Utility of Chromosomal Microarray in Children with Unexplained Developmental Delay/Intellectual Disability

Kamath, Vandana; Yoganathan, Sangeetha; Thomas, Maya; Gowri, Mahasampath; Chacko, Mary Purna

doi:10.1080/15513815.2020.1791292

Cited by 7 publications

(5 citation statements)

References 27 publications

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“…In our study, we excluded patients with epilepsy to obtain a more homogeneous group of patients specific to NDDs. Facial dysmorphism was the most common comorbidity, similar to the literature [Kamath et al, 2022].…”

Section: Discussionsupporting

confidence: 84%

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Clinical and Genetic Characteristics of Patients with Unexplained Intellectual Disability/Developmental Delay without Epilepsy

Çelebi¹,

Aydin²,

Bolat³

et al. 2023

Mol Syndromol

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Introduction: Global developmental delay (DD), intellectual disability (ID), and autism spectrum disorder (ASD) are mainly evaluated under the neurodevelopmental disorder framework. In this study, we aimed to determine the genetic diagnosis yield using step-by-step genetic analysis in 38 patients with unexplained ID/DD and/or ASD. Methods: In 38 cases (27 male, 11 female) with unexplained ID/DD and/or ASD, chromosomal microarray (CMA) analysis, clinical exome sequencing (CES), and whole-exome sequencing (WES) analysis were applied, respectively. Results: We found a diagnostic rate of only CMA analysis as 21% (8/38) presenting 8 pathogenic and likely pathogenic CNVs. The rate of patients diagnosed with CES/WES methods was 32.2% (10/31). When all pathogenic and likely pathogenic variants were evaluated, the diagnosis rate was 44.7% (17/38). A dual diagnosis was obtained in a case with 16p11.2 microduplication and de novo SNV. We identified eight novel variants: TUBA1A (c.787C>G), TMEM63A (c.334-2A>G), YY1AP1 (c.2051_2052del), ABCA13 (c.12064C>T), ABCA13 (c.13187G>A), USP9X (c.1189T>C), ANKRD17 (c.328_330dup), and GRIA4 (c.17G>A). Conclusion: We present diagnostic rates of a complementary approach to genetic analysis (CMA, CES, and WES). The combined use of genetic analysis methods in unexplained ID/DD and/or ASD cases has contributed significantly to diagnosis rates. Also, we present detailed clinical characteristics to improve genotype-phenotype correlation in the literature for rare and novel variants.

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Section: Discussionsupporting

confidence: 84%

“…When all pathogenic and likely pathogenic variants were evaluated, the diagnosis rate was 44.7%. In studies investigating the genetic etiology of ID/DD patients, a genetic cause was found in approximately 40% of the patients (25-50%) [Nambot et al, 2018;Elmas et al, 2019;Kamath et al, 2022;Türkyılmaz et al, 2022].…”

Section: Discussionmentioning

confidence: 99%

Clinical and Genetic Characteristics of Patients with Unexplained Intellectual Disability/Developmental Delay without Epilepsy

Çelebi¹,

Aydin²,

Bolat³

et al. 2023

Mol Syndromol

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“…CMA focuses on copy number variations (CNV) and is recommended as the first-tier method to diagnose ID or GDD by many associations (Miller et al, 2010; Subspecialty Group of Neurology, Chinese Society of Pediatrics, Chinese Medical Association, & Project Expert Group of Childhood Neuropathy, China Neurologist Association, 2018). The diagnostic yield of CMA in this population ranges from 12% to 30% (Fan et al, 2018;Kamath et al, 2020;Miller et al, 2010;Moeschler et al, 2014;Yuan et al, 2021). A recent metaanalysis revealed that ES helped to solve 36% (range 8%-90%) of cases in patients with suspected neurodevelopmental disorders (NDD), and has been recommended as a first-tier clinical diagnostic test for NDD (Srivastava et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Genome sequencing demonstrates high diagnostic yield in children with undiagnosed global developmental delay/intellectual disability: A prospective study

Sun

Peng

et al. 2022

Human Mutation

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Genome sequencing (GS) has been used in the diagnosis of global developmental delay (GDD)/intellectual disability (ID). However, the performance of GS in patients with inconclusive results from chromosomal microarray analysis (CMA) and exome sequencing (ES) is unknown. We recruited 100 pediatric GDD/ID patients from multiple sites in China from February 2018 to August 2020 for GS. Patients have received at least one genomic diagnostic test before enrollment. Reanalysis of their CMA/ES data was performed. The yield of GS was calculated and explanations for missed diagnoses by CMA/ES were investigated. Clinical utility was assessed by interviewing the parents by phone. The overall diagnostic yield of GS was 21%. Seven cases could have been solved with reanalysis of ES data. Thirteen families were missed by previous CMA/ES due to improper methodology. Two remained unsolved after ES reanalysis due to complex variants missed by ES, and a CNV in untranslated regions. Follow‐up of the diagnosed families revealed that nine families experienced changes in clinical management, including identification of targeted treatments, cessation of unnecessary treatment, and considerations for family planning. GS demonstrated high diagnostic yield and clinical utility in this undiagnosed GDD/ID cohort, detecting a wide range of variant types of different sizes in a single workflow.

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“…Although the benefit of establishing a genetic diagnosis is apparent, resources are limited for marginalized groups and in developing countries [ 10 ]. Many developing countries are only starting to adopt CMA as the first-tier evaluation for GDD/ID [ 36 , 45 ]. It is, again, a shared decision-making process for the patient/family and the ordering provider.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Sequencing Modalities for Children with Unexplained Global Developmental Delay and Intellectual Disabilities—A Narrative Review

Chen

2023

Children

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Unexplained global developmental delay (GDD) and intellectual disabilities (ID) together affect nearly 2% of the pediatric population. Establishing an etiologic diagnosis is crucial for disease management, prognostic evaluation, and provision of physical and psychological support for both the patient and the family. Advancements in genome sequencing have allowed rapid accumulation of gene–disorder associations and have accelerated the search for an etiologic diagnosis for unexplained GDD/ID. We reviewed recent studies that utilized genome-wide analysis technologies, and we discussed their diagnostic yield, strengths, and limitations. Overall, exome sequencing (ES) and genome sequencing (GS) outperformed chromosomal microarrays and targeted panel sequencing. GS provides coverage for both ES and chromosomal microarray regions, providing the maximal diagnostic potential, and the cost of ES and reanalysis of ES-negative results is currently still lower than that of GS alone. Therefore, singleton or trio ES is the more cost-effective option for the initial investigation of individuals with GDD/ID in clinical practice compared to a staged approach or GS alone. Based on these updated evidence, we proposed an evaluation algorithm with ES as the first-tier evaluation for unexplained GDD/ID.

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Utility of Chromosomal Microarray in Children with Unexplained Developmental Delay/Intellectual Disability

Cited by 7 publications

References 27 publications

Clinical and Genetic Characteristics of Patients with Unexplained Intellectual Disability/Developmental Delay without Epilepsy

Clinical and Genetic Characteristics of Patients with Unexplained Intellectual Disability/Developmental Delay without Epilepsy

Genome sequencing demonstrates high diagnostic yield in children with undiagnosed global developmental delay/intellectual disability: A prospective study

Genome-Wide Sequencing Modalities for Children with Unexplained Global Developmental Delay and Intellectual Disabilities—A Narrative Review

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