Expanding the Spectrum of KDM5C Neurodevelopmental Disorder: A Novel De Novo Stop Variant in a Young Woman and Emerging Genotype-Phenotype Correlations

As a consequence of the implementation of NGS technologies, the diagnostic yield of neurodevelopmental disorders has dramatically increased during the past two decades. Among neurodevelopmental genes, transcription-related genes and chromatin remodeling genes are the most represented category of disease-causing genes. Indeed, the term chromatinopathies is now widely used to describe epigenetic disorders caused by mutations in these genes. We hereby describe a twenty-seven-year-old female patient diagnosed with moderate intellectual disability comorbid with other neuropsychiatric and behavioral issues carrying a de novo heterozygous stop variant in the KDM5C gene (NM_004187.5: c. 3847G>T, p.Glu1283*), encoding a histone demethylase that specifically acts on the H3K4 lysines. The gene is located on the X chromosome and has been associated with Claes-Jensen-type intellectual disability, an X-linked syndromic disorder. We discuss our case in relation to previously reported affected females harboring pathogenic mutations in the KDM5C gene with the objective of delineating genotype-phenotype correlations and further defining a common recognizable phenotype. We also highlight the importance of reverse phenotyping in relation to whole-exome sequencing results.

Automated summary

Due to the implementation of NGS technologies, the diagnostic yield of neurodevelopmental disorders has significantly increased. Transcription-related genes and chromatin remodeling genes are the most commonly implicated genes in these disorders. In this study, a 27-year-old female patient with moderate intellectual disability and other neuropsychiatric and behavioral issues was found to have a de novo heterozygous stop variant in the KDM5C gene. The findings contribute to the understanding of genotype-phenotype correlations and the characterization of a recognizable phenotype associated with KDM5C mutations.