A Novel Recurrent Breakpoint Responsible for Rearrangements in the Williams-Beuren Region

2015 ◽  
Vol 146 (3) ◽  
pp. 181-186 ◽  
Author(s):  
Alberto Plaja ◽  
Neus Castells ◽  
Anna M. Cueto-González ◽  
Miguel del Campo ◽  
Teresa Vendrell ◽  
...  
Keyword(s):  
Motor Skills ◽  
Neurodevelopmental Disorders ◽  
Array Cgh ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Global Developmental Delay ◽  
Speech Delay ◽  
Commercial Fish ◽  
The Third ◽  
Multisystem Involvement

Copy number variants (CNVs) of the Williams-Beuren syndrome (WBS) 7q11.23 region are responsible for neurodevelopmental disorders with multisystem involvement and variable expressivity. We found 2 patients with a deletion and 1 patient with a duplication in this region sharing a common breakpoint located between the LIMK1 and EIF4H(WBSCR1) genes. One patient had a WBS phenotype, although testing with a commercially available FISH assay was negative for the deletion. A further test using array CGH showed an atypical WBS region deletion. The second patient showed global developmental delay, speech delay and poor motor skills with a deletion outside the WBS region. The third patient had manifestations compatible with an autism spectrum disorder showing a duplication in the WBS region. Our findings point to the existence of a previously unrecognized recurrent breakpoint responsible for rearrangements in the WBS region. Given that most commercial FISH assays include probes flanking this novel breakpoint, further testing with array CGH should be performed in patients with WBS and negative FISH results.

scholarly journals Actionable and incidental neuroradiological findings in twins with neurodevelopmental disorders

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Lynnea Myers ◽  
Mai-Lan Ho ◽  
Elodie Cauvet ◽  
Karl Lundin ◽  
Torkel Carlsson ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number Variants ◽  
Cross Sectional Study ◽  
Autism Spectrum ◽  
Molecular Signaling ◽  
Mri Findings ◽  
Cross Sectional ◽  
Increased Risk ◽  
Magnetic Resonance Imaging Mri ◽  
Morphological Variants

AbstractWhile previous research has investigated neuroradiological findings in autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD), the entire range of neurodevelopmental disorders (NDDs) has not yet been well-studied using magnetic resonance imaging (MRI). Considering the overlap among NDDs and simultaneous development of the brain and face, guided by molecular signaling, we examined the relationship of actionable and incidental (non-actionable) MRI findings and NDD diagnoses together with facial morphological variants and genetic copy number variants (CNVs). A cross-sectional study was conducted with a twin cohort 8–36 years of age (57% monozygotic, 40% dizygotic), including 372 subjects (46% with NDDs; 47% female) imaged by MRI, 280 with data for facial morphological variants, and 183 for CNVs. Fifty-one percent of participants had MRI findings. Males had a statistically significantly higher percentage of MRI findings (57.7%) compared with females (43.8%, p = 0.03). Twin zygosity was not statistically significantly correlated with incidence or severity of specific MRI findings. No statistically significant association was found between MRI findings and any NDD diagnosis or facial morphological variants; however, MRI findings were statistically significantly associated with the number of CNVs (OR 1.20, 95% CI 1.00–1.44, p = 0.05, adjusted OR for sex 1.24, 95% CI 1.03–1.50, p = 0.02). When combining the presence of MRI findings, facial morphological variants, and CNVs, statistically significant relationships were found with ASD and ADHD diagnoses (p = 0.0006 and p = 0.002, respectively). The results of this study demonstrate that the ability to identify NDDs from combined radiology, morphology, and CNV assessments may be possible. Additionally, twins do not appear to be at increased risk for neuroradiological variants.

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.

scholarly journals Comparison of the diagnostic yield of aCGH and genome-wide sequencing across different neurodevelopmental disorders

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Francisco Martinez-Granero ◽  
Fiona Blanco-Kelly ◽  
Carolina Sanchez-Jimeno ◽  
Almudena Avila-Fernandez ◽  
Ana Arteche ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Neurodevelopmental Disorders ◽  
Diagnostic Yield ◽  
Genetic Diagnosis ◽  
Diagnostic Algorithm ◽  
Signs And Symptoms ◽  
Autism Spectrum ◽  
Global Developmental Delay ◽  
Comparative Genomic ◽  
Clinical Exome Sequencing

AbstractMost consensus recommendations for the genetic diagnosis of neurodevelopmental disorders (NDDs) do not include the use of next generation sequencing (NGS) and are still based on chromosomal microarrays, such as comparative genomic hybridization array (aCGH). This study compares the diagnostic yield obtained by aCGH and clinical exome sequencing in NDD globally and its spectrum of disorders. To that end, 1412 patients clinically diagnosed with NDDs and studied with aCGH were classified into phenotype categories: global developmental delay/intellectual disability (GDD/ID); autism spectrum disorder (ASD); and other NDDs. These categories were further subclassified based on the most frequent accompanying signs and symptoms into isolated forms, forms with epilepsy; forms with micro/macrocephaly and syndromic forms. Two hundred and forty-five patients of the 1412 were subjected to clinical exome sequencing. Diagnostic yield of aCGH and clinical exome sequencing, expressed as the number of solved cases, was compared for each phenotype category and subcategory. Clinical exome sequencing was superior than aCGH for all cases except for isolated ASD, with no additional cases solved by NGS. Globally, clinical exome sequencing solved 20% of cases (versus 5.7% by aCGH) and the diagnostic yield was highest for all forms of GDD/ID and lowest for Other NDDs (7.1% versus 1.4% by aCGH) and ASD (6.1% versus 3% by aCGH). In the majority of cases, diagnostic yield was higher in the phenotype subcategories than in the mother category. These results suggest that NGS could be used as a first-tier test in the diagnostic algorithm of all NDDs followed by aCGH when necessary.

scholarly journals Milestone Development in Genetic Conditions from SFARI Registries

2021 ◽  
Author(s):  
Jordan Wickstrom ◽  
Cristan Farmer ◽  
LeeAnne Green Snyder ◽  
Andrew R. Mitz ◽  
Stephan J. Sanders ◽  
...  
Keyword(s):  
Motor Skills ◽  
Neurodevelopmental Disorders ◽  
Genetic Diagnosis ◽  
Age Of Acquisition ◽  
Autism Spectrum ◽  
Inclusion Criteria ◽  
Autism Research ◽  
Genetic Groups ◽  
Research Initiative ◽  
Normative Expectations

Abstract Background: Several recent initiatives have sought to better understand characteristic behaviors of rare genetic conditions associated with autism spectrum disorder (ASD). The onset of developmentally expected skills, such as walking and talking, serve as readily quantifiable aspects of the behavioral phenotype. The goals of this study were to describe attainment of major motor and language milestones in genetic conditions implicated in the etiology of ASD and other neurodevelopmental disorders and to compare those phenotypes to idiopathic ASD. Methods: Participants ages 3 years and older were drawn from two Simons Foundation Autism Research Initiative-funded registries with consistent phenotyping protocols. Inclusion criteria consisted of a confirmed genetic diagnosis for one of 16 specific genetic conditions (Simons Searchlight), and absence of pathogenic genetic findings in idiopathic ASD controls (SPARK). Parent-reported age of acquisition of three motor and two language milestones was described and quantified as on-time or delayed relative to normative expectations. Results: Delay was more common among participants with rare genetic conditions than idiopathic ASD for all milestones. Compared to the idiopathic ASD group, the median odds of delay among the genetic groups were 8.3 times (IQR 5.8-16.3) higher for sitting, 12.4 times (IQR 5.3-19.5) higher for crawling, 26.8 times (IQR 7.7-41.1) higher for walking, 2.7 times (IQR 1.7-5.5) higher for single words, and 5.7 times (IQR 2.8-18.3) higher for combined words. Conclusion: Delays in major developmental milestones, particularly in motor skills, may be among the earliest clues that developmental processes may be differentially affected in specific genetically defined conditions versus a behaviorally defined disorder such as idiopathic ASD.

scholarly journals Genetic Testing in Neurodevelopmental Disorders

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.

scholarly journals Cognitive performance and functional outcomes of carriers of pathogenic copy number variants: analysis of the UK Biobank

2019 ◽  
Vol 214 (5) ◽  
pp. 297-304 ◽  
Author(s):  
Kimberley M. Kendall ◽  
Matthew Bracher-Smith ◽  
Harry Fitzpatrick ◽  
Amy Lynham ◽  
Elliott Rees ◽  
...  
Keyword(s):  
Cognitive Performance ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Cognitive Test ◽  
Carrier Status ◽  
Cognitive Tests ◽  
Uk Biobank ◽  
The Uk

BackgroundRare copy number variants (CNVs) are associated with risk of neurodevelopmental disorders characterised by varying degrees of cognitive impairment, including schizophrenia, autism spectrum disorder and intellectual disability. However, the effects of many individual CNVs in carriers without neurodevelopmental disorders are not yet fully understood, and little is known about the effects of reciprocal copy number changes of known pathogenic loci.AimsWe aimed to analyse the effect of CNV carrier status on cognitive performance and measures of occupational and social outcomes in unaffected individuals from the UK Biobank.MethodWe called CNVs in the full UK Biobank sample and analysed data from 420 247 individuals who passed CNV quality control, reported White British or Irish ancestry and were not diagnosed with neurodevelopmental disorders. We analysed 33 pathogenic CNVs, including their reciprocal deletions/duplications, for association with seven cognitive tests and four general measures of functioning: academic qualifications, occupation, household income and Townsend Deprivation Index.ResultsMost CNVs (24 out of 33) were associated with reduced performance on at least one cognitive test or measure of functioning. The changes on the cognitive tests were modest (average reduction of 0.13 s.d.) but varied markedly between CNVs. All 12 schizophrenia-associated CNVs were associated with significant impairments on measures of functioning.ConclusionsCNVs implicated in neurodevelopmental disorders, including schizophrenia, are associated with cognitive deficits, even among unaffected individuals. These deficits may be subtle but CNV carriers have significant disadvantages in educational attainment and ability to earn income in adult life.Declaration of interestNone.

scholarly journals Neurodevelopmental disorders—the history and future of a diagnostic concept

2020 ◽  
Vol 22 (1) ◽  
pp. 65-72 ◽  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Genetic Research ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Hyperactivity Disorder ◽  
Diagnostic Categories ◽  
Dsm 5 ◽  
French And English ◽  
History Of ◽  
English Speaking

This article describes the history of the diagnostic class of neurodevelopmental disorders (NDDs) up to DSM-5. We further analyze how the development of genetics will transform the classification and diagnosis of NDDs. In DSM-5, NDDs include intellectual disability (ID), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD). Physicians in German-, French- and English-speaking countries (eg, Weikard, Georget, Esquirol, Down, Asperger, and Kanner) contributed to the phenomenological definitions of these disorders throughout the 18th and 20th centuries. These diagnostic categories show considerable comorbidity and phenotypic overlap. NDDs are one of the chapters of psychiatric nosology most likely to benefit from the approach advocated by the National Institute of Mental Health’s Research Domain Criteria project. Genetic research supports the hypothesis that ID, ASD, ADHD, schizophrenia, and bipolar disorder lie on a neurodevelopmental continuum. The identification of recurrently observed copy number variants and disruptive gene variants in ASD (eg, CDH8, 16p11.2, SCN2A) led to the adoption of the genotype-first approach to characterize individuals at the etiological level.

scholarly journals Perinatal Exposure to Environmental Endocrine Disruptors in the Emergence of Neurodevelopmental Psychiatric Diseases: A Systematic Review

2019 ◽  
Vol 16 (8) ◽  
pp. 1318 ◽  
Author(s):  
Fabrice Rivollier ◽  
Marie-Odile Krebs ◽  
Oussama Kebir
Keyword(s):  
Systematic Review ◽  
Psychiatric Disorders ◽  
Endocrine Disruptors ◽  
Neurodevelopmental Disorders ◽  
Endocrine Disruptor ◽  
Communication Disorders ◽  
Autism Spectrum ◽  
Global Developmental Delay ◽  
Perinatal Exposure ◽  
Developmental Abnormalities

Background: Exposure to endocrine disruptors is on the rise, with new compounds regularly incriminated. In animals and humans, this exposure during critical developmental windows has been associated with various developmental abnormalities, including the emergence of psychiatric disorders. We aimed to review the association between perinatal endocrine disruptor exposure and neurodevelopmental disorders in humans, focusing on cognitive and psychiatric disorders. Methods: We performed a systematic review with key words referring to the fields of neurodevelopment and endocrine disruptors. We reviewed 896 titles, choosing studies on the basis of titles and abstracts. We searched through the methodology sections to find perinatal exposure and neurodevelopmental disorders, following the categories indicated in the Diagnostic and Statistic Manual of Mental Disorders (5th edition). References in some studies brought us to a total of 47 studies included here. Results: Convergent studies report an association between exposure to endocrine disruptors and autism spectrum disorder, attention-deficit hyperactivity disorder, global developmental delay, intellectual disability, communication disorders and unspecified neurodevelopmental disorders. Conclusion: Sufficient data exist to report that exposure to some endocrine disruptors is a risk factor for the emergence of neurodevelopmental disorders. Studying endocrine disruptor exposure in humans is still associated with some limits that are difficult to overcome.

scholarly journals Comparing Motor Skills in Autism Spectrum Individuals With and Without Speech Delay

2015 ◽  
Vol 8 (6) ◽  
pp. 682-693 ◽  
Author(s):  
Elise B. Barbeau ◽  
Andrée‐Anne S. Meilleur ◽  
Thomas A. Zeffiro ◽  
Laurent Mottron
Keyword(s):  
Motor Skills ◽  
Autism Spectrum ◽  
Speech Delay
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