Screening of copy number variants in the 22q11.2 region of congenital heart disease patients from the São Miguel Island, Azores, revealed the second patient with a triplication

Pires, Rita F.; Pires, Luís Miguel; Vaz, Sara; Maciel, Paula; Anjos, Rui; Moniz, Raquel; Branco, Cláudia C.; Cabral, Rita; Carreira, Isabel M.; Mota-Vieira, Luísa

doi:10.1186/s12863-014-0115-6

Cited by 13 publications

(9 citation statements)

References 30 publications

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“…These six patients had various CHDs, including VSD, ASD, PDA, RVOTS, DORV, PH or Down’s syndrome (table 2). As reported, patients with small atypical amplification of TOP3B present mild mental retardation and generalised overgrowth,31 or mild developmental delay and learning difficulties 40…”

Section: Discussionmentioning

confidence: 54%

Genetic characterisation of 22q11.2 variations and prevalence in patients with congenital heart disease

et al. 2019

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ObjectivesThe 22q11.2 deletion syndrome is considered the most frequent chromosomal microdeletion syndrome in humans and the second leading chromosomal cause of congenital heart disease (CHD). We aimed to identify the prevalence and the detailed genetic characterisation of 22q11.2 region in children with CHD including simple defects and to explore the genotype-phenotype relationship between deletion/amplification type and clinical data.MethodsPatients with CHD for surgery were screened by multiplex ligation-dependent probe amplification and capillary electrophoresis methods. Universal Probe Library technology was applied for validation.ResultsIn 354 patients with CHD, 40 (11.3%) carried different levels of deletions/amplifications at the 22q11.2 region with various phenotypes. The affected genes at this region include CDC45 (15 patients), TBX1 (8), USP18 (8), RTDR1 (7), SNAP29 (6), TOP3B (6), ZNF74 (4) and other genes with less frequency. Among those, two patients carried 3 Mb typically deleted region from CLTCL1 to LZTR1 (low copy repeats A–D) or 1.5 Mb deletions from CLTCL1 to MED15 (low copy repeats A–C). Clinical facial manifestations were found in 12 patients.ConclusionsThis study revealed an unexpected high prevalence of chromosome 22q11.2 variations in patients with CHD even in simple defects. The genotype-phenotype relationship analysis suggests that genetic detection of 22q11.2 may become necessary in all patients with CHD and that detection of unique deletions or amplifications may provide useful insight into personalised management in patients with CHD.

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Section: Discussionmentioning

confidence: 54%

Genetic characterisation of 22q11.2 variations and prevalence in patients with congenital heart disease

et al. 2019

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“…TOP3B is nonetheless highly relevant for human health, as revealed by studies showing that TOP3B deficiency is linked to the development of neurodevelopmental defects. Indeed, the TOP3B gene resides on chromosome 22q11.2 in the human genome, a region frequently affected by deletions or duplications leading to congenital heart disease, facial malformation and cognitive dysfunction (68,(161)(162)(163)(164)(165). Consistent with this, copy number variants and de novo mutations in TOP3B have been linked to an increased risk of neurodevelopmental and cognitive disorders, including autism and schizophrenia (68,(166)(167)(168)(169).…”

Section: Roles Of Top3b In Rna Metabolismmentioning

confidence: 89%

The many lives of type IA topoisomerases

Bizard

Hickson

2020

Journal of Biological Chemistry

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The double helical structure of genomic DNA is both elegant and functional in that it serves both to protect vulnerable DNA bases and to facilitate DNA replication and compaction. However, these design advantages come at the cost of having to evolve and maintain a cellular machinery that can manipulate a long polymeric molecule that readily becomes topologically entangled whenever it has to open for translation, replication, or repair. If such a machinery fails to eliminate detrimental topological entanglements, utilization of the information stored in the DNA double helix is compromised. As a consequence, the use of Bform DNA as the carrier of genetic information must have co-evolved with a means to manipulate its complex topology. This duty is performed by DNA topoisomerases, which therefore are, unsurprisingly, ubiquitous in all kingdoms of life. In this review, we focus on how DNA topoisomerases catalyze their impressive range of DNA-conjuring tricks, with a particular emphasis on DNA topoisomerase III (TOP3). Once thought to be the most unremarkable of topoisomerases, the many lives of these type IA topoisomerases are now being progressively revealed. This research interest is driven by a realization that their substrate versatility and their ability to engage in intimate collaborations with translocases and other DNA-processing enzymes are far more extensive and impressive than was thought hitherto. This, coupled with the recent associations of TOP3s with developmental and neurological pathologies in humans, is clearly making us reconsider their undeserved reputation as being unexceptional enzymes.

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“… 9 , 10 Our proband had pulmonic stenosis, while another triplication proband had sub-aortic stenosis and a ventricular septal defect. 11 , 12 Although experimental evidence is lacking, it is plausible that increased dosage of these genes could also predispose to aberrant cardiac development. The only other report of a proband with a 22q11.2 triplication, also (3:1), is an 8-year-old girl with a strikingly similar phenotype to our proband: learning difficulties, social immaturity, and similar dysmorphic features.…”

Section: Discussionmentioning

confidence: 99%

Atypical autism in a boy with double duplication of 22q11.2: implications of increasing dosage

Dale

Jilderda

et al. 2017

npj Genomic Med

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Duplication of chromosome 22q11.2 (LCR A-D) has been reported at higher frequencies in clinical samples than the general population, but phenotypes vary widely. Triplication (4 copies) is rare, but studying the associated phenotype may provide insight into dosage-sensitivity of the genes in this chromosomal interval. We describe a proband with a triplication, specifically a “double duplication” (two copies per chromosome) of the 22q11.2 region, while his parents and two siblings each have a single duplication (3 copies). The proband had a heart malformation, dysmorphic features, and learning and socialization deficits, whereas the other family members did not. This family illustrates that while duplication of the 22q11.2 may not be sufficient to cause clinically significant neurodevelopmental or health-related phenotypes, triplication of the same region may result in a phenotype characterized by a mild neurodevelopmental disorder, facial dysmorphism, and possibly cardiac anomalies.

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Screening of copy number variants in the 22q11.2 region of congenital heart disease patients from the São Miguel Island, Azores, revealed the second patient with a triplication

Cited by 13 publications

References 30 publications

Genetic characterisation of 22q11.2 variations and prevalence in patients with congenital heart disease

Genetic characterisation of 22q11.2 variations and prevalence in patients with congenital heart disease

The many lives of type IA topoisomerases

Atypical autism in a boy with double duplication of 22q11.2: implications of increasing dosage

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