scholarly journals Uptake and Diagnostic Yield of Chromosomal Microarray in an Australian Child Development Clinic

Children ◽  
2014 ◽  
Vol 1 (1) ◽  
pp. 21-30
Author(s):  
Dylan Mordaunt ◽  
Michael Gabbett ◽  
Melanie Waugh ◽  
Karen O'Brien ◽  
Helen Heussler
Keyword(s):  
Child Development ◽  
Diagnostic Yield ◽  
Chromosomal Microarray ◽  
Australian Child

scholarly journals The genetic landscape of intellectual disability and epilepsy in adults and the elderly: a systematic genetic work-up of 150 individuals

2021 ◽  
Author(s):  
Pia Zacher ◽  
Thomas Mayer ◽  
Frank Brandhoff ◽  
Tobias Bartolomaeus ◽  
Diana Le Duc ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Diagnostic Yield ◽  
Fragile X ◽  
Genetic Diagnostics ◽  
High Yield ◽  
Chromosomal Microarray ◽  
Limited Information ◽  
Single Nucleotide Variants ◽  
Elderly Individuals

Abstract Purpose Genetic diagnostics of neurodevelopmental disorders with epilepsy (NDDE) are predominantly applied in children, thus limited information is available regarding adults or elderly. Methods We investigated 150 adult/elderly individuals with NDDE by conventional karyotyping, FMR1 testing, chromosomal microarray, panel sequencing, and for unresolved cases, also by exome sequencing (nsingle = 71, ntrios = 24). Results We identified (likely) pathogenic variants in 71 cases (47.3%) comprising fragile X syndrome (n = 1), disease-causing copy number (n = 23), and single-nucleotide variants (n = 49). Seven individuals displayed multiple independent genetic diagnoses. The diagnostic yield correlated with the severity of intellectual disability. Individuals with anecdotal evidence of exogenic early-life events (e.g., nuchal cord, complications at delivery) with alleged/unproven association to the disorder had a particularly high yield of 58.3%. Screening for disease-specific comorbidities was indicated in 45.1% and direct treatment consequences arose in 11.8% of diagnosed individuals. Conclusion Panel/exome sequencing displayed the highest yield and should be considered as first-tier diagnostics in NDDE. This high yield and the numerous indications for additional screening or treatment modifications arising from genetic diagnoses indicate a current medical undersupply of genetically undiagnosed adult/elderly individuals with NDDE. Moreover, knowledge of the course of elderly individuals will ultimately help in counseling newly diagnosed individuals with NDDE.

Clinical and Genetic Profile of Autism Spectrum Disorder–Epilepsy (ASD-E) Phenotype: Two Sides of the Same Coin!

2020 ◽  
Vol 51 (6) ◽  
pp. 390-398 ◽  
Author(s):  
Sudhakar Karunakaran ◽  
Ramshekhar N. Menon ◽  
Sruthi S. Nair ◽  
S. Santhakumar ◽  
Muralidharan Nair ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Age Of Onset ◽  
Focal Epilepsy ◽  
Diagnostic Yield ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Chromosomal Microarray ◽  
Seizure Type ◽  
Epilepsy Syndrome ◽  
Genetic Profile

The clinical phenotype of autism spectrum disorder and epilepsy (ASD-E) is a common neurological presentation in various genetic disorders, irrespective of the underlying pathophysiological mechanisms. Here we describe the demographic and clinical profiles, coexistent neurological conditions, type of seizures, epilepsy syndrome, and EEG findings in 11 patients with ASD-E phenotype with proven genetic etiology. The commonest genetic abnormality noted was CDKL5 mutation (3), MECP2 mutation (2), and 1p36 deletion (2). The median age of onset of clinical seizures was 6 months (range, 10 days to 11 years). The most common seizure type was focal onset seizures with impaired awareness, observed in 7 (63.6%) patients followed by epileptic spasms in 4 (30.8%), generalized tonic-clonic and atonic seizures in 3 (27.3%) patients each and tonic seizures in 2 (18.2%) patients and myoclonic seizures in 1 (9.1%) patient. Focal and multifocal interictal epileptiform abnormalities were seen in 6 (54.6%) and 5 (45.5%) patients, respectively. Epileptic encephalopathy and focal epilepsy were seen in 7 (63.6%) and 4 (36.4%) patients, respectively. The diagnostic yield of genetic testing was 44% (11 of 25 patients) and when variants of unknown significance and metabolic defects were included, the yield increased to 60% (15 of 25 patients). We conclude that in patients with ASD-E phenotype with an underlying genetic basis, the clinical seizure type, epilepsy syndrome, and EEG patterns are variable. Next-generation exome sequencing and chromosomal microarray need to be considered in clinical practice as part of evaluation of children with ASD-E phenotype.

scholarly journals Simultaneous Detection of CNVs and SNVs Improves the Diagnostic Yield of Fetuses with Ultrasound Anomalies and Normal Karyotypes

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1397
Author(s):  
Qingwei Qi ◽  
Yulin Jiang ◽  
Xiya Zhou ◽  
Hua Meng ◽  
Na Hao ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Diagnostic Yield ◽  
Simultaneous Detection ◽  
Genetic Diagnosis ◽  
Copy Number Variations ◽  
Molecular Diagnostic ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Single Nucleotide Variants ◽  
Sequential Approach

The routine assessment to determine the genetic etiology for fetal ultrasound anomalies follows a sequential approach, which usually takes about 6–8 weeks turnaround time (TAT). We evaluated the clinical utility of simultaneous detection of copy number variations (CNVs) and single nucleotide variants (SNVs)/small insertion-deletions (indels) in fetuses with a normal karyotype with ultrasound anomalies. We performed CNV detection by chromosomal microarray analysis (CMA) or low pass CNV-sequencing (CNV-seq), and in parallel SNVs/indels detection by trio-based clinical exome sequencing (CES) or whole exome sequencing (WES). Eight-three singleton pregnancies with a normal fetal karyotype were enrolled in this prospective observational study. Pathogenic or likely pathogenic variations were identified in 30 cases (CNVs in 3 cases, SNVs/indels in 27 cases), indicating an overall molecular diagnostic rate of 36.1% (30/83). Two cases had both a CNV of uncertain significance (VOUS) and likely pathogenic SNV, and one case carried both a VOUS CNV and an SNV. We demonstrated that simultaneous analysis of CNVs and SNVs/indels can improve the diagnostic yield of prenatal diagnosis with shortened reporting time, namely, 2–3 weeks. Due to the relatively long TAT for sequential procedure for prenatal genetic diagnosis, as well as recent sequencing technology advancements, it is clinically necessary to consider the simultaneous evaluation of CNVs and SNVs/indels to enhance the diagnostic yield and timely TAT, especially for cases in the late second trimester or third trimester.

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.

Chromosomal microarray in a highly consanguineous population: diagnostic yield, utility of regions of homozygosity, and novel mutations

2016 ◽  
Vol 91 (4) ◽  
pp. 616-622 ◽  
Author(s):  
M.A. Alabdullatif ◽  
M.A. Al Dhaibani ◽  
M.Y. Khassawneh ◽  
A.W. El-Hattab
Keyword(s):  
Diagnostic Yield ◽  
Chromosomal Microarray ◽  
Novel Mutations ◽  
Regions Of Homozygosity

scholarly journals Relationship between Clinical Parameters and Chromosomal Microarray Data in Infants with Developmental Delay

Healthcare ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 305
Author(s):  
Zeeihn Lee ◽  
Byung Joo Lee ◽  
Sungwon Park ◽  
Donghwi Park
Keyword(s):  
Developmental Delay ◽  
Diagnostic Yield ◽  
Copy Number Variations ◽  
Gene Copy ◽  
Chromosomal Microarray ◽  
Clinical Parameters ◽  
Brain Anomalies ◽  
Pathogenic Cnvs ◽  
Clinical Records ◽  
The Relationship

Chromosomal microarray (CMA) is considered a first-tier test for genetic analysis as it can be used to examine gene copy number variations (CNVs) throughout the entire genome, with enhanced sensitivity for detecting submicroscopic deletions and duplications. However, its cost can represent a heavy burden. Moreover, the diagnostic yield of CMA in infants with developmental delay (DD) was reported to be less than 10%. Therefore, we aimed to investigate the relationship between CMA results and clinical features and risk factors of DD. The study included 59 infants with DD who were recruited between August 2019 and February 2020 during a visit to the outpatient clinic of a rehabilitation department. We reviewed the clinical records of the infants regarding gender, age, body weight at birth, delivery method, brain imaging data, perinatal history, and parent-related clinical parameters, such as mother and father age at birth. The infants were categorized according to CMA results, and differences in clinical parameters were evaluated. Except for brain anomalies, there was no statistically significant differences between infants who had pathogenic and variants of unknown significance (VOUS)-likely pathogenic CNVs groups compared with those within the VOUS-likely no sub-classification, VOUS-likely benign, benign, and normal CNVs groups. The incidence of brain anomalies was significantly higher within infants with pathogenic and VOUS-likely pathogenic CNVs groups (p < 0.05). Our study suggests that infants with DD who present dysmorphism or brain anomaly may benefit from early CMA analysis, for adequate diagnosis and timely treatment. Further studies are warranted to confirm the relationship between DD clinical parameters and CMA results.

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