Normal Chromosomal Microarray Analysis Research Articles

Diagnosis of Fetal Kabuki Syndrome By Exome Sequencing Following Non-Specific Ultrasound Findings

Fetal exome sequencing is becoming a crucial modality for genetic investigation whenever fetal malformations are documented in the context of normal chromosomal microarray analysis (CMA). When ultrasound findings are non-specific, the robustness of exome sequencing may be the only way to achieve a molecular diagnosis during pregnancy. We describe a case of multiple non-specific fetal findings with the eventual diagnosis of fetal Kabuki syndrome by exome sequencing (due to a deleterious mutation in KMT2D). This case stresses the importance of fetal exome sequencing when sonographic fetal abnormalities are visualized, without any specific candidate diagnosis. The multi-organ findings raised the index of suspicion; exome sequencing was performed following the normal CMA. Most Kabuki syndrome patients have a recognizable facial dysmorphism that generally cannot be observed prenatally.

Microarray analysis: First-trimester maternal serum free β-hCG and the risk of significant copy number variants.

To determine whether abnormal levels of first-trimester maternal serum free β-hCG and PAPP-A are associated with significant copy number variants (CNVs) on chromosomal microarray analysis (CMA). Retrospective cohort of singleton prenatal CMA studies (n=2880). Cases with an abnormal karyotype, benign familial or de novo variants, and absence of heterozygosity were excluded. The prevalence of abnormal serum analytes was compared between patients with significant CNVs (n=56) and those with normal CMA (n=884). Odds ratios (ORs) and 95% confidence intervals (CI) were calculated using Fisher's exact test. Mantel-Haenszel method was utilized to adjust ORs for prenatal diagnostic procedure type and indications for testing. Statistical significance was determined as P value<0.05. Abnormally low serum free β-hCG (≤0.45 MoM) was associated with an increased risk of significant CNVs (OR 3.53, 95% CI, 1.25-8.66, P<0.01). This association remained significant after adjusting for abnormal nuchal translucency and advanced maternal age (AMA) (adjusted OR 3.04, 95% CI, 1.05-7.48, P<0.05) or procedure type and AMA (adjusted OR 3.21, 95% CI 1.13-8.16, P<0.05). The associations of abnormally high serum free β-hCG, low PAPP-A, and high PAPP-A with significant CNVs were not statistically significant. Low first-trimester serum β-hCG is associated with an increased risk of significant CNVs on CMA.

Prenatal diagnosis of posterior fossa anomalies: Additional value of chromosomal microarray analysis in fetuses with cerebellar hypoplasia.

To elucidate the relationship between copy number variations (CNVs) detected by high-resolution chromosomal microarray analysis (CMA) and the type of prenatal posterior fossa anomalies (PFAs), especially cerebellar hypoplasia (CH). This study involved 77 pregnancies with PFAs who underwent CMA. Chromosomal aberrations including pathogenic CNVs and variants of unknown significance were detected in 31.2% (24/77) of all cases by CMA and in 18.5% (12/65) in fetuses with normal karyotypes. The high detection rate of clinically significant CNVs was evident in fetuses with cerebellar hypoplasia (54.6%, 6/11), vermis hypoplasia (33.3%, 1/3), and Dandy-Walker malformation (25.0%, 3/12). Compare with fetuses without other anomalies, cases with CH and additional malformations had the higher CMA detection rate (33.3% vs 88.9%). Three cases of isolated unilateral CH with intact vermis and normal CMA result had normal outcomes. The deletion of 5p15, 6q terminal deletion, and X chromosome aberrations were the most frequent genetic defects associated with cerebellar hypoplasia. Among fetuses with PFA, those with cerebellar hypoplasia, vermis hypoplasia, or Dandy-Walker malformation are at the highest risk of clinically significant CNVs. Chromosomal microarray analysis revealed the most frequent chromosomal aberrations associated with CH.

Cost Effectiveness of Karyotyping, Chromosomal Microarray Analysis, and Targeted Next-Generation Sequencing of Patients with Unexplained Global Developmental Delay or Intellectual Disability.

Genetic diagnosis of unexplained global developmental delay and intellectual disability (GDD/ID) often ends the diagnostic odyssey and can lead to changes in clinical management. The objective of this study was to investigate the cost effectiveness of testing scenarios involving several methods used to diagnose GDD/ID: karyotyping, chromosomal microarray analysis (CMA), and targeted next-generation sequencing (NGS). We used decision-tree models to estimate the number of genetic diagnoses, the cost from a payers' perspective in the USA, and the incremental cost per additional genetic diagnosis. Model parameters were taken from peer-reviewed literature and governmental fee schedules. CMA testing results in more genetic diagnoses at an incremental cost of US $2692 per additional diagnosis compared with karyotyping, which has an average cost per diagnosis of US $11,033. Performing both tests sequentially results in the same number of diagnoses, but the total cost is less when CMA testing is done first and karyotyping second. Furthermore, when CMA testing yields a variant of unknown significance, additional genetic diagnoses can be obtained at an incremental cost of US $4220 by CMA testing of both parents, and when parents are not available or the patient had a normal CMA result, targeted NGS of the patient can add diagnoses at a further incremental cost of US $12,295. These results provide a cost effectiveness rationale for the use of CMA as the first-tier test for the genetic diagnosis of unexplained GDD/ID and further indicate that testing of both parents may be cost effective when a variant of unknown significance is detected in the patient.

Can clinical characteristics be criteria to perform chromosomal microarray analysis in children and adolescents with autism spectrum disorders?

Chromosomal microarray analysis (CMA) has become increasingly important in the assessment of patients with autism spectrum disorders (ASD), but is sometimes restricted to patients with specific additional characteristics or comorbidities. We aim to evaluate whether certain clinical characteristics could be criteria to perform CMA and also to investigate the diagnostic value of CMA compared to other genetic analyses in our patient population. The files of 311 children diagnosed with ASD were retrospectively analyzed. The retrieved clinical characteristics included: intellectual disability, major congenital anomalies, epilepsy, prematurity, familial history of ASD, electroencephalography, and brain MRI findings. Results of the genetic analyses, including CMA, were collected and statistical analysis was performed. CMA was performed in 79 patients and was found to be normal in 55 (group 1) and abnormal in 23 children (group 2). We found no statistically significant difference between groups in the presence of the clinical characteristics. The diagnostic yield of CMA (8.9%) was higher than in conventional karyotyping (1.6%) and other genetic analyses (3.8%). In our study, there was no significant difference in the presence of clinical characteristics in patients diagnosed with ASD who had abnormal CMA results compared to patients with normal CMA results. Therefore, the presence of these characteristics should not be used as criteria to perform CMA. Secondly, the diagnostic yield of CMA is higher than that of other genetic analyses. Our study supports the general recommendation that CMA should be offered as a first-tier test in the assessment of patients with ASD.

Physicians' perspectives on the uncertainties and implications of chromosomal microarray testing of children and families

Chromosomal microarray analysis (CMA) has improved the diagnostic rate of genomic disorders in pediatric populations, but can produce uncertain and unexpected findings. This article explores clinicians' perspectives and identifies challenges in effectively interpreting results and communicating with families about CMA. Responses to an online survey were obtained from 40 clinicians who had ordered CMA. Content included practice characteristics and perceptions, and queries about a hypothetical case involving uncertain and incidental findings. Data were analyzed using nonparametric statistical tests. Clinicians' comfort levels differed significantly for explaining uncertain, abnormal, and normal CMA results, with lowest levels for uncertain results. Despite clinical guidelines recommending informed consent, many clinicians did not consider it pertinent to discuss the potential for CMA to reveal information concerning biological parentage or predisposition to late-onset disease, in a hypothetical case. Many non-genetics professionals ordering CMA did not feel equipped to interpret the results for patients, and articulated needs for education and access to genetics professionals. This exploratory study highlights key challenges in the practice of genomic medicine, and identifies needs for education, disseminated practice guidelines, and access to genetics professionals, especially when dealing with uncertain or unexpected findings.

Comparison of chromosome analysis and chromosomal microarray analysis: what is the value of chromosome analysis in today’s genomic array era?

Chromosomal microarray analysis enables the detection of microdeletions/duplications and has become the standard in clinical diagnostic testing for individuals with congenital anomalies and developmental disabilities. In the era of genomic arrays, the value of traditional chromosome analysis needs to be reassessed. We studied 3,710 unrelated patients by chromosomal microarray analysis and chromosome analysis simultaneously and compared the results. We found that chromosomal microarray analysis detected the chromosomal imbalances that were identified by chromosome analysis with the exception of six cases (0.16%) that had mosaic abnormalities. Of note, one case showed mosaicism for two abnormal cell lines, resulting in a balanced net effect and a normal chromosomal microarray analysis. Further structural abnormalities such as unbalanced translocations, rings, and complex rearrangements were subsequently clarified by chromosome analysis in 18% of the cases with abnormal chromosomal microarray analysis results. Apparently balanced rearrangements were detected by chromosome analysis in 30 cases (0.8%). Our data demonstrate that although chromosomal microarray analysis should be the first-tier test for clinical diagnosis of chromosome abnormalities, chromosome analysis remains valuable in the detection of mosaicism and delineation of chromosomal structural rearrangements.