Dataset Information

Differences in the importance of microcephaly, dysmorphism, and epilepsy in the detection of pathogenic CNVs in ID and ASD patients.

ABSTRACT: Background:Autism spectrum disorders (ASD) and intellectual disabilities (ID) are heterogeneous and complex developmental diseases with significant genetic backgrounds and overlaps of genetic susceptibility loci. Copy number variants (CNVs) are known to be frequent causes of these impairments. However, the clinical heterogeneity of both disorders causes the diagnostic efficacy of CNV analysis to be modest. This could be resolved by stratifying patients according to their clinical features. Aim:First, we sought to assess the significance of particular clinical features for the detection of pathogenic CNVs in separate groups of ID and ASD patients and determine whether and how these groups differ from each other in the significance of these variables. Second, we aimed to create a statistical model showing how particular clinical features affect the probability of pathogenic CNV findings. Method:We tested a cohort of 204 patients with ID (N = 90) and ASD (N = 114) for the presence of pathogenic CNVs. We stratified both groups according to their clinical features. Fisher's exact test was used to determine the significance of these variables for pathogenic CNV findings. Logistic regression was used to create a statistical model of pathogenic CNV findings. Results:The frequency of pathogenic CNV was significantly higher in the ID group than in the ASD group: 18 (19.78%) versus 8 (7%) (p < 0.004). Microcephaly showed a significant association with pathogenic findings in ID patients (p < 0.01) according to Fisher's exact test, whereas epilepsy showed a significant association with pathogenic findings in ASD patients (p < 0.01). The probability of pathogenic CNV findings when epilepsy occurred in ASD patients was more than two times higher than if epilepsy co-occurred with ID (29.6%/14.0%). Facial dysmorphism was a significant variable for detecting pathogenic CNVs in both groups (ID p = 0.05, ASD p = 0.01). However, dysmorphism increased the probability of pathogenic CNV detection in the ID group nearly twofold compared to the ASD group (44.4%/23.7%). The presence of macrocephaly in the ASD group showed a 25% probability of pathogenic CNV findings by logistic regression, but this was insignificant according to Fisher's exact test. The probability of detecting pathogenic CNVs decreases up to 1% in the absence of dysmorphism, macrocephaly, and epilepsy in the ASD group. Conclusion:Dysmorphism, microcephaly, and epilepsy increase the probability of pathogenic CNV findings in ID and ASD patients. The significance of each feature as a predictor for pathogenic CNV detection differs depending on whether the patient has only ASD or ID. The probability of pathogenic CNV findings without dysmorphism, macrocephaly, or epilepsy in ASD patients is low. Therefore the efficacy of CNV analysis is limited in these patients.

SUBMITTER: Capkova Z

PROVIDER: S-EPMC6859875 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Differences in the importance of microcephaly, dysmorphism, and epilepsy in the detection of pathogenic CNVs in ID and ASD patients.

Capkova Zuzana Z Capkova Pavlina P Srovnal Josef J Staffova Katerina K Becvarova Vera V Trkova Marie M Adamova Katerina K Santava Alena A Curtisova Vaclava V Hajduch Marian M Prochazka Martin M

PeerJ 20191115

<h4>Background</h4>Autism spectrum disorders (ASD) and intellectual disabilities (ID) are heterogeneous and complex developmental diseases with significant genetic backgrounds and overlaps of genetic susceptibility loci. Copy number variants (CNVs) are known to be frequent causes of these impairments. However, the clinical heterogeneity of both disorders causes the diagnostic efficacy of CNV analysis to be modest. This could be resolved by stratifying patients according to their clinical feature ...[more]

PMID: 31741789

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Project description:ObjectiveTo identify and summarize clinical practice guidelines for autism spectrum disorder (ASD) and intellectual disability (ID) for the Package of Interventions for Rehabilitation for the World Health Organization (WHO).Data sourcesAcademic databases, Google Scholar, guideline databases, and professional society websites were searched using the general criteria "ASD/ID" AND "rehabilitation" AND "guideline," restricted to English-only guidelines.Study selectionWork group members independently screened titles and abstracts (1952 ASD; 1027 ID) and excluded articles if not (1) a guideline; (2) about rehabilitation; (3) published since 2008; or (4) about ASD/ID. Full-text screening (29 ASD; 5 ID) involved 3 additional exclusion criteria: (1) contained conflict of interest; (2) lacked information on strength of recommendation; or (3) failed the Appraisal of Guidelines for Research and Evaluation II instrument. Six guidelines (4 ASD: 2 on youth, 1 on adults, 1 on all ages; 2 ID: 1 on challenging behaviors, 1 on mental health) resulted.Data extractionWork group members extracted 524 recommendations (386 ASD; 138 ID) from the guidelines including the level of evidence, diagnostic and age group, recommendation type (assessment, intervention, service), target, and valence.Data synthesisOf the 270 intervention recommendations (212 ASD; 58 ID), only 36 for ASD and 47 for ID were empirically based. Most comprised biomedical (23%), pharmacologic (29%), and psychosocial (21%) interventions for ASD and behavioral (14%), pharmacologic (29%), and psychological (14%) interventions for ID. Intervention recommendations primarily targeted coexisting conditions (56% ASD; 93% ID), whereas core symptoms received much less attention (26% ASD).ConclusionsClinical practice guidelines reviewed for ASD and ID primarily contained recommendations based on expert opinion, with the plurality of recommendations relating to pharmacologic treatment. Vital next steps include identifying relevant interventions for inclusion in the WHO Package and continuing to conduct rigorous intervention research, particularly on core symptoms of these conditions, to extend recommendations for high-quality guidelines.

Project description:BackgroundDNA copy number variants (CNVs) are found in 15% of subjects with ID but their association with phenotypic abnormalities has been predominantly studied in smaller cohorts of subjects with detailed yet non-systematically categorized phenotypes, or larger cohorts (thousands of cases) with smaller number of generalized phenotypes.MethodsWe evaluated the association of de novo, familial and common CNVs detected in 78 ID subjects with phenotypic abnormalities classified using the Winter-Baraitser Dysmorphology Database (WBDD) (formerly the London Dysmorphology Database). Terminology for 34 primary (coarse) and 169 secondary (fine) phenotype features were used to categorize the abnormal phenotypes and determine the prevalence of each phenotype in patients grouped by the type of CNV they had.ResultsIn our cohort more than 50% of cases had abnormalities in primary categories related to head (cranium, forehead, ears, eye globes, eye associated structures, nose) as well as hands and feet. The median number of primary and secondary abnormalities was 12 and 18 per subject, respectively, indicating that the cohort consisted of subjects with a high number of phenotypic abnormalities (median De Vries score for the cohort was 5). The prevalence of each phenotypic abnormality was comparable in patients with de novo or familial CNVs in comparison to those with only common CNVs, although a trend for increased frequency of cranial and forehead abnormalities was noted in subjects with rare de novo and familial CNVs. Two clusters of subjects were identified based on the prevalence of each fine phenotypic feature, with an average of 28.3 and 13.5 abnormal phenotypes/subject in the two clusters respectively (P?<?0.05).ConclusionsOur study is a rare example of using standardized, deep morphologic phenotype clustering with phenotype/CNV correlation in a cohort of subjects with ID. The composition of the cohort inevitably influences the phenotype/genotype association, and our studies show that the influence of the de novo CNVs on the phenotype is less obvious in cohorts consisting of subjects with a high number of phenotypic abnormalities. The outcome of phenotype/genotype analysis also depends on the choice of phenotypes assessed and standardized phenotyping is required to minimize variability.

Dataset Information

Differences in the importance of microcephaly, dysmorphism, and epilepsy in the detection of pathogenic CNVs in ID and ASD patients.

Publications

Differences in the importance of microcephaly, dysmorphism, and epilepsy in the detection of pathogenic CNVs in ID and ASD patients.

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