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

Autor: Leonardi, Emanuela, Aspromonte, Maria Cristina, Drongitis, Denise, Bettella, Elisa, Verrillo, Lucia, Polli, Roberta, McEntagart, Meriel, Licchetta, Laura, Dilena, Robertino, D’Arrigo, Stefano, Ciaccio, Claudia, Esposito, Silvia, Leuzzi, Vincenzo, Torella, Annalaura, Baldo, Demetrio, Lonardo, Fortunato, Bonato, Giulia, Pellegrin, Serena, Stanzial, Franco, Posmyk, Renata, Kaczorowska, Ewa, Carecchio, Miryam, Gos, Monika, Rzońca-Niewczas, Sylwia, Miano, Maria Giuseppina, Murgia, Alessandra
Zdroj: European Journal of Human Genetics: EJHG; February 2023, Vol. 31 Issue: 2 p202-215, 14p
Abstrakt: Lysine-specific demethylase 5C (KDM5C)has been identified as an important chromatin remodeling gene, contributing to X-linked neurodevelopmental disorders (NDDs). The KDM5Cgene, 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 KDM5Cvariants. Our cohort includes the first reported case of somatic mosaicism in a male carrying a KDM5Cnucleotide substitution, and a dual molecular finding in a female carrying a homozygous truncating FUCA1alteration together with a de novo KDM5Cvariant. 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 KDM5Cphenotypic 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 KDM5Cphenotypic spectrum.
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