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Mosaic triploidy case showing facial profile (a), flat rocker bottom foot ((b) clinical and (c) X-ray), and triploid metaphase cell (d).
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The present study evaluated the role of SNP microarray in 101 cases of clinically suspected FISH negative (noninformative/normal) 22q11.2 microdeletion syndrome. SNP microarray was carried out using 300 K HumanCytoSNP-12 BeadChip array or CytoScan 750 K array. SNP microarray identified 8 cases of 22q11.2 microdeletions and/or microduplications in a...
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Citations
... deletion was not observed in fetuses with SA and/or SV, the main reason might be due to the small sample size.. Most likely for the same reasons, our results indicated an incremental diagnostic yield of 4.5% on CMA (4.5%, 2/44) which was lower than the previously reported incremental diagnostic yield of CMA ranging from 8 to 11% in CHD [18][19][20]. Whether the incidence of 22q11.2 deletion is relatively low in the special population of SA and/or SV still requires large-scale research to confirm. ...
Objective
This study aimed to investigate the genetic etiologies of fetuses with single atria and/or ventricle (SA or/and SV) using different genetic detection methods in a Chinese prenatal cohort.
Methods
In this retrospective study, the various genetic results of 44 fetuses with SA and/or SV were analyzed. All 44 cases were tested by chromosomal microarray analysis (CMA) and karyotyping simultaneously, and 8 underwent whole exome sequencing (WES). Data on the pregnancy outcomes and neonatal prognoses were collected from medical records and postnatal follow-up.
Results
The whole cohort of 44 fetuses included 14 SA cases (31.8%), 12 SV cases (27.3%), and 18 SA and SV cases (40.9%). A total of 9 pathogenic genetic results were detected by conventional karyotyping, CMA and trio-WES, indicating an overall detection rate of 20.5% (9/44). Six pathogenic chromosomal abnormalities were identified by CMA among the 44 cases, showing a detection rate of 13.6% (6/44). Two microdeletions being missed by karyotyping were diagnosed by CMA, showing an additional diagnostic yield of 4.5% for CMA in present cohort(2/44). Three pathogenic variants in two fetuses were identified by WES, indicating an incremental diagnostic yield of 4.5%(2/44) for WES in fetuses with SA or/and SV.
Conclusion
In this study, WES achieved an additional diagnostic yield of 4.5% in fetuses with SA or/and SV. WES is valuable for fetal prognosis assessment and could add diagnostic value for fetuses with SA and/or SV when CMA is negative. It would be a valuable technique for the identification of underlying pathogenic variants in prenatal cohorts.
... It detects most microscopic and sub-microscopic chromosomal changes from any DNA source in a single experiment without prior knowledge of abnormalities. 12 The aCGH is recommended by several authorities as the first line of test in evaluating multiple malformations, developmental/mental retardation and prenatal diagnosis. Another vital application of aCGH is in the field of cancer. ...
... A DNA microarray (SNP microarray) identifies not only CNVs (microdeletions or microduplications) but also any unbalanced chromosomal abnormalities (trisomy, triploidy, partial aneuploidy, and mosaicism) as well as uniparental disomy disorders. 12 Microdeletion/ microduplication syndrome cases are frequently associated with second/more hits (deletion or duplication) elsewhere in the genome. 12 The DNA microarray (SNP microarray) is a superior technique and covers the whole genome hence should be used as the first step for evaluating multiple malformations. ...
... 12 Microdeletion/ microduplication syndrome cases are frequently associated with second/more hits (deletion or duplication) elsewhere in the genome. 12 The DNA microarray (SNP microarray) is a superior technique and covers the whole genome hence should be used as the first step for evaluating multiple malformations. It is essential in clinically doubtful cases, which is often evident in the early weeks of life when dysmorphic features are challenging to recognize, in particular sick neonates on life support. ...
Genetics and genomics play a role in the causation of various human diseases. A large number of human reproductive disorders also arise as a result of genetic and genomic abnormalities. Reproductive disorders associated with predominantly genetics and genomic abnormalities are infertility, early pregnancy loss, congenital malformations, difference or disorder of sex development and reproductive cancers. The genetic etiology of human reproductive disorders is increasing with improved molecular biology techniques such as DNA microarray and next-generation sequencing.
... regions. However, FISH probes cannot detect deletions proximal or distal to the particular probe used; besides, it only provides information on targeted locations [9,10]. Therefore, it does not allow a comprehensive evaluation of the whole genome. ...
Background:
The 22q11.2 deletion syndrome (22q11.2DS) is the most common form of deletion disorder in humans. Low copy repeats flanking the 22q11.2 region confers a substrate for nonallelic homologous recombination (NAHR) events leading to rearrangements which have been reported to be associated with highly variable and expansive phenotypes. The 22q11.2DS is reported as the most common genetic cause of congenital heart defects (CHDs).
Methods:
A total of 42 patients with congenital heart defects, as confirmed by echocardiography, were recruited. Genetic molecular analysis using a fluorescence in situ hybridization (FISH) technique was conducted as part of routine 22q11.2DS screening, followed by multiplex ligation-dependent probe amplification (MLPA), which serves as a confirmatory test.
Results:
Two of the 42 CHD cases (4.76%) indicated the presence of 22q11.2DS, and interestingly, both cases have conotruncal heart defects. In terms of concordance of techniques used, MLPA is superior since it can detect deletions within the 22q11.2 locus and outside of the typically deleted region (TDR) as well as duplications.
Conclusion:
The incidence of 22q11.2DS among patients with CHD in the east coast of Malaysia is 0.047. MLPA is a scalable and affordable alternative molecular diagnostic method in the screening of 22q11.2DS and can be routinely applied for the diagnosis of deletion syndromes.
... features, the SNP array is recommended to confirm the diagnosis, as about 5-10% of individuals with a clinical finding of the 22q11.2 deletion syndrome have normal routine cytogenetic studies and normal FISH results [4,97,98]. These rare patients are diagnosed with DiGeorge syndrome [4]. ...
Chromosomal 22q11.2 deletion syndrome (22q11.2DS) (ORPHA: 567) caused by microdeletion in chromosome 22 is the most common chromosomal microdeletion disorder in humans. Despite the same change on the genome level, like in the case of monozygotic twins, phenotypes are expressed differently in 22q11.2 deletion individuals. The rest of the genome, as well as epigenome and environmental factors, are not without influence on the variability of phenotypes. The penetrance seems to be more genotype specific than deleted locus specific. The transcript levels of deleted genes are not usually reduced by 50% as assumed due to haploinsufficiency. 22q11.2DS is often an undiagnosed condition, as each patient may have a different set out of 180 possible clinical manifestations. Diverse dysmorphic traits are present in patients from different ethnicities, which makes diagnosis even more difficult. 22q11.2 deletion syndrome serves as an example of a genetic syndrome that is not easy to manage at all stages: diagnosis, consulting and dealing with.
... However, whole-genome SNP-array analysis has demonstrated higher resolution and more accurate CNV detection than BoBs™ technology [9]. In addition, SNP-array analysis can detect many other pathogenic/likely pathogenic microdeletions/duplications in addition to aneuploidy/partial aneuploidy, triploidy, UPD, and other disorders [17]. FISH detection had been the gold standard for identifying microdeletions and microduplications. ...
Background:
22q11.2 deletion syndrome (22q11.2DS) and 22q11.2 duplication syndrome (22q11.2DupS) are the most common copy number variations in humans. The clinical phenotypes of these two syndromes are variable, and there are no large sample data on the prenatal detection rate for these two syndromes in the Chinese population.
Results:
We recruited 411 pregnant women who showed either abnormal prenatal ultrasound findings or positive prenatal BoBs™ results or who had given birth to a child with chromosomal abnormalities. SNP-array analysis and interphase FISH analysis identified five fetuses with 22q11.2 copy number variants (CNVs), three of which were 22q11.2 deletion syndrome (22q11.2DS) (3/411) and two of which were 22q11.2 duplication syndrome (22q11.2DupS). In all 5 cases of diagnosed 22q11.2 abnormalities, inheritance could not be identified because the parents did not undergo further testing.
Conclusion:
Our case reports provide a detection rate of 22q11.2 CNVs for fetuses with prenatal diagnostic indications, and early diagnosis of these two syndromes was essential for prenatal intervention in these cases. SNP-array technology is an effective tool in the prenatal diagnosis of 22q11.2 CNVs. The prenatal diagnosis of these two syndromes is helpful for early intervention, which is of great clinical significance.
... The case was further investigated with Yq microdeletion (AZF) STS-PCR for qualitative assessment of various targets (AZFa, AZFb, AZFc regions and SRY) as described earlier (Simoni, Bakker, & Krausz, 2004). Finally, the case was investigated by SNP microarray (HumanCytoSNP 12 v2.1 BeadChip; Catalog # WG3202101) to investigate patient's genome for chromosomal aneuploidy, polyploidy, segmental CNV and loss of heterozygosity as described before (Halder, Jain, & Kalsi, 2016;Halder, Kumar, Jain, & Iyer, 2017). Table 1. ...
The dicentric Y chromosome is the most common cytogenetically visible structural abnormality of Y chromosome. The sites of break and fusion of dicentric Y are variable, but break and fusion at Yq12 (proximal to the pseudoautosomal region 2/PAR 2) is very rare. Dicentric Y chromosome is unstable during cell division and likely to generate chromosomal mosaicism. Here, we report a case of infertile male with nonmosaic 46,XY where chromosome Y was dicentric with break and fusion at Yq12 (proximal to PAR 2). Clinical presentation of the case was nonobstructive azoospermia due to early maturation arrest at the primary spermatocyte stage. Various molecular techniques such as FISH, STS-PCR and DNA microarray were carried out to characterise genetic defect leading to testicular maturation arrest in the patient. The break and fusion was found at Yq12 (proximal to PAR 2) and resulted in near total duplication of Y chromosome (excluding PAR 2). The reason for maturation arrest seems due to CNVs of PARs (gain in PAR 1 and loss of PAR 2) and azoospermia factors (gain).
... American College of Medical Genetics (ACMG) standards and guidelines for postnatal constitutional copy number variants were followed up for interpretation and reporting. SNP microarray was used to detect chromosomal abnormality (aneuploidy, triploidy, mosaicism, etc.) as well as microdeletion, microduplication, LOH, etc., as described earlier (Halder et al., 2016). Later, FISH with XY probes, conventional cytogenetics on lymphocytes and STS PCR was carried out to confirm some of microarray findings (chromosomal abnormalities and AZF deletions). ...
... CNVs of study group were then compared with CNVs of controls (although number was only 10), public normal/control databases and literature reports besides our previous study on suspected 22q11.2 microdeletions (Halder et al., 2016) before considering as possible aetiological associations. LOH was not included for aetiological association because of requirements of additional work to establish link. ...
... This is in contrast to sex chromosome CNVs (27%) observed in clinically suspected 22q11.2 microdeletion syndrome (55 sex chromosome CNVs out of 203 CNVs) (Halder et al., 2016) as well as controls (very few CNVs of Y chromosome; 4 CNVs of Y out of 12 sex chromosome CNVs). This indicates that sex chromosomes are extremely important in investigation of azoospermia. ...
Testicular maturation arrest is characterized by interruption of germ cell development and differentiation. Genetic factors play important role in the causation of human disease, including male infertility. The objective was to study copy number variations in testicular maturation arrest using single nucleotide polymorphism (SNP) microarray technique. Conventional cytogenetics, targeted fluorescence in situ hybridization (FISH) and sequence-tagged site (STS) polymerase chain reaction (PCR) were used to confirm some of the SNP microarray findings. SNP microarray on 68 cases of testicular maturation arrest detected copy number variations (CNVs) mostly on sex chromosomes involving pseudoautosomal regions (PAR) 1, 2 and 3 as well as azoospermic factors (AZFs) besides three cases of chromosomal abnormalities (two Klinefelter syndromes and one case of dicentric Y). The AZF deletion was observed in 14 (20.6%) cases and the AZFc gain was observed in 6 (8.8%) cases. PAR 1 and 2 CNVs was observed in 5 (7.3%) cases. PAR 3 CNVs was detected in 19 cases and 2 controls. The TSPY2 gene gain (within PAR 3 CNVs) was observed in 16 cases and 1 control. CNV containing autosomal genes possibly associated with male infertility in this study was SPATA31A2-A5 (9p12) in five cases. In this study, SNP microarray identified possible underlying aetiology in 55.9% (38/68) cases besides identifying minimal critical region of AZFc deletion as 0.51 mb (Y:24356128–24873665) involving TTY5, RBMY2FP, RBMY1F, RBMY1J, TTY6 and PRY genes. SNP microarray seems superior, sensitive, specific as well as cost-effective method and has potential to be the first tier investigations to explore underlying genomic factors of testicular maturation arrest. The present study is an attempt to find out probable genomic factors with idiopathic testicular maturation arrest.
Congenital heart disease (CHD) is the most prevalent hereditary disorder, affecting approximately 1% of all live births. A reduction in morbidity and mortality has been achieved with advancements in surgical intervention, yet challenges in managing complications, extracardiac abnormalities, and comorbidities still exist. To address these, a more comprehensive understanding of the genetic basis underlying CHD is required to establish how certain variants are associated with the clinical outcomes. This will enable clinicians to provide personalized treatments by predicting the risk and prognosis, which might improve the therapeutic results and the patient’s quality of life. We review how advancements in genome sequencing are changing our understanding of the genetic basis of CHD, discuss experimental approaches to determine the significance of novel variants, and identify barriers to use this knowledge in the clinics. Next-generation sequencing technologies are unravelling the role of oligogenic inheritance, epigenetic modification, genetic mosaicism, and noncoding variants in controlling the expression of candidate CHD-associated genes. However, clinical risk prediction based on these factors remains challenging. Therefore, studies involving human-induced pluripotent stem cells and single-cell sequencing help create preclinical frameworks for determining the significance of novel genetic variants. Clinicians should be aware of the benefits and implications of the responsible use of genomics. To facilitate and accelerate the clinical integration of these novel technologies, clinicians should actively engage in the latest scientific and technical developments to provide better, more personalized management plans for patients.
Introduction: Microdeletion syndrome is characterized by sub-microscopic chromosomal deletion smaller than 5 Million bp (5Mb) and frequently associated with multiple congenital anomalies. Fluorescent In Situ Hybridization (FISH), Multiplex Ligation-Dependent Probe Amplification (MLPA), Quantitative Fluorescence Polymerase Chain Reaction (QFPCR), array Comparative Genomic Hybridization (aCGH), Single Nucleotide Polymorphism (SNP) microarray and Next-Generation Sequencing (NGS) techniques are commonly used for precise genetic diagnosis of microdeletion syndrome.
Aim: To study the role of mosaicism for the causation of phenotypic heterogeneity in 22q11.2 microdeletion syndrome.
Materials and Methods: In this study, for over the period of 10 years, we worked on detection of 22q11.2 microdeletion and observed mosaicism frequently. FISH analysis was used to assess level of mosaicism in metaphase and interphase cells derived from peripheral blood culture (lymphocytes) and interphase cells of various tissues like blood nucleated cells (mesodermal origin), buccal cells (ectodermal origin) and urinary exfoliated cells (endodermal origin). We have also used SNP microarray and QF PCR for further characterization.
Result: Among 257 cases of clinically suspected 22q11.2 microdeletion syndrome, presence of 22q11.2 microdeletion was confirmed in 39 cases (15.2%) by FISH. Eleven of 22q11.2 microdeletion cases (28.2%) were found to have mosaicism. We report high (28.2%) prevalence of mosaicism in 22q11.2 microdeletion syndrome and often (about 36% cases) low grade mosaicism (<35% deleted cells). Outsourced SNP microarray failed to detect low grade mosaicism. We also observed wide variations in deleted cell concentration amongst various tissues (blood, buccal and urinary cells).
Conclusion: We conclude that mosaicism in 22q11.2 microdeletion is common (28.2%) and interphase FISH should be the choice of test for detecting mosaicism.
