Here/In This Issue and There/Abstract Thinking: Genetic Testing in Neurodevelopmental Disorders

Abstract Objective: To compare the genetic testing results of neonates with CHD by chromosomal microarray to karyotyping and fluorescence in situ hybridisation analysis. Methods: This was a single-centre retrospective comparative study of patients with CHD and available genetic testing results admitted to the cardiac ICU between January, 2004 and December, 2017. Patients from 2004 to 2010 were tested by karyotyping and fluorescence in situ hybridisation analysis, while patients from 2012 to 2017 were analysed by chromosomal microarray. Results: Eight-hundred and forty-nine neonates with CHD underwent genetic testing, 482 by karyotyping and fluorescence in situ hybridization, and 367 by chromosomal microarray. In the karyotyping and fluorescence in situ hybridisation analysis group, 86/482 (17.8%) had genetic abnormalities detected, while in the chromosomal microarray group, 135/367 (36.8%) had genetic abnormalities detected (p < 0.00001). Of patients with abnormal chromosomal microarray results, 41/135 (30.4%) had genetic abnormality associated with neurodevelopmental disorders that were exclusively identified by chromosomal microarray. Conotruncal abnormalities were the most common diagnosis in both groups, with karyotyping and fluorescence in situ hybridisation analysis detecting genetic abnormalities in 26/160 (16.3%) patients and chromosomal microarray detecting abnormalities in 41/135 (30.4%) patients (p = 0.004). In patients with d-transposition of the great arteries, 0/68 (0%) were found to have genetic abnormalities by karyotyping and fluorescence in situ hybridisation compared to 7/54 (13.0%) by chromosomal microarray. Conclusions: Chromosomal microarray identified patients with CHD at genetic risk of neurodevelopmental disorders, allowing earlier intervention with multidisciplinary care and more accurate pre-surgical prognostic counselling.

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De novo Variants in Neurodevelopmental Disorders with Epilepsy

10.1101/123323 ◽

2017 ◽

Cited By ~ 5

Author(s):

Henrike O. Heyne ◽

Tarjinder Singh ◽

Hannah Stamberger ◽

Rami Abou Jamra ◽

Hande Caglayan ◽

...

Keyword(s):

Intellectual Disability ◽

Genetic Testing ◽

Neurodevelopmental Disorders ◽

Disease Gene ◽

De Novo ◽

Genetic Diagnosis ◽

Disease Association ◽

Joint Analysis ◽

Limited Evidence ◽

Significant Excess

AbstractEpilepsy is a frequent feature of neurodevelopmental disorders (NDD) but little is known about genetic differences between NDD with and without epilepsy. We analyzed de novo variants (DNV) in 6753 parent-offspring trios ascertained for different NDD. In the subset of 1942 individuals with NDD with epilepsy, we identified 33 genes with a significant excess of DNV, of which SNAP25 and GABRB2 had previously only limited evidence for disease association. Joint analysis of all individuals with NDD also implicated CACNA1E as a novel disease gene. Comparing NDD with and without epilepsy, we found missense DNV, DNV in specific genes, age of recruitment and severity of intellectual disability to be associated with epilepsy. We further demonstrate to what extent our results impact current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDD with epilepsy.

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5.1 The Use of Diagnostic Genetic Testing in Autism and Other Neurodevelopmental Disorders

Journal of the American Academy of Child & Adolescent Psychiatry ◽

10.1016/j.jaac.2017.07.812 ◽

2017 ◽

Vol 56 (10) ◽

pp. S8

Author(s):

Sunil Q. Mehta

Keyword(s):

Genetic Testing ◽

Neurodevelopmental Disorders ◽

Diagnostic Genetic Testing

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Neurodevelopmental disorders and genetic testing: Current approaches and future advances

Annals of Neurology ◽

10.1002/ana.23950 ◽

2013 ◽

pp. n/a-n/a ◽

Cited By ~ 2

Author(s):

Elliott H. Sherr ◽

David J. Michelson ◽

Michael I. Shevell ◽

John B. Moeschler ◽

Andrea L. Gropman ◽

...

Keyword(s):

Genetic Testing ◽

Neurodevelopmental Disorders

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Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders

Epilepsia ◽

10.1111/epi.14074 ◽

2018 ◽

Vol 59 (5) ◽

pp. 1062-1071 ◽

Cited By ~ 68

Author(s):

Amanda S. Lindy ◽

Mary Beth Stosser ◽

Elizabeth Butler ◽

Courtney Downtain‐Pickersgill ◽

Anita Shanmugham ◽

...

Keyword(s):

Genetic Testing ◽

Neurodevelopmental Disorders ◽

Patients With Epilepsy ◽

Diagnostic Outcomes

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Genetic Testing in Neurodevelopmental Disorders

Frontiers in Pediatrics ◽

10.3389/fped.2021.526779 ◽

2021 ◽

Vol 9 ◽

Author(s):

Juliann M. Savatt ◽

Scott M. Myers

Keyword(s):

Autism Spectrum Disorder ◽

Intellectual Disability ◽

Genetic Testing ◽

Neurodevelopmental Disorders ◽

Diagnostic Yield ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Chromosomal Microarray ◽

Global Developmental Delay ◽

Cgg Repeat

Neurodevelopmental disorders are the most prevalent chronic medical conditions encountered in pediatric primary care. In addition to identifying appropriate descriptive diagnoses and guiding families to evidence-based treatments and supports, comprehensive care for individuals with neurodevelopmental disorders includes a search for an underlying etiologic diagnosis, primarily through a genetic evaluation. Identification of an underlying genetic etiology can inform prognosis, clarify recurrence risk, shape clinical management, and direct patients and families to condition-specific resources and supports. Here we review the utility of genetic testing in patients with neurodevelopmental disorders and describe the three major testing modalities and their yields – chromosomal microarray, exome sequencing (with/without copy number variant calling), and FMR1 CGG repeat analysis for fragile X syndrome. Given the diagnostic yield of genetic testing and the potential for clinical and personal utility, there is consensus that genetic testing should be offered to all patients with global developmental delay, intellectual disability, and/or autism spectrum disorder. Despite this recommendation, data suggest that a minority of children with autism spectrum disorder and intellectual disability have undergone genetic testing. To address this gap in care, we describe a structured but flexible approach to facilitate integration of genetic testing into clinical practice across pediatric specialties and discuss future considerations for genetic testing in neurodevelopmental disorders to prepare pediatric providers to care for patients with such diagnoses today and tomorrow.

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