Clinical and genomic characterization of 8p cytogenomic disorders

Okur, Volkan; Hamm, Laura; Kavus, Haluk; Mebane, Caroline; Robinson, Scott; Levy, Brynn

doi:10.1038/s41436-021-01270-2

Cited by 4 publications

(14 citation statements)

References 27 publications

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“…It is important to note that the frequency of inversion heterozygotes is increased in the normal population (26% in the European population) [16]. It is believed that the presence of inversion polymorphism (inv(8)(p23.1)) in a heterozygous state in one of the parents, most often the mothers, is a predisposing factor to the formation of inv dup del(8p) through non-allelic homologous recombination [1,4,9,10].…”

Section: Discussionmentioning

confidence: 99%

“…Most cases of inv dup del(8p) reported in the literature are referred to as recurrent chromosomal rearrangements, implying ectopic recombination as the main mechanism of imbalance formation [1,4,9]. When an inverted 8p duplication/deletion is formed due to ectopic recombination, microarray analysis reveals a certain pattern of genomic imbalance, such as the obligatory presence of an interstitial duplication, an adjacent terminal deletion, and a disomic region-a spacer about 5-5.5 Mb in size [1,4,13].…”

Section: Discussionmentioning

confidence: 99%

“…To date, more than 100 postnatal cases with 8p inverted duplication/deletion syndrome have been published [4][5][6]. The clinical manifestations of this chromosomal/genomic imbalance include mild-to-severe intellectual disability, characteristic dysmorphic facial features, CNS malformations such as hypoplasia/agenesis of the corpus callosum (67%), cardiovascular diseases (65%), musculoskeletal problems (59%), hypotonia (88%), and seizures (55%).…”

Section: Introductionmentioning

confidence: 99%

“…The clinical manifestations of this chromosomal/genomic imbalance include mild-to-severe intellectual disability, characteristic dysmorphic facial features, CNS malformations such as hypoplasia/agenesis of the corpus callosum (67%), cardiovascular diseases (65%), musculoskeletal problems (59%), hypotonia (88%), and seizures (55%). Dysmorphic facial features in individuals with inv dup del(8p) include microcephaly, large and prominent forehead, mildly arched eyebrows, deep-set eyes, ptosis or hooded eyelids, full cheeks, wide mouth, and micrognathia [4].…”

Section: Introductionmentioning

confidence: 99%

“…The first (required) event is the formation of a symmetric dicentric chromosome in which breaks occur due to functional instability, and this leads to the formation of a monocentric chromosome with an inverted duplication having an adjacent deletion and a chromosome with a terminal deletion [11]. Dicentric chromosome 8 formation can occur by two different mechanisms: U-type exchange and non-allelic homologous recombination mediated by parental paracentric inversion inv(8)(p23.1) [4,12,13]. The latter mechanism is a consequence of ectopic recombination, which is most characteristic of inv dup del(8p); as a result of this mechanism, a chromosomal imbalance with an intervening disomic spacer is formed [1].…”

Section: Introductionmentioning

confidence: 99%

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Clinical Manifestations of Various Molecular Cytogenetic Variants of Eight Cases of “8p Inverted Duplication/Deletion Syndrome”

et al. 2022

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Inverted duplication syndrome with an adjacent terminal deletion of the short arm of chromosome 8—inv dup del(8p)—is a rare complex structural chromosomal rearrangement with a wide range of clinical manifestations. Molecular cytogenetic variants of chromosomal imbalance depend on the mechanism of rearrangement formation. We analyzed the clinical–genetic and molecular cytogenetic characteristics of the 8p inverted duplication/deletion syndrome, as well as the genotype–phenotype correlation in eight unrelated cases with the rearrangement of inv dup del(8p). The main clinical manifestations in all cases are psychomotor and language delay, muscle hypotonia, and dysmorphic facial features. Malformations of the central nervous system, such as corpus callosum agenesis, were found in five cases. Seizures were reported in only one case. We found that the cause of the formation of the rearrangement was generally ectopic recombination (seven out of eight cases) and this was due to U-type exchange in only one case. Depending on the mechanism of formation, the characteristics of the genomic imbalance were different, which made it possible to identify two molecular cytogenetic variants in the cases we describe here. No association between molecular cytogenetic variants and clinical manifestations was found.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinical Manifestations of Various Molecular Cytogenetic Variants of Eight Cases of “8p Inverted Duplication/Deletion Syndrome”

et al. 2022

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Neurodevelopmental copy-number variants: A roadmap to improving outcomes by uniting patient advocates, researchers, and clinicians for collective impact

Buttermore¹,

Chamberlain²,

Cody³

et al. 2022

The American Journal of Human Genetics

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Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

et al. 2023

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Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice.

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Clinical and genomic characterization of 8p cytogenomic disorders

Cited by 4 publications

References 27 publications

Clinical Manifestations of Various Molecular Cytogenetic Variants of Eight Cases of “8p Inverted Duplication/Deletion Syndrome”

Clinical Manifestations of Various Molecular Cytogenetic Variants of Eight Cases of “8p Inverted Duplication/Deletion Syndrome”

Neurodevelopmental copy-number variants: A roadmap to improving outcomes by uniting patient advocates, researchers, and clinicians for collective impact

Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

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