsy and autism spectrum disorder (ASD). We also thank Francesco Benedicenti (Department of Pediatrics, Regional Hospital of Bolzano, Bolzano, Italy), Vincenzo Nigro (Department of Precision Medicine, University “Luigi Vanvitelli”, Naples, Italy; Telethon Institute of Genetics and Medicine TIGEM, Pozzuoli, Italy) and Tommaso Pippucci (University of Bologna, Bologna, Italy) for their generous collaboration in recruiting KDM5C cases. This study makes use of DECIPHER (http://www.deciphergenomics.org), which is funded by Wellcome. AM, AT, CC, SD and EK are members of the European Reference Network for Rare malformation syndromes, intellectual and other neurodevelopmental disorders (ERN-ITHACA; https://ern-ithaca.eu/); LL is member of the European Reference Network for Rare and Complex Epilepsies (ERN-EPICARE; https://epi-care.eu/).

Funding

This work was supported by Italian Ministry of Economic Development (Grant F/050011/02/X32 to MGM); Italian Ministry of Health Young Investigator (Grant GR-2011-02347754 to EL); Fondazione Pierfranco e Luisa Mariani (Grant CM22 to CC); Polish National Science Center (Grant 2012/07/B/NZ4/01764); Telethon Foundation, Telethon Undiagnosed Diseases Program (Grant GSP15001) and Maria Rosaria Maglione Onlus Foundation (Grant MRM#2020 to DD).

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AM, MGM, MCA and EL conceived, wrote, and reviewed the work; EL, MCA, SRN and MG performed experiments, analysed and interpreted the data; EL and MCA designed the computational framework and curated collected data; EB, RP (Roberta Polli), MCA, and EL carried out the NGS methodological set-up; DD, LV, MM, LL, RD, SD, CC, SE, VL, AT, DB, FL, GB, SP, FS, RP, E.K., MC, SRN, provided clinical data. All authors revised and approved the final version of the paper.

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Correspondence to Maria Giuseppina Miano or Alessandra Murgia.

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According to approved protocols of each referring clinical center, written informed consent was obtained from the probands or their legal representatives for specimen collection and genetic analysis. All individuals recruited provided informed consent for their participation in the study and publication of relevant findings.

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Leonardi, E., Aspromonte, M.C., Drongitis, D. et al. Expanding the genetics and phenotypic spectrum of Lysine-specific demethylase 5C (KDM5C): a report of 13 novel variants. Eur J Hum Genet 31, 202–215 (2023). https://doi.org/10.1038/s41431-022-01233-4

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