Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder

Tammimies, Kristiina; Marshall, Christian R.; Walker, Susan; Kaur, Gaganjot; Thiruvahindrapuram, Bhooma; Lionel, Anath C.; Yuen, Ryan K. C.; Uddin, Mohammed; Roberts, Wendy; Weksberg, Rosanna; Woodbury‐Smith, Marc; Zwaigenbaum, Lonnie; Anagnostou, Evdokia; Wang, Zhuozhi; Wei, John; Howe, Jennifer; Gazzellone, Matthew J.; Lau, Lynette; Sung, Wilson W L; Whitten, Kathy; Vardy, Cathy; Crosbie, Victoria; Tsang, Brian; D’Abate, Lia; Tong, Winnie W. L.; Luscombe, Sandra; Doyle, Tyna; Carter, Melissa T.; Szatmári, Péter; Stuckless, Susan; Merico, Daniele; Stavropoulos, Dimitri J.; Scherer, Stephen W.; Fernandez, Bridget A.

doi:10.1001/jama.2015.10078

Cited by 366 publications

(379 citation statements)

References 48 publications

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“…Lenroot and Yeung (2013) reported that the majority of individuals diagnosed with ASD had typical brain and head size. However, in other studies, approximately 10 to 24 % of individuals diagnosed with ASD had persisting macrocephaly (Gillberg and de Souza 2002;Lainhart 2015;Nebel et al 2015;Sacco et al 2015;Tammimies et al 2015). In addition, a number of studies have reported that 3 to 15 % of individuals with ASD had persisting microcephaly (Gillberg and de Souza 2002;Nebel et al 2015;Roullet et al 2013;Stevens et al 2013).…”

Section: Does Asd Have Neurobiological Validity?mentioning

confidence: 94%

“…In a meta-analysis, Sacco et al (2015) found only 5.7 % of individuals with ASD had macrocephaly and just 9.1 % had brain overgrowth. Tammimies et al (2015) also found that only 63 of 258 children with ASD had macrocephaly. Also countering the ASD early brain overgrowth model, 3 to 15 % of individuals diagnosed with ASD have been born with microcephalic brains (Nebel et al 2015;Roullet et al 2013;Stevens et al 2013).…”

Section: Does Asd Have Neurobiological Validity?mentioning

confidence: 95%

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ASD Validity

Waterhouse

London

Gillberg

2016

Rev J Autism Dev Disord

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ASD research is at an important crossroads. The ASD diagnosis is important for assigning a child to early behavioral intervention and explaining a child's condition. But ASD research has not provided a diagnosis-specific medical treatment, or a consistent early predictor, or a unified life course. If the ASD diagnosis also lacks biological and construct validity, a shift away from studying ASD-defined samples would be warranted. Consequently, this paper reviews recent findings for the neurobiological validity of ASD, the construct validity of ASD diagnostic criteria, and the construct validity of ASD spectrum features. The findings reviewed indicate that the ASD diagnosis lacks biological and construct validity. The paper concludes with proposals for research going forward.Keywords DSM-5 . ASD . Autism . Diagnosis . Validity . Comorbidity . HeterogeneityThe goal of the DSM-3 nosology (American Psychiatric Association 1980) was to create reliable and standard categorical psychiatric diagnoses (Robins and Guze 1970). However, in the past 30 years, clinical, genetics, and neuroscience findings have revealed that the DSM diagnoses are not biologically valid. The National Institutes of Mental Health (NIMH) responded by proposing the Research Domain Criteria (RDoC) framework for a brain-based transdiagnostic psychiatric symptom nosology (Cuthbert and Insel 2013;Insel et al. 2010;Lilienfeld and Treadway 2016). Peterson (2015) and Weinberger et al. (2015) argued that the RDoC could not replace the DSM-5 psychiatric nosology (American Psychiatric Association 2013) or the parallel International Classification of Diseases (ICD) psychiatric nosology (World Health Organization 2012). But BFor the foreseeable future, RDoC is not envisioned as a system of psychiatric classification in its own right. Instead, in the near term, RDoC and DSM-ICD are expected to coexist. Nevertheless, RDoC is intended to provide scaffolding for a large-scale research program that will ultimately yield an alternative to DSM-ICD^ (Lilienfeld and Treadway 2016, p. 445).RDoC advocates accept that DSM-5/ICD psychiatric categories remain necessary in clinical practice, but argue that researchers should shift to RDoC study designs immediately. They assert that studying psychiatric categories lacking biological validity blocks the discovery of brain bases for psychopathology and thus cannot lead to effective medical treatments for specific psychiatric symptoms (Cuthbert and Insel 2013;Insel et al. 2010;Lilienfeld and Treadway 2016;Yee et al. 2015). Against this RDoC imperative for biological validity, Weinberger et al. (2015) countered that current DSM-5 psychiatric behavioral diagnoses were valid when they yielded effective medical treatment, clear prognosis, and a life course specific to a diagnosis.Autism spectrum disorder (ASD) research has been productive (Dawson 2016;de la Torre-Ubieta et al. 2016;Szatmari et al. 2016), but no ASD research findings have met the validity criteria of Weinberger et al. (2015). DSM-5 ASD research has found no s...

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Section: Does Asd Have Neurobiological Validity?mentioning

confidence: 94%

Section: Does Asd Have Neurobiological Validity?mentioning

confidence: 95%

ASD Validity

Waterhouse

London

Gillberg

2016

Rev J Autism Dev Disord

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“…Nitric oxide, critical for blood flow regulation, is involved in the immune response and is believed to be a novel neurotransmitter. Production of the monoamine neurotransmitters dopamine, serotonin and norepinephrine as well as the circadian regulator melatonin, all require BH 4 . Interestingly, abnormalities in all of these pathways have been associated with ASD [23].…”

Section: Folate One Of the Body's Most Important Vitaminsmentioning

confidence: 99%

“…A notion of a pure genetic etiology is tempered by the fact that single gene and chromosomal defects are found in a minority of ASD cases, accounting for only 15.8% of cases when both chromosomal microarray and whole exome sequencing were used in one recent large study [4]. ASD has also been associated with exposures to numerous environmental agents during the prenatal and postnatal period [5].…”

mentioning

confidence: 99%

Folate Metabolism Abnormalities in Autism: Potential Biomarkers

2017

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Autism spectrum disorder (ASD) has been linked to abnormalities in folate metabolism. Polymorphisms in folate genes may act in complex polygenic ways to increase the risk of developing ASD. Autoantibodies that block folate transport into the brain have been associated with ASD and children with ASD and these autoantibodies respond to high doses of a reduced form of folate known as folinic acid (leucovorin calcium). Some of the same abnormalities are also found in mothers of children with ASD and supplementing folate during preconception and gestational periods reduces the risk to the offspring from developing ASD. These data suggest that folate pathway abnormalities may be a major metabolic disturbance underlying ASD that can be leveraged as biomarkers to improve symptoms and prevent ASD. Autism spectrum disorder: an emerging disorder with unclear etiology Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects about 2% of children in the USA [1]. Although it is defined through observation of the presence of abnormal behavior and absence of typical developmental milestones, ASD is associated with a wide range of medical abnormalities such as sleep, immune and gastrointestinal disorders and epilepsy. In addition to medical comorbidities, many children with ASD have disruptions in body physiology such as abnormalities in folate, cobalamin, tetrahydrobiopterin (BH 4 ), neurotransmitter, carnitine, redox and mitochondrial metabolism [2]. The connection between underlying physiological abnormalities and behavior is an area of active research. In this review, we will provide evidence that abnormalities of one-carbon folate metabolism are particularly important in ASD.Although the etiology of ASD is not known, genetics has been the focus of ASD research for many decades [3]. A notion of a pure genetic etiology is tempered by the fact that single gene and chromosomal defects are found in a minority of ASD cases, accounting for only 15.8% of cases when both chromosomal microarray and whole exome sequencing were used in one recent large study [4]. ASD has also been associated with exposures to numerous environmental agents during the prenatal and postnatal period [5]. Studies that have examined the contribution of the environmental and genetic components highlight that ASD arises as a consequence of complicated interactions between genetic predisposition and environmental factors [6,7]. As we will outline in this review, abnormalities in folate metabolism provide an excellent model of how environment factors can interact with genetic predisposition to cause ASD.At this time, the standard of care for ASD treatment is applied behavioral analysis and other equivalent behavioral interventions along with educational, developmental, occupational and speech therapy. Optimal application of behavioral therapy requires full-time one-on-one therapist for many years; however, even when this optimal therapy is applied, suboptimal outcomes are common. In addition, controlled studies examining the efficacy of variou...

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“…The diagnostic yield of known ASD patients through CMA is found to be 15-20% in most studies, as well as almost 30% by prior screening on complex cases of ASD [6]. In this procedure, a blood sample is taken from the patient, and the genetic material is then comprehensively scanned in comparison to a healthy genome control [10,11]. In identifying distinct variants from the control, this reveals mutations that may be related to the development of ASD in the patient [9].…”

Section: Introductionmentioning

confidence: 99%

Can genetic research motivate parents to pursue genomic testing for children with autism spectrum disorder?

Floyd¹,

Liu²

2017

J Autism

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Advanced genomic tests such as Chromosomal Microarray Analysis (CMA) have been clinically offered to children with Autism Spectrum Disorder(ASD). However, the actual utilization of these tests is low among parents of children with ASD. The aim of this study is to examine the association between parental perceptions regarding autism research and their intention to take their children to undergo recommended genomic tests. We conducted a web-based survey using a community strategy in Eastern North Carolina among parents of children with ASD. Our final sample constituted 204 parents. The majority were mothers, married and Caucasian. Parents' test intention was high among this sample, and those desiring to help and expressing favorable perceptions toward ASD genetic research were more likely to test. Our findings suggest a link between parental attitudes towards genetic research and their decision to test a child with ASD. This study can influence patient education approaches of health professionals in counseling parental genetic testing decision, as well as informing policy creation about access and outreach for parents toward ASD research.

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Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder

Cited by 366 publications

References 48 publications

ASD Validity

ASD Validity

Folate Metabolism Abnormalities in Autism: Potential Biomarkers

Can genetic research motivate parents to pursue genomic testing for children with autism spectrum disorder?

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