scholarly journals Chromosomal Microarray in Children With Developmental Delay: The Experience of a Tertiary Center in Korea

2021 ◽  
Vol 9 ◽  
Author(s):  
Eun Hye Yang ◽  
Yong Beom Shin ◽  
Soo Han Choi ◽  
Hye Won Yoo ◽  
Hye Young Kim ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Diagnostic Yield ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Chromosomal Microarray ◽  
Size Difference ◽  
Korean Children ◽  
Tertiary Center ◽  
Pathogenic Cnvs ◽  
Attention Deficit Hyperactivity Disorders

Background and Objectives: Chromosomal microarray (CMA) is a first-tier genetic test for children with developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), and multiple congenital anomalies (MCA). In this study, we report our experiences with the use of CMA in Korean children with unexplained DD/ID.Methods: We performed CMA in a cohort of 308 children with DD/ID between January 2010 and September 2020. We also retrospectively reviewed their medical records. The Affymetrix CytoScan 750 K array with an average resolution of 100 kb was used to perform CMA.Results: Comorbid neurodevelopmental disorders were ASD (37 patients; 12.0%), epilepsy (34 patients; 11.0%), and attention deficit hyperactivity disorders (12 patients; 3.9%). The diagnostic yield was 18.5%. Among the 221 copy number variants (CNVs) identified, 70 CNVs (57 patients; 18.5%) were pathogenic. Deletion CNVs were more common among pathogenic CNVs (PCNVs) than in non-PCNVs (P < 0.001). The size difference between PCNVs and non-PCNVs was not significant (P = 0.023). The number of included genes within CNV intervals was significantly higher in PCNVs (average 8.6; 0–347) than in non-PCNVs (average 47.5; 1–386) (P < 0.001). Short stature and hearing difficulty were also more common in the PCNV group than in the non-PCNV group (P = 0.010 and 0.070, respectively).Conclusion: This study provides additional evidence for the usefulness of CMA in genetic testing of children with DD/ID in Korea. The pathogenicity of CNVs correlated with the number of included genes within the CNV interval and deletion type of the CNVs, but not with CNV size.

scholarly journals Chromosomal Microarray Analysis in Children with Unexplained Developmental Delay/Intellectual Disability

2018 ◽  
Vol 08 (01) ◽  
pp. 001-009
Author(s):  
Pinar Arican ◽  
Berk Ozyilmaz ◽  
Dilek Cavusoglu ◽  
Pinar Gencpinar ◽  
Kadri Erdogan ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
De Novo ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Genetic Syndromes ◽  
Pathogenic Cnvs ◽  
Spectrum Disorders

AbstractChromosomal microarray (CMA) analysis for discovery of copy number variants (CNVs) is now recommended as a first-line diagnostic tool in patients with unexplained developmental delay/intellectual disability (DD/ID) and autism spectrum disorders. In this study, we present the results of CMA analysis in patients with DD/ID. Of 210 patients, pathogenic CNVs were detected in 26 (12%) and variants of uncertain clinical significance in 36 (17%) children. The diagnosis of well-recognized genetic syndromes was achieved in 12 patients. CMA analysis revealed pathogenic de novo CNVs, such as 11p13 duplication with new clinical features. Our results support the utility of CMA as a routine diagnostic test for unexplained DD/ID.

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.

scholarly journals Chromosomal microarray analysis of 410 Han Chinese patients with autism spectrum disorder or unexplained intellectual disability and developmental delay

2022 ◽  
Vol 7 (1) ◽  
Author(s):  
Yi Liu ◽  
Yuqiang Lv ◽  
Mehdi Zarrei ◽  
Rui Dong ◽  
Xiaomeng Yang ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Microarray Analysis ◽  
Diagnostic Yield ◽  
Autism Spectrum ◽  
Han Chinese ◽  
Chinese Patients ◽  
European Ancestry ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis

AbstractCopy number variants (CNVs) are recognized as a crucial genetic cause of neurodevelopmental disorders (NDDs). Chromosomal microarray analysis (CMA), the first-tier diagnostic test for individuals with NDDs, has been utilized to detect CNVs in clinical practice, but most reports are still from populations of European ancestry. To contribute more worldwide clinical genomics data, we investigated the genetic etiology of 410 Han Chinese patients with NDDs (151 with autism and 259 with unexplained intellectual disability (ID) and developmental delay (DD)) using CMA (Affymetrix) after G-banding karyotyping. Among all the NDD patients, 109 (26.6%) carried clinically relevant CNVs or uniparental disomies (UPDs), and 8 (2.0%) had aneuploidies (6 with trisomy 21 syndrome, 1 with 47,XXY, 1 with 47,XYY). In total, we found 129 clinically relevant CNVs and UPDs, including 32 CNVs in 30 ASD patients, and 92 CNVs and 5 UPDs in 79 ID/DD cases. When excluding the eight patients with aneuploidies, the diagnostic yield of pathogenic and likely pathogenic CNVs and UPDs was 20.9% for all NDDs (84/402), 3.3% in ASD (5/151), and 31.5% in ID/DD (79/251). When aneuploidies were included, the diagnostic yield increased to 22.4% for all NDDs (92/410), and 33.6% for ID/DD (87/259). We identified a de novo CNV in 14.9% (60/402) of subjects with NDDs. Interestingly, a higher diagnostic yield was observed in females (31.3%, 40/128) compared to males (16.1%, 44/274) for all NDDs (P = 4.8 × 10−4), suggesting that a female protective mechanism exists for deleterious CNVs and UPDs.

scholarly journals EIF2AK2-related Neurodevelopmental Disorder With Leukoencephalopathy, Developmental Delay, and Episodic Neurologic Regression Mimics Pelizaeus-Merzbacher Disease

2020 ◽  
Vol 7 (1) ◽  
pp. e539
Author(s):  
Daniel G. Calame ◽  
Meagan Hainlen ◽  
Danielle Takacs ◽  
Leah Ferrante ◽  
Kayla Pence ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Copy Number Variants ◽  
Retrospective Chart Review ◽  
Missense Variant ◽  
Chromosomal Microarray ◽  
Single Nucleotide Variants ◽  
Pelizaeus Merzbacher Disease ◽  
Delayed Myelination

ObjectiveTo demonstrate that de novo missense single nucleotide variants (SNVs) in EIF2AK2 cause a neurodevelopmental disorder with leukoencephalopathy resembling Pelizaeus-Merzbacher disease (PMD).MethodsA retrospective chart review was performed of 2 unrelated males evaluated at a single institution with de novo EIF2AK2 SNVs identified by clinical exome sequencing (ES). Clinical and radiographic data were reviewed and summarized.ResultsBoth individuals presented in the first year of life with concern for seizures and developmental delay. Common clinical findings included horizontal and/or pendular nystagmus during infancy, axial hypotonia, appendicular hypertonia, spasticity, and episodic neurologic regression with febrile viral illnesses. MRI of the brain demonstrated severely delayed myelination in infancy. A hypomyelinating pattern was confirmed on serial imaging at age 4 years for proband 1. In proband 2, repeat imaging at age 13 months confirmed persistent delayed myelination. These clinical and radiographic features led to a strong suspicion of PMD. However, neither PLP1 copy number variants nor pathogenic SNVs were detected by chromosomal microarray and trio ES, respectively. Reanalysis of trio ES identified heterozygous de novo EIF2AK2 missense variant c.290C>T (p.Ser97Phe) in proband 1 and c.326C>T (p.Ala109Val) in proband 2.ConclusionsThe autosomal dominant EIF2AK2-related leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome should be considered in the differential diagnosis for PMD and other hypomyelinating leukodystrophies (HLDs). A characteristic history of developmental regression with febrile illnesses may help distinguish it from other HLDs.

Genomic Syndromes in Schizophrenia

2013 ◽  
pp. 247-255
Author(s):  
George Kirov ◽  
Michael C. O’Donovan ◽  
Michael J. Owen
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Individual Risk ◽  
Genomic Deletions ◽  
Pathogenic Cnvs ◽  
Cognition And Learning

Several submicroscopic genomic deletions and duplications known as copy number variants (CNVs) have been reported to increase susceptibility to schizophrenia. Those for which the evidence is particularly strong include deletions at chromosomal segments 1q21.1, 3q29, 15q11.2, 15q13.3, 17q12 and 22q11.2, duplications at 15q11.2-q13.1, 16p13.1, and 16p11.2, and deletions atthe gene NRXN1. The effect of each on individual risk is relatively large, but it does not appear that any of them is alone sufficient to cause disorder in carriers. These CNVs often arise as new mutations(de novo). Analyses of genes enriched among schizophrenia implicated CNVs highlight the involvement in the disorder of post-synaptic processes relevant to glutamatergicsignalling, cognition and learning. CNVs that contribute to schizophrenia risk also contribute to other neurodevelopmental disorders, including intellectual disability, developmental delay and autism. As a result of selection, all known pathogenic CNVs are rare, and none makes a sizeable contribution to overall population risk of schizophrenia, although the study of these mutations is nevertheless providing important insights into the origins of the disorder.

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 CHROMOSOMAL MICROARRAY TESTING IN A DEVELOPMENTAL PAEDIATRICS SETTING

2018 ◽  
Vol 23 (suppl_1) ◽  
pp. e33-e33
Author(s):  
Brock Jenkin ◽  
Clare Mitchell
Keyword(s):  
Autism Spectrum Disorder ◽  
Developmental Delay ◽  
Clinical Management ◽  
Developmental Disorders ◽  
Autism Spectrum ◽  
Chromosomal Microarray ◽  
Test Results ◽  
First Line ◽  
Management Decisions ◽  
Positive Results

Abstract BACKGROUND Current guidelines recommend chromosomal microarray (CMA) testing as a first line etiologic investigation for developmental disorders such as intellectual disability or autism spectrum disorder (ASD). How often a copy number variation (CNV) is found, a definitive etiologic diagnosis is made and a change in clinical management occurs has not been well studied in a community setting. OBJECTIVES The study objective was to examine the real world use of CMA testing in a developmental paediatric setting: the prevalence of positive results and management decisions. DESIGN/METHODS This was a retrospective, descriptive study. The charts of 170 children seen by a single developmental paediatrician in a small city over a 7 year period (2010 - 2017) were reviewed. Referrals were received from both urban and rural communities. Information regarding reason for referral, clinical diagnosis, requests for CMA testing, test results and subsequent management decisions were extracted. The patient age ranged from 1 to 18 years (average 5.1 years). Children were referred for a wide variety of developmental and behavioural problems. Developmental delay, disruptive behavior, possible autism spectrum disorder or speech delay were the most common reasons for referral. Children were considered for CMA testing according to published guidelines. The most common clinical diagnoses in referred children were attention deficit hyperactivity disorder (ADHD), ASD and global developmental delay (GDD). Clinical management decisons were obtained from the medical chart and included follow-up visits. RESULTS CMA testing was recommended for 78 children, of which 65 had CMA testing completed (83%). Of these, 15 (23%) had an abnormal result and 6 (9%) were deemed pathogenic. The most common finding was a CNV at 2p16.3 in 2 children (3%). Of the children with pathogenic CNVs, 3 (50%) had more than one CNV. One child had a previously diagnosed trisomy X. One child with normal CMA had further testing, and a genetic diagnosis of atypical Rett Syndrome was made. The primary management decisions based on the CMA test results included parent education, genetic counselling and prognosis clarification. CONCLUSION In a developmental paediatrics setting, the use of CMA testing for first-line etiologic assessment in children with developmental disorders obtains positive results in close to 10% of tested children. This is similar to previously published results. Approximately 1/6 tested children had results of uncertain significance which require further study over time.

A Study from Turkey: Identification of Copy Number Variants in Children and Adolescents with Autism Spectrum Disorder

2021 ◽  
Author(s):  
Ahmet Özaslan ◽  
Gülsüm Kayhan ◽  
Elvan İşeri ◽  
Mehmet Ali Ergün ◽  
Esra Güney ◽  
...  
Keyword(s):  
Copy Number ◽  
Diagnostic Yield ◽  
Venous Blood ◽  
Copy Number Variants ◽  
Clinical Importance ◽  
Turkish Population ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Turkish Children ◽  
Children With Asd

Abstract Recent studies suggest that copy number variations (CNVs) play a significant role in the aetiology of ASD. This study aims to investigate CNVs, which are thought to be an important factor in ASD etiology. In addition it was aimed to specify the clinical usefulness of chromosomal microarrays (CMA) in the examination of ASD patients in Turkish population. Of 47 children (60.34±25.60 months; 82.9% boys) with ASD were constructed the sample. The karyotype structure of all participants was found to be normal using conventional cytogenetic methods. DNA obtained from the venous blood samples of the participants was evaluated using SurePrint G3 ISCA V2 CGH 8x60K Array (Agilent Technologies Santa Clara, CA, USA). We have identified 8 CNVs, ranging in size from 55 kb to 6.5 Mb in 7 (5 boys) of 47 children with ASD of the 4 of 8 CNVs were classified as pathogenic, which were 9p24.3p24.2 deletion in 3 Mb size, 15q11-q13 duplication in 6.5 Mb size, 16p11.2 deletion in 598 kb size and 22q13.3 deletion in 55 kb size. According to results has been demonstrated that diagnostic yield of CMA in Turkish children with ASD was 8.5%. Our results indicate that CNVs contribute a part to the genetic aetiology of Turkish children with ASD. In accordance with the literature, these results emphasize the clinical importance of CMA to investigate the aetiology of ASD.

scholarly journals Clinical Performance of an Ultrahigh Resolution Chromosomal Microarray Optimized for Neurodevelopmental Disorders

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Karen S. Ho ◽  
Hope Twede ◽  
Rena Vanzo ◽  
Erin Harward ◽  
Charles H. Hensel ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Detection Rate ◽  
Clinical Performance ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Ultrahigh Resolution ◽  
Significant Difference

Copy number variants (CNVs) as detected by chromosomal microarray analysis (CMA) significantly contribute to the etiology of neurodevelopmental disorders, such as developmental delay (DD), intellectual disability (ID), and autism spectrum disorder (ASD). This study summarizes the results of 3.5 years of CMA testing by a CLIA-certified clinical testing laboratory 5487 patients with neurodevelopmental conditions were clinically evaluated for rare copy number variants using a 2.8-million probe custom CMA optimized for the detection of CNVs associated with neurodevelopmental disorders. We report an overall detection rate of 29.4% in our neurodevelopmental cohort, which rises to nearly 33% when cases with DD/ID and/or MCA only are considered. The detection rate for the ASD cohort is also significant, at 25%. Additionally, we find that detection rate and pathogenic yield of CMA vary significantly depending on the primary indications for testing, the age of the individuals tested, and the specialty of the ordering doctor. We also report a significant difference between the detection rate on the ultrahigh resolution optimized array in comparison to the array from which it originated. This increase in detection can significantly contribute to the efficient and effective medical management of neurodevelopmental conditions in the clinic.

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