Using extended pedigrees to identify novel autism spectrum disorder (ASD) candidate genes

Woodbury‐Smith, Marc; Paterson, Andrew D.; Thiruvahindrapduram, Bhooma; Lionel, Anath C.; Marshall, Christian R.; Merico, Daniele; Fernandez, Bridget A.; Duku, Eric; Sutcliffe, James S.; O’Conner, Irene; Chrysler, Christina; Thompson, Ann; Kellam, Barbara; Tammimies, Kristiina; Walker, Susan; Yuen, Ryan K. C.; Uddin, Mohammed; Howe, Jennifer; Parlier, Morgan; Whitten, Kathy; Szatmári, Péter; Vieland, Veronica J.; Piven, Joseph; Scherer, Stephen W.

doi:10.1007/s00439-014-1513-6

Cited by 22 publications

(32 citation statements)

References 61 publications

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“…Family-based association studies in families with at least two affected males have shown that over-transmission of a DRD1 haplotype occurs from mother-to-son and genotype-phenotype assessments revealed significant associations with DRD1 polymorphisms (Hettinger et al, 2008). However, GWAS from ASD patients have mostly failed to identify candidate causative genes (Chaste et al, 2015;Woodbury-Smith et al, 2015), thereby warranting further studies to identify novel targets underlying the male bias in ASD.…”

Section: Autism Spectrum Disordersmentioning

confidence: 92%

Biological factors underlying sex differences in neurological disorders

Loke

Harley

Lee

2015

The International Journal of Biochemistry & Cell Biology

124

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Section: Autism Spectrum Disordersmentioning

confidence: 92%

Biological factors underlying sex differences in neurological disorders

Loke

Harley

Lee

2015

The International Journal of Biochemistry & Cell Biology

124

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“…Similarly, Bernier et al (2012) reported that in families where more than one family member was diagnosed with ASD, more undiagnosed family members expressed BAP symptoms. Woodbury-Smith et al (2015) looked for a genetic link between parents' BAP and presence of specific CNVs in their children diagnosed with ASD, but could only find, Ba small number of CNVs transmitted from BAP parents to ASD offspring^(p. 196).…”

Section: Rates Of Recovery From Asd Are Variedmentioning

confidence: 99%

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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“…For example, four candidate ASD genes were identified in seven ASD/BAP pedigrees with ≥3 affected individuals 43 . Larger multiplex families remain scarce in the literature 20,44 . Here, we identified more subtle indicators of carrier status in two large families, using a robust endophenotyping method with good sensitivity and specificity to detect the BAP in two independent samples.…”

Section: Discussionmentioning

confidence: 99%

“…In other complex disorders, such as epilepsy, phenotypic characterisation of such families has proved powerful in gene discovery 18 , however this approach has received limited attention in ASD 1818 . In multiplex ASD families, the identification of family members with BAP traits, or endophenotypes, may serve as markers of carrier status 19,20 . In turn, this may facilitate gene identification 21 .…”

mentioning

confidence: 99%

Tracing Autism Traits in Large Multiplex Families to Identify Endophenotypes of the Broader Autism Phenotype

Trevis

Brown

Green

et al. 2019

Preprint

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27Families comprising many individuals with Autism Spectrum Disorder (ASD) may carry a 28 dominant predisposing mutation. Our aim was to use rigorous phenotyping of the 'Broader 29 Autism Phenotype' (BAP) in large multiplex ASD families to identify endophenotypes of the 30 BAP for future genetic studies. We evaluated ASD/BAP features using standardised tests and a 31 semi-structured interview to assess social, intellectual, executive and adaptive functioning in 109 32 individuals, including two large multiplex families (Family A: 30; Family B: 34) and an 33 independent sample of small families (n=45). Our protocol identified four psychological 34 endophenotypes of the BAP that were evident in both samples, and showed high sensitivity 35(97%) and specificity (82%) for individuals classified with the BAP. The patterns of inheritance 36 of these endophenotypes varied in the two large families, supporting their utility for identifying 37 genes in autism. 38 39 Keywords: Broader autism phenotype, genetic, autism spectrum disorder, multiplex family 40 Tracing Autism Traits 3 Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that spans deficits in two 41 domains: social communication, and restricted interests or repetitive behaviours APA 2013. 42 Recent estimates from the Center for Disease Control and Prevention indicate prevalence of 43 ASD is one in 68 children aged 8 years 1 making ASD a critical international health problem. 44Clinical and molecular research provides evidence for a genetic aetiology in ASD, yet despite 45 recent molecular advances the cause remains unidentified in the majority of cases. 46

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Using extended pedigrees to identify novel autism spectrum disorder (ASD) candidate genes

Cited by 22 publications

References 61 publications

Biological factors underlying sex differences in neurological disorders

Biological factors underlying sex differences in neurological disorders

ASD Validity

Tracing Autism Traits in Large Multiplex Families to Identify Endophenotypes of the Broader Autism Phenotype

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