A Case of CDKL5 Deficiency Due to an X Chromosome Pericentric Inversion: Delineation of Structural Rearrangements as an Overlooked Recurrent Pathological Mechanism

• Published in: International journal of molecular sciences 2024-06, Vol.25 (13), p.6912
• Main Authors: Lombardo, Antonietta, Sinibaldi, Lorenzo, Genovese, Silvia, Catino, Giorgia, Mei, Valerio, Pompili, Daniele, Sallicandro, Ester, Falasca, Roberto, Liambo, Maria Teresa, Faggiano, Maria Vittoria, Roberti, Maria Cristina, Di Donato, Maddalena, Vitelli, Anna, Russo, Serena, Giannini, Rosalinda, Micalizzi, Alessia, Pietrafusa, Nicola, Digilio, Maria Cristina, Novelli, Antonio, Fusco, Lucia, Alesi, Viola
• Format: Article
• Language: English
• Subjects: Child development; Chromosome Inversion; Chromosomes, Human, X - genetics; Convulsions & seizures; Electroencephalography; Epilepsy; Epileptic Syndromes - genetics; Female; Genetic Diseases, X-Linked - genetics; Genomes; Genotype & phenotype; Humans; Intellectual disabilities; Kinases; Metabolism; Patients; Protein Serine-Threonine Kinases - deficiency; Protein Serine-Threonine Kinases - genetics; Spasms, Infantile; X chromosomes
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25136912

CDKL5 deficiency disorder (CDD) is an X-linked dominant epileptic encephalopathy, characterized by early-onset and drug-resistant seizures, psychomotor delay, and slight facial features. Genomic variants inactivating or impairing its protein product kinase activity have been reported, making next-generation sequencing (NGS) and chromosomal microarray analysis (CMA) the standard diagnostic tests. We report a suspicious case of CDD in a female child who tested negative upon NGS and CMA and harbored an X chromosome de novo pericentric inversion. The use of recently developed genomic techniques (optical genome mapping and whole-genome sequencing) allowed us to finely characterize the breakpoints, with one of them interrupting at intron 1. This is the fifth case of CDD reported in the scientific literature harboring a structural rearrangement on the X chromosome, providing evidence for the hypothesis that this type of anomaly can represent a recurrent pathogenic mechanism, whose frequency is likely underestimated, with it being overlooked by standard techniques. The identification of the molecular etiology of the disorder is extremely important in evaluating the pathological outcome and to better investigate the mechanisms associated with drug resistance, paving the way for the development of specific therapies. Karyotype and genomic techniques should be considered in all cases presenting with CDD without molecular confirmation.