Chromosomal Microarray Testing for Children With Unexplained Neurodevelopmental Disorders

Martin, Christa Lese; Ledbetter, David H.

doi:10.1001/jama.2017.7272

Cited by 22 publications

(14 citation statements)

References 8 publications

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“…22 In addition, without universal chromosomal microarray testing, other abnormalities including copy number variants may be missed. 23 Therefore, the incidence of genetic anomalies may be higher than what we have reported.…”

Section: Discussioncontrasting

confidence: 57%

Outcomes of Isolated Fetal Ventriculomegaly That Resolve In Utero

et al. 2020

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Objective Isolated fetal ventriculomegaly is often an incidental finding on antenatal ultrasound. It is benign in up to 90% of cases, although it can be associated with genetic, structural, and neurocognitive disorders. The literature suggests that over 40% of isolated mild ventriculomegaly will resolve in utero, but it is unclear if resolution decreases the associated risks.The aim of this study is to compare the fetal and neonatal genetic outcomes of ventriculomegaly that persists or resolves on subsequent ultrasound. Study Design This is a retrospective cohort study of women diagnosed with isolated ventriculomegaly via fetal ultrasound at a tertiary referral center between 2011 and 2019. Patients were excluded if other structural anomalies were identified on ultrasound. Results A total of 49 patients were included in the study, 19 in the resolved ventriculomegaly group and 30 in the persistent ventriculomegaly group. Women in the resolved ventriculomegaly group were more likely to be diagnosed earlier (24 vs. 28 weeks, p = 0.007). Additionally, they were more likely to have mild ventriculomegaly (63 vs. 84%, p = 0.15), and less likely to have structural neurological abnormalities diagnosed on postnatal imaging (5 vs. 17%, p = 0.384), although these were not statistically significant. Aneuploidy risk for resolved compared with persistent ventriculomegaly was similar (5 vs. 7%, p = 0.999). Conclusion This study suggests that resolution of isolated ventriculomegaly in utero may not eliminate the risk of genetic or chromosomal abnormalities in this population and may warrant inclusion as part of the counselling of these at-risk patients. Larger prospective studies are needed to confirm these findings. Key Points

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Section: Discussioncontrasting

confidence: 57%

Outcomes of Isolated Fetal Ventriculomegaly That Resolve In Utero

et al. 2020

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“…The diagnostic yield of chromosomal microarray testing has been found to be 12–20% [ 20 , 37 , 38 ]. Furthermore, the diagnostic yield does not vary depending on the type of platform used, such as comparative genomic hybridization or single-nucleotide polymorphism, indicating that it does not depend on the resolution of the microarrays.…”

Section: Diagnostic Yield Of the Methods Used For Genetic Testingmentioning

confidence: 99%

Genomic Aberrations Associated with the Pathophysiological Mechanisms of Neurodevelopmental Disorders

Yamamoto

2021

Cells

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Genomic studies are increasingly revealing that neurodevelopmental disorders are caused by underlying genomic alterations. Chromosomal microarray testing has been used to reliably detect minute changes in genomic copy numbers. The genes located in the aberrated regions identified in patients with neurodevelopmental disorders may be associated with the phenotypic features. In such cases, haploinsufficiency is considered to be the mechanism, when the deletion of a gene is related to neurodevelopmental delay. The loss-of-function mutation in such genes may be evaluated using next-generation sequencing. On the other hand, the patients with increased copy numbers of the genes may exhibit different clinical symptoms compared to those with loss-of-function mutation in the genes. In such cases, the additional copies of the genes are considered to have a dominant negative effect, inducing cell stress. In other cases, not the copy number changes, but mutations of the genes are responsible for causing the clinical symptoms. This can be explained by the dominant negative effects of the gene mutations. Currently, the diagnostic yield of genomic alterations using comprehensive analysis is less than 50%, indicating the existence of more subtle alterations or genomic changes in the untranslated regions. Copy-neutral inversions and insertions may be related. Hence, better analytical algorithms specialized for the detection of such alterations are required for higher diagnostic yields.

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“…However, the diagnostic yield in patients was low. The expected yield of FMR1 trinucleotide repeat analysis was 1%-5% in males [10], and the diagnostic yield of G-banded karyotype for patients with NDD developmental delay, intellectual disability, and autism spectrum disorder (ASD) was 5% [10,11]. With technological advancements and the growing need to make an accurate diagnosis in more patients, the implementation of chromosome microarray analysis (CMA) as part of the first-line evaluation for children with NDD achieved a diagnostic yield of 10-15% [12,13].…”

Section: Conventional Genetic Testing Methodsmentioning

confidence: 99%

Diagnostic Utility of Genome-Wide DNA Methylation Analysis in Mendelian Neurodevelopmental Disorders

Haghshenas

Bhai

Aref‐Eshghi

et al. 2020

IJMS

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Mendelian neurodevelopmental disorders customarily present with complex and overlapping symptoms, complicating the clinical diagnosis. Individuals with a growing number of the so-called rare disorders exhibit unique, disorder-specific DNA methylation patterns, consequent to the underlying gene defects. Besides providing insights to the pathophysiology and molecular biology of these disorders, we can use these epigenetic patterns as functional biomarkers for the screening and diagnosis of these conditions. This review summarizes our current understanding of DNA methylation episignatures in rare disorders and describes the underlying technology and analytical approaches. We discuss the computational parameters, including statistical and machine learning methods, used for the screening and classification of genetic variants of uncertain clinical significance. Describing the rationale and principles applied to the specific computational models that are used to develop and adapt the DNA methylation episignatures for the diagnosis of rare disorders, we highlight the opportunities and challenges in this emerging branch of diagnostic medicine.

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Chromosomal Microarray Testing for Children With Unexplained Neurodevelopmental Disorders

Cited by 22 publications

References 8 publications

Outcomes of Isolated Fetal Ventriculomegaly That Resolve In Utero

Outcomes of Isolated Fetal Ventriculomegaly That Resolve In Utero

Genomic Aberrations Associated with the Pathophysiological Mechanisms of Neurodevelopmental Disorders

Diagnostic Utility of Genome-Wide DNA Methylation Analysis in Mendelian Neurodevelopmental Disorders

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