Submicroscopic Chromosomal Abnormalities Research Articles

Single nucleotide polymorphism array (SNP-array) analysis for fetuses with abnormal nasal bone.

This study aims to evaluate the prevalence of submicroscopic chromosomal abnormalities found on single nucleotide polymorphism array (SNP array) in pregnancies with either an absent or hypoplastic nasal bone. This retrospective study included 333 fetuses with either nasal bone hypoplasia or absence identified on prenatal ultrasound. SNP array analysis and conventional karyotyping were performed in all the subjects. The prevalence of chromosomal abnormalities was adjusted for maternal age and other ultrasound findings. Fetuses with either an isolated nasal bone absence or hypoplasia, those that had additional soft ultrasound markers, and those where structural defects were found on ultrasound were divided into three groups: A, B, and C, respectively. Among the total cohort of 333 fetuses, 76 (22.8%) had chromosomal abnormalities, including 47 cases of trisomy 21, 4 cases of trisomy 18, 5 cases of sex chromosome aneuploidy, and 20 cases of copy number variations of which 12 were pathogenic or likely pathogenic. The prevalence of chromosomal abnormalities in group A (n = 164), B (n = 79), and C (n = 90) was 8.5%, 29.1% and 43.3%, respectively. The incremental yields by SNP-array compared with karyotyping in group A, B, and C were 3.0%, 2.5% and 10.7%, respectively (p > 0.05). Compared to karyotype analysis, SNP array detected an additional 2 (1.2%), 1 (1.3%), and 5 (5.6%) pathogenic or likely pathogenic CNVs in groups A, B, and C, respectively. In the 333 fetuses, the prevalence of chromosomal abnormalities in women with advanced maternal age (AMA) was significantly higher than that in non-AMA women, (47.8% vs. 16.5%, p < 0.05). In addition to Down's syndrome, many other chromosomal abnormalities are present in fetuses with abnormal nasal bone. SNP array can improve the prevalence of chromosomal abnormalities associated with nasal bone abnormalities, especially in pregnancies with non-isolated nasal bone abnormalities and advanced maternal age.

Prenatal diagnosis in the fetal hyperechogenic kidneys: assessment using chromosomal microarray analysis and exome sequencing

Fetal hyperechogenic kidneys (HEK) is etiologically a heterogeneous disorder. The aim of this study was to identify the genetic causes of HEK using prenatal chromosomal microarray analysis (CMA) and exome sequencing (ES). From June 2014 to September 2022, we identified 92 HEK fetuses detected by ultrasound. We reviewed and documented other ultrasound anomalies, microscopic and submicroscopic chromosomal abnormalities, and single gene disorders. We also analyzed the diagnostic yield of CMA and ES and the clinical impact the diagnosis had on pregnancy management. In our cohort, CMA detected 27 pathogenic copy number variations (CNVs) in 25 (25/92, 27.2%) fetuses, with the most common CNV being 17q12 microdeletion syndrome. Among the 26 fetuses who underwent further ES testing, we identified 7 pathogenic/likely pathogenic variants and 8 variants of uncertain significance in 9 genes in 12 fetuses. Four novel variants were first reported herein, expanding the mutational spectra for HEK-related genes. Following counseling, 52 families chose to continue the pregnancy, and in 23 of them, postnatal ultrasound showed no detectable renal abnormalities. Of these 23 cases, 15 had isolated HEK on prenatal ultrasound. Taken together, our study showed a high rate of detectable genetic etiologies in cases with fetal HEK at the levels of chromosomal (aneuploidy), sub-chromosomal (microdeletions/microduplications), and single gene (point mutations). Therefore, we speculate that combined CMA and ES testing for fetal HEK is feasible and has good clinical utility. When no genetic abnormalities are identified, the findings can be transient, especially in the isolated HEK group.

Robust Parsing and Automated ELN Risk Classification for Acute Myeloid Leukemia

Introduction: Tumor karyotype is determined from cytogenetic analysis and is among the most valuable features for prognosis and therapy selection in many hematological malignancies. The International System for Human Cytogenetic Nomenclature (ISCN) standardizes the reporting of karyotypes. However, karyotype strings can be extremely complicated, sometimes leading to confusion in their interpretation by non-cytogeneticists. To improve the speed and accuracy of karyotype interpretation and classification, we developed an automated system to parse and interpret cytogenetics reports and have initially applied this to risk prediction in AML. Previous work in automated cytogenetics parsing (e.g. the CyDAS project Bradtke 2004) have not included inferred abnormalities (e.g. arm deletions inferred from isochromosomes and whole-arm translocations) or logic to categorize more general types of abnormalities (e.g. “any 17p abnormality”) which may have specific phenotypic significance or prognostic risk classifications, and require some level of both cytogenetic and programming expertise to utilize effectively.Methods: In previous work (Silgard, 2015), we developed a modular set of python scripts that process a batch of cytogenetics reports, identify and clean ISCN formulas, and parse ISCN into an efficient representation of cells and their clonal abnormalities as well as classify karyotypes according to Southwestern Oncology Group (SWOG) risk categories (Slovak, 2000). We extended this system to (1) effectively group abnormalities by types (e.g. translocation, deletion, duplication, inversions, etc.) and by the chromosome and arm affected, and (2) classify karyotypes according to the European Leukemia Net (ELN) risk categories (Döhner, 2017), and output salient abnormalities, risk categories, and text span references to the supporting evidence for interpretation. We classified each case according to ELN risk categories: favorable, unfavorable, or intermediate. Notable improvements upon the previous system include logic for inferred abnormalities (e.g. i(12)(q10) implies both a deletion of 12p as well as a duplication of 12q) as well as an optional minimum cell count to determine clonality. Complex karyotype and monosomal karyotype are also delineated.Results: Upon expert review of the automated parsing of 724 karyotype strings from 470 AML patients treated at the University of Washington/Fred Hutch Cancer Consortium between 1991 and 2016, automated ELN classification had an accuracy of 97.1%. Codification of chromosome arm specific abnormalities using 12p as a prototype (i.e. deletions, additions, translocations, duplications, inversions, and -12) collectively had micro-averaged sensitivity, specificity, and overall accuracy of 82.26%, 99.93%, and 99.68%; identifications of complex and monosomal karyotypes had sensitivity, specificity, and overall accuracy of 95.83%, 99.68%, 99.17% and 86.89%, 99.4%, 98.34%, respectively. The majority of the parsing errors were due either to typos in karyotype strings and non-standard nomenclature or to single cell count abnormalities that were assumed non-clonal.Conclusions: The automated karyotype parsing is an effective way to deliver condensed cytogenetic information to a more diverse audience of clinicians and researchers who lack either time or expertise to decipher complex karyotype strings or are unfamiliar with the updated risk stratification criteria for each disease. We have addressed any errors that arose from program defaults not associated with typos in the ISCN string and have included an optional clonality detection parameter to allow for some customization to individual lab reporting standards. Our next steps include extending the system to parse fluorescence in situ hybridization (FISH) nomenclature strings from cytogenetic lab reports, which can detect low-level or submicroscopic chromosomal abnormalities that cannot be detected by standard chromosomal analysis. We aim to provide the parsing and classification as an openly available web service for the broader community in the near future. DisclosuresNo relevant conflicts of interest to declare.

Non-invasive prenatal testing and genetic analysis of a fetus with partial trisomy 21

To carry out prenatal diagnosis for a fetus with high risk predicted by non-invasive prenatal testing (NIPT). Next-generation sequencing (NGS) was used to analyze free fetal DNA (ffDNA) in the maternal plasma. Chromosomal karyotyping and single nucleotide polymorphism array (SNP-array) were used to ascertain copy number variation in the fetus and its parents. SNP-array analysis and chromosomal karyotyping revealed that the fetus had a 15.018 Mb duplication at 4q34.1q35.2 and a 7.678 Mb duplication at 21q11.2q21.1, which were derived from a t(4;21)(q34.1;q21.1) translocation carried by its mother. NIPT is capable of detecting submicroscopic chromosomal abnormalities of the fetus. Combined use of genetic techniques, in particular SNP-array, is crucial for the diagnosis of partial trisomy 21q in this case.

Microarray and RASopathy-disorder testing in fetuses with increased nuchal translucency.

To determine the incidence of chromosomal abnormalities, submicroscopic chromosomal abnormalities and RASopathy-disorder (RD) pathogenic variants in a cohort of pregnancies with nuchal translucency thickness (NT) ≥ 3.5 mm, and to propose a clinical protocol for surveillance of this group of patients. This was a retrospective chart review of patients referred to The Prenatal Diagnosis and Medical Genetics Program at Mount Sinai Hospital between January 2013 and December 2015, due to NT ≥ 3.5 mm, who underwent chorionic villus sampling or amniocentesis. Patients underwent extensive genetic counseling prior to invasive procedures and testing. Quantitative fluorescence polymerase chain reaction (QF-PCR) was performed as the first-line test for aneuploidy. If the result was negative, patients underwent karyotyping and/or chromosomal microarray analysis (CMA), and if the findings were normal, they had testing for RD pathogenic variants, which included nine known genes. Patients also underwent detailed fetal ultrasound examinations and echocardiography, performed by expert operators. A total of 226 eligible patients were identified. In 116/226 (51.3%) patients, QF-PCR identified a chromosomal aneuploidy. The remaining 110/226 (48.7%) patients had further genetic testing. Karyotyping/CMA detected an abnormal/pathogenic cytogenetic result in 9/110 (8.2%) patients, as well as five variants of unknown significance (VOUS). RD testing yielded three pathogenic variants (3/103), giving a detection rate of 2.9%, and one VOUS. The optimal NT cut-off for RD screening was 7.9 mm in this population. In 92/110 (83.6%) patients, the genetic investigations were normal. Of these pregnancies, an early (14-16 weeks' gestation) detailed fetal ultrasound examination identified a structural abnormality in 24 (26.1%), 15 (16.3%) had an abnormal detailed ultrasound examination at 18-22 weeks' gestation and fetal echocardiography showed a cardiac abnormality in nine (9.8%). The birth outcome in the 83 pregnancies that had normal genetic investigations and known outcome included seven (8.4%) cases of termination of pregnancy, seven (8.4%) cases of intrauterine fetal death and 69 (83.1%) cases of live birth. Nine (9.8%) patients were lost to follow-up. Both CMA and molecular testing for RD are important investigations in pregnancies with NT ≥ 3.5 mm. The use of genetic testing combined with fetal ultrasound examination provides valuable information that can influence pregnancy outcome, and provide recurrence risks, in this patient population. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Further Phenotypic Delineation of Partial Trisomy 17q and Partial Monosomy 20q due to Rare t(17;20)

Copy number variations in subtelomeric regions of chromosomes 17 and 20 are associated with intellectual disability and various systemic manifestations. Microarray analysis allows identification of submicroscopic chromosomal abnormalities and is applicable to elucidate the etiology of cognitive impairment in approximately one-fifth of the cases. In the present study, we report on 3 male children from 2 sisters, who suffered from intellectual disability, facial dysmorphism, and epilepsy. Despite the initial suggestion of an X-linked inheritance, the condition was associated with 17q25.3 duplication and concomitant 20q13.33 deletion, as detected by microarray analysis. Coexistence of a deletion and a duplication suggests unbalanced segregation of a parental balanced translocation. Further investigations revealed maternal balanced translocations, which resulted in copy number aberrations in the children following unbalanced segregations. The work-up underlined the importance of genomic screening using microarrays as the first-tier diagnostic tool in intellectual disability, despite an apparent X-linked segregation in the pedigree.

Risk factors associated with fetal pleural effusion in prenatal diagnosis: a retrospective study in a single institute in Southern China

The aim of this study was to analyse the factors associated with fetal pleural effusion over the past five years in a single institute in the South of China. Between January 2011 and May 2016, 129 foetuses with pleural effusion were referred to the Fetal Medicine Unit in Guangzhou’s Women and Children’s Medical Center. Seventy-nine women accepted an invasive procedure to rule out chromosomal abnormalities, fetal anaemia, intrauterine infections or some of the submicroscopic chromosomal abnormalities. Our results showed that chromosomal anomalies occurred in 15.2% (12/79) of cases including 8 Turner syndrome (45, X) (10.1%), 3 trisomy 21 (3.8%) and 1 trisomy 13 (1.3%). Pathological microdeletion or microduplication syndrome occurred in 3 out of 36 (8.3%) prenatal samples with normal karyotype and structural defects. Eight foetuses (10.1%) affected with haemoglobin Bart’s disease showed pleural effusion at second or third trimester. Two cases (2.5%) were found to have an intrauterine infection. In conclusion, fetal pleural effusion has a close correlation with chromosomal abnormality. CMA may increase the detection rate of chromosomal aberrations, especially for micro-deletion or micro-duplication syndromes. In the South of China, Thalassemia must be considered when a fetal pleural effusion is detected.Impact statementWhat is already known on this subject? The aetiology of fetal pleural effusion includes a chromosomal abnormality, a congenital heart disease, congenital infections and a number of genetic syndromes.What do the results of this study add? This is the first retrospective study to analyse the aetiology of fetal pleural effusion in one institute in the South of China.What are the implications of these findings for clinical practice and/or further research? Besides the chromosomal abnormality, micro-deletion and micro-duplication syndromes were also detected in our study. We feel that thalassemia must be considered when fetal pleural effusion is detected in South China.

Efficacy of copy-number variation sequencing technology in prenatal diagnosis.

Background Classical karyotyping and copy-number variation sequencing (CNV-seq) are useful methods for the prenatal detection of chromosomal abnormalities. Here, we examined the potential of using a combination of the two methods for improved and accurate diagnosis. Methods From February 2013 to January 2018, 64 pregnant women showing indications for fetal chromosomal examination in the affiliated hospital of the Inner Mongolia Medical University were selected for this study. Amniotic fluid was collected and used for karyotype analysis and CNV-seq. Results Karyotype analysis of the 64 cases showed that six cases (9.38%) had chromosomal abnormalities. Using CNV-seq, in addition to three cases with numerical abnormalities of chromosomes, 14 cases were detected with CNV, of which five were pathogenic CNV, four were of uncertain clinical significance and five were polymorphic CNV. However, CNV-seq failed to detect one case with sex chromosome mosaicism and a balanced translocation carrier. The rate of abnormal chromosome and CNV detection was 26.56% (17/64) by CNV-seq. Conclusion Application of CNV-seq in prenatal diagnosis could allow the detection of submicroscopic chromosomal abnormalities and effectively reduce the birth of children with microdeletion and microduplication syndrome. Additionally, the combined application of karyotype analysis and CNV-seq can effectively improve the detection rate of chromosome abnormalities.

Combined use of bacterial artificial chromosomes-on-beads with karyotype detection improves prenatal diagnosis

BackgroundThis study evaluated the individual and combined diagnostic performance of the bacterial artificial chromosomes (BACs)-on-Beads (BoBs™) assay and conventional karyotyping for the prenatal detection of chromosomal abnormalities in pregnant women who were 35 or more years-old.MethodThe primary outcome was concordance of any numerical, structural, or submicroscopic chromosomal abnormalities between BoBs™ and conventional karyotyping of amniotic fluid specimens from pregnant women at 17 to 22 weeks gestation.ResultsWe examined samples from 4852 pregnant women. BoBs™ indicated that 4708 samples were normal (97.03%), and 144 were abnormal (2.97%); conventional karyotyping indicated that 4656 (95.96%) samples were normal and 196 (4.04%) were abnormal. The combined use of both methods indicated that 4633 of 4852 samples were normal (95.49%) and 219 of 4852 samples (4.51%) were abnormal. The kappa coefficient of the combined test was 0.70, indicating substantial consistency between BoBs™ and conventional karyotyping (95% CI = 0.65–0.76, P < 0.001).ConclusionsOur results indicate that the combined use of BoBs™ and conventional karyotyping detected more fetal abnormalities than either test alone.

Chromosomal microarray analysis in fetuses with congenital anomalies of the kidney and urinary tract: A prospective cohort study and meta-analysis.

To evaluate the usefulness and incremental diagnostic yield of chromosomal microarray analysis (CMA) compared with standard karyotyping in fetuses with congenital anomalies of the kidney and urinary tract (CAKUT). A prospective cohort study and systematic review of the literature were conducted. In the prospective cohort study, 123 fetuses with CAKUT, as detected by prenatal ultrasound at our center, were enrolled and evaluated using karyotyping and CMA. In the meta-analysis, articles in PubMed and ISI Web of Knowledge databases describing copy number variations (CNVs) in prenatal cases of CAKUT were included. Among the 123 fetuses in our prospective cohort study, 13 fetuses were detected with chromosomal abnormalities or submicroscopic chromosomal abnormalities by both karyotyping and CMA. In the remaining 110 fetuses, four pathogenic CNVs in four fetuses were only detected by CMA, indicating an excess diagnostic yield of 3.6%. Six publications and our own study met the inclusion criteria for the meta-analysis. In total, 615 fetuses with CAKUT were included. The pooled data from all of the reviewed studies indicate that the incremental yield of CMA over karyotyping was 3.8%. The use of CMA provides a 3.8% incremental yield of detecting pathogenic CNVs in fetuses with CAKUT and normal karyotype.

Application of chromosomal microarray in fetuses with increased nuchal translucency

Objective: To evaluate submicroscopic chromosomal abnormalities in fetuses with increased nuchal translucency (NT) and normal karyotype. Methods: A total of 319 fetuses with increased NT (≥3.0 mm) were tested using conventional karyotyping. When cytogenetic analysis showed normal chromosomes, the parents then received a consultation for chromosomal microarray (CMA) analysis, and a subsequent morphology scan was performed between 20 and 24 weeks gestation. Submicroscopic chromosomal abnormalities were assessed and compared between the fetuses with and without structural defects. Likewise, the prevalence of pathologic copy number variants (CNVs) among cases with increased NT was compared with the 926 low-risk cases consisted of patients whose sole indication for testing was advanced maternal age. Results: Chromosomal abnormality was identified in 32.29 (103/319) of fetuses, and 137 samples were tested using CMA. Additional pathogenic copy number variants (CNVs) were also detected in 5.12% (7/137) of the fetuses. There was no significant difference in the abnormal detection rate between fetuses showing an abnormal morphology scan and those with a normal morphology scan (11.11% [2/18] versus 4.20% [5/119], respectively; p > .05). The prevalence of pathological CMA results in cases with increased NT was significantly higher when compared with the low-risk patients (5.12% [7/137] versus 1.19% [11/926], respectively; p = .0009). Conclusions: Nuchal translucency (NT) ≥3.0 mm are associated with the highest risk for a CMA abnormality. Submicroscopic chromosomal abnormalities should be accessed when the fetus was found to be with increased NT and normal karyotype. It is, therefore, important to inform parents in a professional prenatal counseling setting regarding the potential advantages of CMA.

Submicroscopic chromosomal imbalances contribute to early abortion

BackgroundChromosomal abnormalities are one of the genetic mechanisms associated with abortion. However, the roles of submicroscopic chromosomal imbalances in early abortion are still unclear. This study aims to find out whether submicroscopic chromosomal imbalances contribute to early abortion.MethodsA total of 78 chorionic villus specimens from early spontaneous abortion patients with no obvious abnormality are collected after miccroassay analysis (the case group). At the same time, 60 chorionic villus specimens from induced abortion patients with no obvious abnormality are selected as the control group. The submicroscopic structures of chromosomes from two groups are analyzed using an array-based comparative genomic hybridization (aCGH).ResultsIn the case group, 15 specimens show submicroscopic chromosomal abnormalities including 14 micro-deletion/micro-duplication in chromosomes 2, 4, 5, 6, 7, 8, 9, 12, 15, 16, 18, and 22, and 1 uniparental disomy (UPD) in chromosome 19. Moreover, no pathogenic copy number variations are found in the control group. The results between these two groups exhibit significantly statistical difference.ConclusionSubmicroscopic chromosomal imbalances may be one of the main reasons for early abortion.

Clinical application of SNP array analysis in fetuses with ventricular septal defects and normal karyotypes.

The present study aims to evaluate the utility of high-resolution single-nucleotide polymorphism (SNP) arrays in fetuses with ventricular septal defects (VSDs) with or without other structural anomalies but with normal karyotypes and to investigate the outcomes of cases of prenatal VSDs via clinical follow-up. We analyzed 144 fetuses with VSDs and normal karyotypes using Affymetrix CytoScan HD arrays and the analyses were carried out a year after birth. Clinically significant CNVs were detected in 12 fetuses (8.3%). The most common pathogenic CNV was a 22q11.2 deletion with a detection rate of 2.8% (4/144). Well-known microdeletion or microduplication syndromes, including Smith-Magenis, Miller-Dieker, 9q subtelomeric deletion, 1p36 microdeletion, 1q21.1 microduplication, and terminal 4q deletion syndrome, were identified in six cases. Three regions of chromosomal imbalance were also identified: microduplication at 12q24.32q24.33, microdeletion at 16p13.13p13.12 and microdeletion at Xp21.1. The genes TBX1, SKI, GJA5, EHMT1, NOTCH1 were identified as established genes and LZTR1, PRDM26, YWHAE, FAT1, AKAP10, ERCC4, and ULK1 were identified as potential candidate genes of fetal VSDs. There was no significant difference in pathogenic CNVs between isolated VSDs and VSDs with additional structural abnormalities. Ninety-five (74.8%) pregnant women with fetuses with benign CNVs chose to continue the pregnancy and had a favorable prognosis, while nine (75%) pregnant women with fetuses with pathogenic CNVs chose to terminate the pregnancy. High-resolution SNP arrays are valuable tools for identifying submicroscopic chromosomal abnormalities in the prenatal diagnosis of VSDs. An excellent outcome can be expected for VSD fetuses that are negative for chromosomal anomalies and other severe anatomic abnormalities.

2 - Chromosomal Microarray as a First Tier Test Following Diagnostic Prenatal Procedure. The Toronto Mount Sinai Hospital Experience

Introduction: Microarray analysis (CMA) has become the gold standard in the investigation of children with congenital anomalies and/or developmental delay and recent publications showed its' accuracy and importance in diagnosing fetal submicroscopic chromosomal abnormalities. In view of this information we instituted CMA as the primary analysis for all CVS/amniocentesis samples at Mount Sinai Hospital.

Submicroscopic chromosomal abnormalities in fetuses with increased nuchal translucency and normal karyotype

Objective: To investigate the submicroscopic chromosomal abnormalities in fetuses with increased nuchal translucency (NT) and normal karyotype.Methods: Total of 296 fetuses with increased NT (≥3.0 mm) were tested by conventional karyotyping. When cytogenetic analysis showed normal chromosome, the pregnancies were then consulted for array-comparative genomic hybridization (CGH) analysis and received subsequent morphology scan between 20 and 24 weeks gestation. Submicroscopic chromosomal abnormalities were assessed and compared between the fetuses with and without structural defects.Results: Chromosomal abnormality was identified in 19.9% (59/296) fetuses. Two hundred and twenty samples were tested by array CGH. Submicroscopic chromosomal abnormalities were detected in 9.1% (20/220) fetuses. For the fetuses with abnormal morphology scan, the detection rate of submicroscopic chromosomal abnormalities was higher than those with normal morphology scan (26.9% versus 6.7%, p < 0.05).Conclusions: Submicroscopic chromosomal abnormalities should be accessed when the fetus was found to be with increased NT and normal karyotype, especially when the structural defects were found at second or third trimester.

Diagnostic Utility of Microarray Testing in Pregnancy Loss

Objectives To determine the frequency of clinically significant chromosomal abnormalities identified by chromosomal microarray in pregnancy losses at any gestational age and to compare microarray performance with that of traditional cytogenetic analysis when testing pregnancy losses. Methods Among 535 fetal demise specimens of any gestational age, clinical microarray-based comparative genomic hybridization (aCGH) was performed successfully on 515, and a subset of 107 specimens underwent additional single nucleotide polymorphism (SNP) analysis. Results Overall, clinically significant abnormalities were identified in 12.8% (64/499) of specimens referred with normal or unknown karyotypes. Detection rates were significantly higher with earlier gestational age. In the subset with normal karyotype, clinically significant abnormalities were identified in 6.9% (20/288). This detection rate did not vary significantly with gestational age, suggesting that, unlike aneuploidy, the contribution of submicroscopic chromosomal abnormalities to fetal demise does not vary with gestational age. In the 107 specimens that underwent aCGH and SNP analysis, seven cases (6.5%) had abnormalities of potential clinical significance detected by the SNP component, including female triploidy. aCGH failed to yield fetal results in 8.3%, which is an improvement over traditional cytogenetic analysis of fetal demise specimens. Conclusions Both the provision of results in cases in which karyotype fails and the detection of abnormalities in the presence of a normal karyotype demonstrate the increased diagnostic utility of microarray in pregnancy loss. Thus, chromosomal microarray testing is a

JAK2 V617F Analysis in Indonesian Myeloproliferative Neoplasms Patients

Background : Three subtypes of myeloproliferative neoplasms (MPNs): Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) showed overlapping phenotype. There has been no specific cytogenetic marker identified in these subtypes. JAK2 V617F mutation prevalence in Caucasian MPNs was first reported as 97% in PV, 57% in ET, and 50% in PMF.Objective: This study was done to define the prevalence of JAK2 V617F mutation and to identify cytogenetic markers in MPNs.Methods : The study design was cross-sectional. Patients who were admitted to Dr. Kariadi Hospital with clinical diagnosis of MPNs were referred for bone marrow cytogenetic analysis in Telogorejo Hospital. JAK2 V617F mutation was tested for using Amplification Refractory Mutation System Polymerase Chain Reaction (ARMS-PCR) from peripheral blood vein. Clinical data were secondary data retrieved from hospital medical records.Results : There was no cytogenetic abnormality found in all MPNs patients. The prevalence of JAK2 V617F mutation in MPNs patients was 73,68%. Mutation prevalence distribution in each subtypes were 100% in PV, 63,6% in ET and 100% in PMF. Conclusion : Chromosomal abnormality was not found using conventional cytogenetic analysis. More sensitive methods might elucidate submicroscopic chromosomal abnormalities in these patients. The prevalence of JAK2 V617F mutation was comparable with studies in Caucasian. It is recommended that JAK2 V617F testing should be incorporated in the management therapy of MPNs in Indonesia.

Diagnostic utility of microarray testing in pregnancy loss.

To determine the frequency of clinically significant chromosomal abnormalities identified by chromosomal microarray in pregnancy losses at any gestational age and to compare microarray performance with that of traditional cytogenetic analysis when testing pregnancy losses. Among 535 fetal demise specimens of any gestational age, clinical microarray-based comparative genomic hybridization (aCGH) was performed successfully on 515, and a subset of 107 specimens underwent additional single nucleotide polymorphism (SNP) analysis. Overall, clinically significant abnormalities were identified in 12.8% (64/499) of specimens referred with normal or unknown karyotypes. Detection rates were significantly higher with earlier gestational age. In the subset with normal karyotype, clinically significant abnormalities were identified in 6.9% (20/288). This detection rate did not vary significantly with gestational age, suggesting that, unlike aneuploidy, the contribution of submicroscopic chromosomal abnormalities to fetal demise does not vary with gestational age. In the 107 specimens that underwent aCGH and SNP analysis, seven cases (6.5%) had abnormalities of potential clinical significance detected by the SNP component, including female triploidy. aCGH failed to yield fetal results in 8.3%, which is an improvement over traditional cytogenetic analysis of fetal demise specimens. Both the provision of results in cases in which karyotype fails and the detection of abnormalities in the presence of a normal karyotype demonstrate the increased diagnostic utility of microarray in pregnancy loss. Thus, chromosomal microarray testing is a preferable, robust method of analyzing cases of pregnancy loss to better delineate possible genetic etiologies, regardless of gestational age.

Re: Diagnosis of fetal submicroscopic chromosomal abnormalities in failed array CGH samples: copy number by sequencing as an alternative to microarrays for invasive fetal testing. K. Cohen, A. Tzika, H. Wood, S. Berri, P. Roberts, G. Mason and E. Sheridan. Ultrasound Obstet Gynecol 2015; 45: 394-401.

Linked Comment: Ultrasound Obstet Gynecol 2015; 45: 394–401

Diagnosis of fetal submicroscopic chromosomal abnormalities in failed array CGH samples: copy number by sequencing as an alternative to microarrays for invasive fetal testing.

Array comparative genomic hybridization (CGH) has become the technology of choice for high-resolution prenatal whole genome analysis. Limitations of microarrays are mainly related to the analog nature of the analysis, and poor-quality DNA can result in failed quality metrics with these platforms. We examined a cohort of abnormal fetuses with failed array CGH results using a next-generation sequencing algorithm, CNV-Seq. We assessed the ability of the platform to handle suboptimal prenatal samples and generate interpretable molecular karyotypes. Nine samples obtained from abnormal fetuses and one from a normal control fetus were sequenced using an Illumina GAIIx. A segmentation algorithm for sequencing data was used to determine regional copy number data on the sequencing datasets. Phred quality scores were satisfactory for analysis of all samples. CNV-Seq identified both large- and small-scale abnormalities in the cohort, and normal results were obtained for fetuses for which microarray data were previously uninterpretable. No variants of uncertain significance were detected. Analysis of the digital sequencing datasets offered some advantages over array CGH output. Using next-generation sequencing for the detection of genomic copy number variants may be advantageous for poor-quality, invasively-acquired prenatal samples. CNV-Seq could become a potential alternative to array CGH in this setting.