A pericentric inversion of chromosome X disrupting<i>F8</i>and resulting in haemophilia A

Yu, Xin; Zhou, Junju; Ding, Qiulan; Chen, Changming; Wu, Xi; Wang, Xuefeng; Wang, Hongli; Jiang, Xiaofeng

doi:10.1136/jclinpath-2016-204050

Cited by 3 publications

(2 citation statements)

References 39 publications

(31 reference statements)

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“…Structural rearrangements are not a rare finding, as they are recorded in roughly 0.7% of the human population [22]. In particular, inversions present with an incidence ranging from 1-2/100 for autosomal chromosomes to 1/28,000 -1/30,000 for sex chromosomes [23].…”

Section: Discussionmentioning

confidence: 99%

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

Lombardo,

Sinibaldi,

Genovese

et al. 2024

IJMS

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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.

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Section: Discussionmentioning

confidence: 99%

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

Lombardo,

Sinibaldi,

Genovese

et al. 2024

IJMS

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show abstract

“…Genetic counseling is incomplete for these patients, hindering genetic family investigation and prenatal diagnosis. In these genetically unresolved patients, deep intronic variation or genomic rearrangement disrupting the F8 could be causal . Herein, we describe an original molecular mechanism in which F8 was disrupted by a 3.8‐Mb Xq11.1q12 inserted duplication leading to the production of an F8/Xq12 (noncoding sequence) fusion transcript.…”

Section: Introductionmentioning

confidence: 99%

Severe hemophilia A caused by an unbalanced chromosomal rearrangement identified using nanopore sequencing

Chatron

Schluth-Bolard

Frétigny

et al. 2019

Journal of Thrombosis and Haemostasis

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Background:No F8 genetic abnormality is detected in about 2% of severe hemophilia A patients using conventional genetic approaches. In these patients, deep intronic variation or F8 disrupting genomic rearrangement could be causal.Objective: To characterize, in a genetically unresolved severe hemophilia A patient, a new Xq28 rearrangement disrupting F8 using comprehensive molecular techniques including nanopore sequencing. Results: Long-range polymerase chain reaction (PCR) performed throughout F8 identified a nonamplifiable region in intron 25 indicating the presence of a genomic rearrangement. F8 messanger ribonucleic acid (mRNA) analysis including 3′rapid amplification of complementary deoxyribonucleic acid (cDNA) ends and nanopore sequencing found the presence of a F8 fusion transcript in which F8 exon 26 was replaced by a 742-bp pseudoexon corresponding to a noncoding region located at the beginning of the long arm of chromosome X (Xq12; chrX: 66 310 352-66 311 093, GRCh37/hg19). Cytogenetic microarray analysis found the presence of a Xq11.1q12 gain of 3.8 Mb. The PCR amplification of junction fragments and fluorescent in situ hybridization (FISH) analysis found that the Xq11q12 duplicated region was inserted in the F8 intron 25 genomic region.

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Whole F8 gene sequencing identified pathogenic structural variants in the remaining unsolved patients with severe hemophilia A

Jourdy,

Chatron,

Frétigny

et al. 2024

Journal of Thrombosis and Haemostasis

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A pericentric inversion of chromosome X disruptingF8and resulting in haemophilia A

Abstract: The characterisation of pericentric inversion involving extended the molecular mechanisms causing HA. The pericentric inversion rearrangement involves by non-homologous end joining is responsible for pathogensis of severe HA.

Cited by 3 publications

References 39 publications

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

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

Severe hemophilia A caused by an unbalanced chromosomal rearrangement identified using nanopore sequencing

Whole F8 gene sequencing identified pathogenic structural variants in the remaining unsolved patients with severe hemophilia A

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