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

Autor:	Lombardo A; Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy., Sinibaldi L; Medical Genetics Unit, IRCCS Bambino Gesù Children Hospital, 00165 Rome, Italy., Genovese S; Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy., Catino G; Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy., Mei V; Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy., Pompili D; Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy., Sallicandro E; Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy., Falasca R; Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy., Liambo MT; Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy., Faggiano MV; Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy., Roberti MC; Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy., Di Donato M; Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy., Vitelli A; Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy., Russo S; Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy., Giannini R; Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy., Micalizzi A; Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.; Medical Genetics Unit, San Pietro Fatebenefratelli Hospital, 00189 Rome, Italy., Pietrafusa N; Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù, IRCCS Children's Hospital, 00165 Rome, Italy., Digilio MC; Medical Genetics Unit, IRCCS Bambino Gesù Children Hospital, 00165 Rome, Italy., Novelli A; Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy., Fusco L; Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù, IRCCS Children's Hospital, 00165 Rome, Italy., Alesi V; Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.
Jazyk:	angličtina
Zdroj:	International journal of molecular sciences [Int J Mol Sci] 2024 Jun 24; Vol. 25 (13). Date of Electronic Publication: 2024 Jun 24.
DOI:	10.3390/ijms25136912
Abstrakt:	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 CDKL5 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 CDKL5 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.
Databáze:	MEDLINE
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