Rapid Diagnosis of Imprinting Disorders Involving Copy Number Variation and Uniparental Disomy Using Genome-Wide SNP Microarrays

2015 ◽  
Vol 146 (1) ◽  
pp. 9-18 ◽  
Author(s):  
Weiqiang Liu ◽  
Rui Zhang ◽  
Jun Wei ◽  
Huimin Zhang ◽  
Guojiu Yu ◽  
...  
Keyword(s):  
Copy Number ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Copy Number Variations ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Imprinting Disorders ◽  
Genome Wide ◽  
Number Variation ◽  
Efficient Alternative

Imprinting disorders, such as Beckwith-Wiedemann syndrome (BWS), Prader-Willi syndrome (PWS) and Angelman syndrome (AS), can be detected via methylation analysis, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), or other methods. In this study, we applied single nucleotide polymorphism (SNP)-based chromosomal microarray analysis to detect copy number variations (CNVs) and uniparental disomy (UPD) events in patients with suspected imprinting disorders. Of 4 patients, 2 had a 5.25-Mb microdeletion in the 15q11.2q13.2 region, 1 had a 38.4-Mb mosaic UPD in the 11p15.4 region, and 1 had a 60-Mb detectable UPD between regions 14q13.2 and 14q32.13. Although the 14q32.2 region was classified as normal by SNP array for the 14q13 UPD patient, it turned out to be a heterodisomic UPD by short tandem repeat marker analysis. MS-MLPA analysis was performed to validate the variations. In conclusion, SNP-based microarray is an efficient alternative method for quickly and precisely diagnosing PWS, AS, BWS, and other imprinted gene-associated disorders when considering aberrations due to CNVs and most types of UPD.

scholarly journals Copy number variation analysis in Chinese children with complete atrioventricular canal and single ventricle

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Xingyu Zhang ◽  
Bo Wang ◽  
Guoling You ◽  
Ying Xiang ◽  
Qihua Fu ◽  
...  
Keyword(s):  
Copy Number ◽  
Trisomy 21 ◽  
Single Ventricle ◽  
Snp Array ◽  
Copy Number Variations ◽  
Chinese Children ◽  
Atrioventricular Canal ◽  
Genome Wide ◽  
Number Variation ◽  
Complete Atrioventricular

Abstract Background Congenital heart disease (CHD) is one of the most common birth defects. Copy number variations (CNVs) have been proved to be important genetic factors that contribute to CHD. Here we screened genome-wide CNVs in Chinese children with complete atrioventricular canal (CAVC) and single ventricle (SV), since there were scarce researches dedicated to these two types of CHD. Methods We screened CNVs in 262 sporadic CAVC cases and 259 sporadic SV cases respectively, using a customized SNP array. The detected CNVs were annotated and filtered using available databases. Results Among 262 CAVC patients, we identified 6 potentially-causative CNVs in 43 individuals (16.41%, 43/262), including 2 syndrome-related CNVs (7q11.23 and 8q24.3 deletion). Surprisingly, 90.70% CAVC patients with detected CNVs (39/43) were found to carry duplications of 21q11.2–21q22.3, which were recognized as trisomy 21 (Down syndrome, DS). In CAVC with DS patients, the female to male ratio was 1.6:1.0 (24:15), and the rate of pulmonary hypertension (PH) was 41.03% (16/39). Additionally, 6 potentially-causative CNVs were identified in the SV patients (2.32%, 6/259), and none of them was trisomy 21. Most CNVs identified in our cohort were classified as rare (< 1%), occurring just once among CAVC or SV individuals except the 21q11.2–21q22.3 duplication (14.89%) in CAVC cohort. Conclusions Our study identified 12 potentially-causative CNVs in 262 CAVC and 259 SV patients, representing the largest cohort of these two CHD types in Chinese population. The results provided strong correlation between CAVC and DS, which also showed sex difference and high incidence of PH. The presence of potentially-causative CNVs suggests the etiology of complex CHD is incredibly diverse, and CHD candidate genes remain to be discovered.

scholarly journals Copy Number Variation of UGT 2B Genes in Indian Families Using Whole Genome Scans

2016 ◽  
Vol 2016 ◽  
pp. 1-7
Author(s):  
Avinash M. Veerappa ◽  
Prakash Padakannaya ◽  
Nallur B. Ramachandra
Keyword(s):  
Copy Number ◽  
Gene Deletion ◽  
Indian Population ◽  
Snp Array ◽  
Copy Number Variations ◽  
Genome Scans ◽  
Genome Wide ◽  
Disease Associations ◽  
Number Variation

Background and Objectives. Uridine diphospho-glucuronosyltransferase 2B (UGT2B) is a family of genes involved in metabolizing steroid hormones and several other xenobiotics. These UGT2B genes are highly polymorphic in nature and have distinct polymorphisms associated with specific regions around the globe. Copy number variations (CNVs) status of UGT2B17 in Indian population is not known and their disease associations have been inconclusive. It was therefore of interest to investigate the CNV profile of UGT2B genes.Methods. We investigated the presence of CNVs in UGT2B genes in 31 members from eight Indian families using Affymetrix Genome-Wide Human SNP Array 6.0 chip.Results. Our data revealed >50% of the study members carried CNVs in UGT2B genes, of which 76% showed deletion polymorphism. CNVs were observed more in UGT2B17 (76.4%) than in UGT2B15 (17.6%). Molecular network and pathway analysis found enrichment related to steroid metabolic process, carboxylesterase activity, and sequence specific DNA binding.Interpretation and Conclusion. We report the presence of UGT2B gene deletion and duplication polymorphisms in Indian families. Network analysis indicates the substitutive role of other possible genes in the UGT activity. The CNVs of UGT2B genes are very common in individuals indicating that the effect is neutral in causing any suspected diseases.

scholarly journals Genome-Wide Analysis of Copy Number Variations in Normal Population Identified by SNP Arrays

2009 ◽  
Vol 2 (1) ◽  
pp. 54-65 ◽  
Author(s):  
Jian Wang ◽  
Tsz-Kwong Man ◽  
Kwong Kwok Wong ◽  
Pulivarthi H. Rao ◽  
Hon-Chiu Eastwood Leung ◽  
...  
Keyword(s):  
Copy Number Variation ◽  
Human Genome ◽  
Copy Number ◽  
Repetitive Sequences ◽  
Snp Array ◽  
Copy Number Variations ◽  
Gene Copy ◽  
Chemical Stimulus ◽  
Genome Wide ◽  
Number Variation

Gene copy number change is an essential characteristic of many types of cancer. However, it is important to distinguish copy number variation (CNV) in the human genome of normal individuals from bona fide abnormal copy number changes of genes specific to cancers. Based on Affymetrix 50K single nucleotide polymorphism (SNP) array data, we identified genome-wide copy number variations among 104 normal subjects from three ethnic groups that were used in the HapMap project. Our analysis revealed 155 CNV regions, of which 37% were gains and 63% were losses. About 21% (30) of the CNV regions are concordant with earlier reports. These 155 CNV regions are located on more than 100 cytobands across all 23 chromosomes. The CNVs range from 68bp to 18 Mb in length, with a median length of 86 Kb. Eight CNV regions were selected for validation by quantitative PCR. Analysis of genomic sequences within and adjacent to CNVs suggests that repetitive sequences such as long interspersed nuclear elements (LINEs) and long terminal repeats (LTRs) may play a role in the origin of CNVs by facilitating non-allelic homologous recombination. Thirty-two percent of the CNVs identified in this study are associated with segmental duplications. CNVs were not preferentially enriched in gene-encoding regions. Among the 364 genes that are completely encompassed by these 155 CNVs, genes related to olfactory sensory, chemical stimulus, and other physiological responses are significantly enriched. A statistical analysis of CNVs by ethnic group revealed distinct patterns regarding the CNV location and gain-to-loss ratio. The CNVs reported here will help build a more comprehensive map of genomic variations in the human genome and facilitate the differentiation between copy number variation and somatic changes in cancers. The potential roles of certain repeat elements in CNV formation, as corroborated by other studies, shed light on the origin of CNVs and will improve our understanding of the mechanisms of genomic rearrangements in the human genome.

scholarly journals Integrated CNV-seq, karyotyping and SNP-array analyses for effective prenatal diagnosis of chromosomal mosaicism

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Na Ma ◽  
Hui Xi ◽  
Jing Chen ◽  
Ying Peng ◽  
Zhengjun Jia ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Sex Chromosome ◽  
Snp Array ◽  
Genomic Rearrangements ◽  
Chromosomal Mosaicism ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Low Level ◽  
Autosomal Aneuploidy ◽  
Number Variation

Abstract Background Emerging studies suggest that low‐coverage massively parallel copy number variation sequencing (CNV-seq) more sensitive than chromosomal microarray analysis (CMA) for detecting low-level mosaicism. However, a retrospective back-to-back comparison evaluating accuracy, efficacy, and incremental yield of CNV-seq compared with CMA is warranted. Methods A total of 72 mosaicism cases identified by karyotyping or CMA were recruited to the study. There were 67 mosaic samples co-analysed by CMA and CNV-seq, comprising 40 with sex chromosome aneuploidy, 22 with autosomal aneuploidy and 5 with large cryptic genomic rearrangements. Results Of the 67 positive mosaic cases, the levels of mosaicism defined by CNV-seq ranged from 6 to 92% compared to the ratio from 3 to 90% by karyotyping and 20% to 72% by CMA. CNV-seq not only identified all 43 chromosomal aneuploidies or large cryptic genomic rearrangements detected by CMA, but also provided a 34.88% (15/43) increased yield compared with CMA. The improved yield of mosaicism detection by CNV-seq was largely due to the ability to detect low level mosaicism below 20%. Conclusion In the context of prenatal diagnosis, CNV-seq identified additional and clinically significant mosaicism with enhanced resolution and increased sensitivity. This study provides strong evidence for applying CNV-seq as an alternative to CMA for detection of aneuploidy and mosaic variants.

Genomic study via chromosomal microarray analysis in a group of Romanian patients with obesity and developmental disability/intellectual disability

2019 ◽  
Vol 32 (7) ◽  
pp. 667-674 ◽  
Author(s):  
Diana Micleaa ◽  
Camelia Al-Khzouza ◽  
Sergiu Osan ◽  
Simona Bucerzan ◽  
Victoria Cret ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Disability ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Genomic Analysis ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Syndromic Obesity ◽  
Genomic Study ◽  
Array Technology

Abstract Background Obesity with developmental disability/intellectual disability (DD/ID) is the most common association in syndromic obesity. Genomic analysis studies have allowed the decipherment of disease aetiology, both in cases of syndromic obesity as well as in cases of isolated or syndromic DD/ID. However, more data are needed to further elucidate the link between the two. The aim of this pangenomic study was to use single nucleotide polymorphism (SNP) array technology to determine the copy number variant (CNV) type and frequency associated with both obesity and DD/ID. Methods Thirty-six patients were recruited from the Clinical Emergency Hospital for Children, in Cluj-Napoca, Romania during the period 2015–2017. The main inclusion criterion was a diagnosis that included both obesity and DD/ID. Genomic analysis via SNP array technology was performed. Results Out of the 36 patients, 12 (33%) presented CNVs with a higher degree of pathogenicity (A group) and 24 (66%) presented benign CNVs (B group). The SNP array results for the A group were as follows: pathogenic CNVs in 8/12 patients (67%); variants of unknown significance (VOUS) in 2/12 patients (16%); and uniparental disomy (UPD) in 2/12 patients (16%). Conclusions Some of these CNVs have already been observed in patients with both obesity and DD/ID, but the others were noticed only in DD/ID patients and have not been described until now in association with obesity.

scholarly journals Comprehensive Evaluation of Non-invasive Prenatal Screening to Detect Fetal Copy Number Variations

2021 ◽  
Vol 12 ◽  
Author(s):  
Jing Wang ◽  
Bin Zhang ◽  
Lingna Zhou ◽  
Qin Zhou ◽  
Yingping Chen ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Pregnant Women ◽  
Copy Number ◽  
Prenatal Screening ◽  
Comprehensive Evaluation ◽  
Copy Number Variations ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Non Invasive ◽  
Pathogenic Cnvs

ObjectiveTo evaluate the effectiveness of non-invasive prenatal screening (NIPS) in prenatal screening of fetal pathogenic copy number variants (CNVs).Materials and MethodsWe evaluated the prenatal screening capacity using traditional and retrospective approaches. For the traditional method, we evaluated 24,613 pregnant women who underwent NIPS; cases which fetal CNVs were suggested underwent prenatal diagnosis with chromosomal microarray analysis (CMA). For the retrospective method, we retrospectively evaluated 47 cases with fetal pathogenic CNVs by NIPS. A systematic literature search was performed to compare the evaluation efficiency.ResultsAmong the 24,613 pregnant women who received NIPS, 124 (0.50%) were suspected to have fetal CNVs. Of these, 66 women underwent prenatal diagnosis with CMA and 13 had true-positive results. The positive predictive value (PPV) of NIPS for fetal CNVs was 19.7%. Among 1,161 women who did not receive NIPS and underwent prenatal diagnosis by CMA, 47 were confirmed to have fetal pathogenic CNVs. Retesting with NIPS indicated that 24 of these 47 cases could also be detected by NIPS, representing a detection rate (DR) of 51.1%. In total, 10 publications, namely, six retrospective studies and four prospective studies, met our criteria and were selected for a detailed full-text review. The reported DRs were 61.10–97.70% and the PPVs were 36.11–80.56%. The sizes of CNVs were closely related to the accuracy of NIPS detection. The DR was 41.9% (13/31) in fetuses with CNVs ≤ 3 Mb, but was 55.0% (11/20) in fetuses with CNVs &gt; 3 Mb. Finally, to intuitively show the CNVs accurately detected by NIPS, we mapped all CNVs to chromosomes according to their location, size, and characteristics. NIPS detected fetal CNVs in 2q13 and 4q35.ConclusionThe DR and PPV of NIPS for fetal CNVs were approximately 51.1% and 19.7%, respectively. Follow-up molecular prenatal diagnosis is recommended in cases where NIPS suggests fetal CNVs.

scholarly journals Application of Chromosome Microarray Analysis in the Investigation of Developmental Disabilities and Congenital Anomalies: Single Center Experience and Review of NRXN3 and NEDD4L Deletions

2020 ◽  
Vol 11 (4) ◽  
pp. 197-206
Author(s):  
Alper Han Çebi ◽  
Şule Altıner
Keyword(s):  
Developmental Disabilities ◽  
Microarray Analysis ◽  
Congenital Anomalies ◽  
Copy Number Variations ◽  
Step Test ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Multiple Congenital Anomalies ◽  
Single Center Experience ◽  
Genome Wide

Chromosomal microarray analysis (CMA) is a first step test used for the diagnosis of patients with developmental delay, intellectual disability, autistic spectrum disorder, and multiple congenital anomalies. Its widespread usage has allowed genome-wide identification of copy number variations (CNVs). In our study, we performed a retrospective study on clinical and microarray data of 237 patients with developmental disabilities and/or multiple congenital anomalies and investigated the clinical utility of CMA. Phenotype-associated CNVs were detected in 15.18% of patients. Besides, we detected submicroscopic losses on 14q24.3q31.1 in a patient with speech delay and on 18q21.31q21.32 in twin patients with seizures. Deletions of <i>NRXN3</i> and <i>NEDD4L</i> were responsible for the phenotypes, respectively. This study showed that CMA is a powerful diagnostic tool in this patient group and expands the genotype-phenotype correlations on developmental disabilities.

scholarly journals High Detection Rate of Copy Number Variations Using Capture Sequencing Data: A Retrospective Study

2020 ◽  
Vol 66 (3) ◽  
pp. 455-462 ◽  
Author(s):  
Yu Sun ◽  
Xiantao Ye ◽  
Yanjie Fan ◽  
Lili Wang ◽  
Xiaomei Luo ◽  
...  
Keyword(s):  
Copy Number ◽  
Diagnostic Yield ◽  
Copy Number Variations ◽  
Systematic Evaluation ◽  
High Yield ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Large Sample Size ◽  
Analytical Sensitivity ◽  
Capture Sequencing

Abstract Background Capture sequencing (CS) is widely applied to detect small genetic variations such as single nucleotide variants or indels. Algorithms based on depth comparison are becoming available for detecting copy number variation (CNV) from CS data. However, a systematic evaluation with a large sample size has not been conducted to evaluate the efficacy of CS-based CNV detection in clinical diagnosis. Methods We retrospectively studied 3010 samples referred to our diagnostic laboratory for CS testing. We used 68 chromosomal microarray analysis–positive samples (true set [TS]) and 1520 reference samples to build a robust CS-CNV pipeline. The pipeline was used to detect candidate clinically relevant CNVs in 1422 undiagnosed samples (undiagnosed set [UDS]). The candidate CNVs were confirmed by an alternative method. Results The CS-CNV pipeline detected 78 of 79 clinically relevant CNVs in TS samples, with analytical sensitivity of 98.7% and positive predictive value of 49.4%. Candidate clinically relevant CNVs were identified in 106 UDS samples. CNVs were confirmed in 96 patients (90.6%). The diagnostic yield was 6.8%. The molecular etiology includes aneuploid (n = 7), microdeletion/microduplication syndrome (n = 40), and Mendelian disorders (n = 49). Conclusions These findings demonstrate the high yield of CS-based CNV. With further improvement of our CS-CNV pipeline, the method may have clinical utility for simultaneous evaluation of CNVs and small variations in samples referred for pre- or postnatal analysis.

scholarly journals Peruvian Newborn Male with 3p13 Deletion Syndrome Encompassing the FOXP1 Gene: Review of the Literature

2020 ◽  
Vol 09 (04) ◽  
pp. 270-278
Author(s):  
Hugo H. Abarca-Barriga ◽  
Milana Trubnykova ◽  
Félix Chavesta-Velásquez ◽  
Claudia Barletta-Carrillo ◽  
Marco Ordoñez-Linares ◽  
...  
Keyword(s):  
Copy Number ◽  
Choanal Atresia ◽  
Copy Number Variant ◽  
Autism Spectrum ◽  
Deletion Syndrome ◽  
Chromosomal Microarray ◽  
Facial Dysmorphism ◽  
Chromosomal Microarray Analysis ◽  
Heart Malformation ◽  
Number Variation

AbstractCopy number variation in loss of 3p13 is an infrequently reported entity characterized by hypertelorism, aniridia, microphthalmia, high palate, neurosensorial deafness, camptodactyly, heart malformation, development delay, autism spectrum disorder, seizures, and choanal atresia. The entity is caused probably by haploinsufficiency for FOXP1, UBA3, FAM19A1, and MITF. We report a newborn male with hypotonia, facial dysmorphism, heart malformation, and without clinical diagnosis; nevertheless, the use of appropriate genetic test, such us the chromosomal microarray analysis allowed identification of a copy number variant in loss of 5.5 Mb at chromosome 3 (p13-p14.1), that included 54 genes, encompassing FOXP1 gene. We compare the findings in our Peruvian patient to those of earlier reported patients; furthermore, add new signs for this entity.

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