Copy number variation (CNV) identification, interpretation, and database from Brazilian patients

Godoy, Victória Cabral Silveira Monteiro de; Bellucco, Fernanda Teixeira da Silva; Colovati, Mileny Esbravatti Stephano; Oliveira-Júnior, Hélio Rodrigues de; Moysés-Oliveira, Mariana; Melaragno, Maria Isabel

doi:10.1590/1678-4685-gmb-2019-0218

Cited by 8 publications

(10 citation statements)

References 33 publications

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“…Indeed in 2020, Godoy et al identified a CNV obtained from three different microarray platforms from a Brazilian population to conform the Brazilian CNV database. They found that a 14q32.33 gain was present in 97.8% of the samples studied [33], similar to that found in our study in 100% of the samples. Interestingly, the origins of the Brazilian population and ours have in common the mixture of the Iberian population that conquered us centuries ago.…”

Section: Discussionsupporting

confidence: 91%

Frequent copy number variants in a cohort of Mexican-Mestizo individuals

et al. 2023

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Background The human genome presents variation at distinct levels, copy number variants (CNVs) are DNA segments of variable lengths that range from several base pairs to megabases and are present at a variable number of copies in human genomes. Common CNVs have no apparent influence on the phenotype; however, some rare CNVs have been associated with phenotypic traits, depending on their size and gene content. CNVs are detected by microarrays of different densities and are generally visualized, and their frequencies analysed using the HapMap as default reference population. Nevertheless, this default reference is inadequate when the samples analysed are from people from Mexico, since population with a Hispanic genetic background are minimally represented. In this work, we describe the variation in the frequencies of four common CNVs in Mexican-Mestizo individuals. Results In a cohort of 147 unrelated Mexican-Mestizo individuals, we found that the common CNVs 2p11.2 (99.6%), 8p11.22 (54.5%), 14q32.33 (100%), and 15q11.2 (71.1%) appeared with unexpectedly high frequencies when contrasted with the HapMap reference (ChAS). Yet, while when comparing to an ethnically related reference population, these differences were significantly reduced or even disappeared. Conclusion The findings in this work contribute to (1) a better description of the CNVs characteristics of the Mexican Mestizo population and enhance the knowledge of genome variation in different ethnic groups. (2) emphasize the importance of contrasting CNVs identified in studied individuals against a reference group that—as best as possible—share the same ethnicity while keeping this relevant information in mind when conducting CNV studies at the population or clinical level.

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Section: Discussionsupporting

confidence: 91%

Frequent copy number variants in a cohort of Mexican-Mestizo individuals

et al. 2023

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“… 18 However, accurate clinical interpretation of CNVs and defining their clinical significance are still challenging, especially when used for prenatal evaluation. 2 , 61 In particular, it is difficult to compare the detected CNVs with the reported CNVs, due to breakpoint uncertainty. 18 Although the current evidence suggests that truncating variants and CNVs at the N-terminus of TOPORS are unlikely to be pathogenic, it is noteworthy that they may be associated with late-onset mild RP as CRX (Yahya S, et al IOVS 2021;62:ARVO E-Abstract 1536) and or even non-RP diseases, which requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Autosomal Dominant Retinitis Pigmentosa–Associated TOPORS Protein Truncating Variants Are Exclusively Located in the Region of Amino Acid Residues 807 to 867

Wang

Jiang

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Purpose Heterozygous truncating variants of TOPORS have been reported to cause autosomal dominant retinitis pigmentosa (adRP). The purpose of this study was to investigate whether all heterozygous truncating variants, including copy number variants (CNVs), are pathogenic. Methods TOPORS truncating variants were collected and reviewed through an in-house dataset and existing databases. Individuals with truncating variants underwent ophthalmological evaluation. Results Six truncating variants were detected in seven families. Three N-terminus truncating variants were detected in three families without RP, and the other three were identified in four unrelated families with typical RP. Based on the in-house dataset and published literature, 17 truncating variants were identified in 47 families with RP. All RP-associated truncating alleles, except one, were distributed in the last exon of TOPORS and clustered in amino acid residues 807 to 867 (46/47, 97.9%). Conversely, in the gnomAD database, only one truncating allele (1/27, 3.7%) was in this region, and the others were outside (26/27, 96.3%), suggesting that the pathogenic truncating variants were significantly clustered in residues 807 to 867 (χ 2 = 65.6, P = 1.1 × 10 –17 ). Additionally, three CNVs involving the N-terminus of TOPORS were recorded in control populations but were absent in affected patients. Conclusions This study suggests that all pathogenic truncating variants of TOPORS were clustered in residues 807 to 867, whereas the truncating variants outside this region and the CNVs involving the N-terminus were not associated with RP. A dominant-negative effect, rather than haploinsufficiency, is speculated to be the underlying pathogenesis. These findings provide valuable information for interpreting variation in TOPORS and other genes in similar situations, especially for CNVs.

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“…As for the OMIM database, CNVs were considered pathogenic when they presented genes associated with diseases. Moreover, CNVs were considered likely pathogenic when they presented genes associated with phenotypic alterations in the OMIM database [ 23 ]. The genome reference of X-CNV was GRCh37/hg19.…”

Section: Methodsmentioning

confidence: 99%

Copy number variant analysis for syndromic congenital heart disease in the Chinese population

Chen

et al. 2022

Hum Genomics

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Background Syndromic congenital heart disease (CHD) is among the most severe conditions in the pediatric population. Copy number variant (CNV) is an important cause of syndromic CHD, but few studies focused on CNVs related to these patients in China. The present study aimed to identify pathogenic CNVs associated with syndromic CHD in the Chinese population. Methods A total of 109 sporadic patients with syndromic CHD were applied chromosomal microarray analysis (CMA). Phenotype spectrum of pathogenic or likely pathogenic CNVs was analyzed. CHD-related genes were prioritized from genes within pathogenic or likely pathogenic CNVs by VarElect, OVA, AMELIE, and ToppGene. Results Using CMA, we identified 43 candidate CNVs in 37/109 patients. After filtering CNVs present in the general population, 29 pathogenic/likely pathogenic CNVs in 24 patients were identified. The diagnostic yield of CMA for pathogenic/likely pathogenic CNVs was 23.1% (24/104), excluding 5 cases with aneuploidies or gross chromosomal aberrations. The overlapping analysis of CHD-related gene lists from different prioritization tools highlighted 16 CHD candidate genes. Conclusion As the first study focused on CNVs in syndromic CHD from the Chinese population, this study reveals the importance of CMA in exploring the genetic etiology of syndromic CHD and expands our understanding of these complex diseases. The bioinformatic analysis of candidate genes suggests several CHD-related genes for further functional research.

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Copy number variation (CNV) identification, interpretation, and database from Brazilian patients

Cited by 8 publications

References 33 publications

Frequent copy number variants in a cohort of Mexican-Mestizo individuals

Frequent copy number variants in a cohort of Mexican-Mestizo individuals

Autosomal Dominant Retinitis Pigmentosa–Associated TOPORS Protein Truncating Variants Are Exclusively Located in the Region of Amino Acid Residues 807 to 867

Copy number variant analysis for syndromic congenital heart disease in the Chinese population

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