Identification of Pathogenic CNVs in Unexplained Developmental Disabilities Using Exome Sequencing: A Family Trio Study

To assess the potential of detecting copy number variations (CNVs) directly from exome sequencing (ES) data in diagnostic settings, we developed a CNV-detection pipeline based on ExomeDepth software and applied it to ES data of 450 individuals. Initially, only CNVs affecting genes in the requested diagnostic gene panels were scored and tested against arrayCGH results. Pathogenic CNVs were detected in 18 individuals. Most detected CNVs were larger than 400 kb (11/18), but three individuals had small CNVs impacting one or a few exons only and were thus not detectable by arrayCGH. Conversely, two pathogenic CNVs were initially missed, as they impacted genes not included in the original gene panel analysed, and a third one was missed as it was in a poorly covered region. The overall combined diagnostic rate (SNVs + CNVs) in our cohort was 36%, with wide differences between clinical domains. We conclude that (1) the ES-based CNV pipeline detects efficiently large and small pathogenic CNVs, (2) the detection of CNV relies on uniformity of sequencing and good coverage, and (3) in patients who remain unsolved by the gene panel analysis, CNV analysis should be extended to all captured genes, as diagnostically relevant CNVs may occur everywhere in the genome.

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The diagnostic yield of intellectual disability: Combined whole genome low-coverage sequencing and medical exome sequencing

10.21203/rs.2.18388/v2 ◽

2020 ◽

Author(s):

Jun Wang ◽

Yan Wang ◽

Liwen Wang ◽

Wangyang Chen

Keyword(s):

Exome Sequencing ◽

Diagnostic Test ◽

Detection Rate ◽

Whole Genome ◽

Single Nucleotide ◽

Detection Scheme ◽

Pathogenic Cnvs ◽

Clinical Detection ◽

Single Nucleotide Variations ◽

Low Coverage

Abstract Background: Intellectual disability (ID) is a heterogeneous neurodevelopmental disorder with a complex genetic underpinning in its etiology. Chromosome microarray (CMA) is recommended as the first-tier diagnostic test for ID due to high detection rate of copy number variation (CNV). Methods: To identify an appropriate clinical detection scheme for ID in Han Chinese patients, a whole genome low-coverage sequencing was performed as the first-tier diagnostic test, followed by medical exome sequencing as the second-tier diagnostic test for those patients with negative results of CNVs. Results: A total of 19 pathogenic CNVs in 16/95(16.84%) ID patients and 11 pathogenic single-nucleotide variations, including 7 novel mutations in 9/79(11.39%) ID patients were identified on whom no pathogenic CNVs were discovered. The detection rate of CNVs in ID s with multiple congenital anomalies (MCA) subgroup was significantly higher than ID s with autism spectrum disorder and the other IDs subgroup. Also single-nucleotide variations showed a higher occurrence rate in the other IDs subgroup. Conclusions: There were differences in the diagnostic yields of different variation types among the three ID subgroups. Our findings provided a new perspective on appropriate clinical detection scheme for different ID subgroups based on the statistical results of different ID subgroups. The application of whole genome low-coverage sequencing as the first-tier diagnostic test for ID with MCA subgroup and medical exome sequencing as the first-tier diagnostic test for other IDs subgroup were considered as an efficient clinical detection schemes.

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The diagnostic yield of intellectual disability: Combined whole genome low-coverage sequencing and medical exome sequencing

10.21203/rs.2.18388/v1 ◽

2019 ◽

Author(s):

Jun Wang ◽

Yan Wang ◽

Liwen Wang ◽

Wangyang Chen

Keyword(s):

Exome Sequencing ◽

Diagnostic Test ◽

Detection Rate ◽

Whole Genome ◽

Single Nucleotide ◽

Detection Scheme ◽

Pathogenic Cnvs ◽

Clinical Detection ◽

Single Nucleotide Variations ◽

Low Coverage

Abstract Background: Intellectual disability (ID) is a heterogeneous neurodevelopmental disorder with a complex genetic underpinning in its etiology. Chromosome microarray (CMA) is recommended as the first-tier diagnostic test for ID due to high detection rate of copy number variation (CNV). Methods: To identify an appropriate clinical detection scheme for ID in Han Chinese patients, a whole genome low-coverage sequencing was performed as the first-tier diagnostic test, followed by medical exome sequencing as the second-tier diagnostic test for those patients with negative results of CNVs. Results: A total of 19 pathogenic CNVs in 16/95(16.84%) ID patients and 11 pathogenic single-nucleotide variations, including 7 novel mutations in 9/79(11.39%) ID patients were identified on whom no pathogenic CNVs were discovered. The detection rate of ID CNVs in multiple congenital anomalies (MCA) subgroup was significantly higher than ID with autism spectrum disorder and the other IDs subgroup. Also single-nucleotide variations showed a higher occurrence rate in the other IDs subgroup. Conclusions: There were differences in the diagnostic yields of different variation types among the three ID subgroups. Our findings provided a new perspective on appropriate clinical detection scheme for different ID subgroups based on the statistical results of different ID subgroups. The application of whole genome low-coverage sequencing as the first-tier diagnostic test for ID with MCA subgroup and medical exome sequencing as the first-tier diagnostic test for other IDs subgroup were considered as an efficient clinical detection schemes.

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Psychiatric and Behavioral Disorders in People with Developmental Disabilities and Mental Retardation. Edited by Nick Bouras. Cambridge University Press, Cambridge, 1999. pp. 464. £35.00 (pb).

Journal of Child Psychology and Psychiatry ◽

10.1017/s0021963099235718 ◽

2000 ◽

Vol 41 (7) ◽

pp. 949-952

Author(s):

T. P. Berney

Keyword(s):

Mental Retardation ◽

Developmental Disabilities ◽

Behavioral Disorders ◽

Cambridge University

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Maximum Output Intensity of the Audiokinetron

American Journal of Speech-Language Pathology ◽

10.1044/1058-0360.0502.68 ◽

1996 ◽

Vol 5 (2) ◽

pp. 68-72 ◽

Cited By ~ 4

Author(s):

Christine M. Rankovic ◽

William M. Rabinowitz ◽

Gregory L. Lof

Keyword(s):

Developmental Disabilities ◽

Maximum Output ◽

Output Intensity ◽

Safety Studies ◽

Auditory Integration Training ◽

Auditory Integration

The Audiokinetron is a device that processes music for earphone presentation to patients undergoing auditory integration training, a treatment for individuals with autism and other developmental disabilities. Intensity levels produced by the Audiokinetron were measured under realistic listening conditions with a KEMAR manikin substituted for a patient. Average levels at the eardrum were 110 dB SPL when the device was adjusted to the highest setting employed by a local, trained AIT practitioner and 118 dB SPL at the maximum setting of the device. These levels are potentially harmful to hearing and warrant further safety studies of AIT instruments and protocols.

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Using Video Modeling Intervention and Speech Generating Devices To Teach Requesting Behaviors to Persons With Autism

Perspectives on Augmentative and Alternative Communication ◽

10.1044/aac20.4.109 ◽

2011 ◽

Vol 20 (4) ◽

pp. 109-113

Author(s):

Karen Copple ◽

Rajinder Koul ◽

Devender Banda ◽

Ellen Frye

Keyword(s):

Developmental Disabilities ◽

Experimental Design ◽

Communication Skills ◽

Observational Learning ◽

Video Modeling ◽

Single Subject ◽

Design Studies ◽

Communicative Behaviors ◽

Speech Generating Device ◽

Treatment Package

Abstract One of the instructional techniques reported in the literature to teach communication skills to persons with autism is video modeling (VM). VM is a form of observational learning that involves watching and imitating the desired target behavior(s) exhibited by the person on the videotape. VM has been used to teach a variety of social and communicative behaviors to persons with developmental disabilities such as autism. In this paper, we describe the VM technique and summarize the results of two single-subject experimental design studies that investigated the acquisition of spontaneous requesting skills using a speech generating device (SGD) by persons with autism following a VM intervention. The results of these two studies indicate that a VM treatment package that includes a SGD as one of its components can be effective in facilitating communication in individuals with autism who have little or no functional speech.

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Examining the Role of Language in Play Among Children With and Without Developmental Disabilities

Language Speech and Hearing Services in Schools ◽

10.1044/2020_lshss-19-00084 ◽

2020 ◽

Vol 51 (3) ◽

pp. 795-806 ◽

Cited By ~ 1

Author(s):

Elizabeth J. Short ◽

Rachael Cooper Schindler ◽

Rita Obeid ◽

Maia M. Noeder ◽

Laura E. Hlavaty ◽

...

Keyword(s):

Developmental Disabilities ◽

Autism Spectrum ◽

Free Play ◽

Group Differences ◽

Typically Developing ◽

Play Skills ◽

Critical Aspect ◽

Hyperactivity Disorder ◽

Better Than

Purpose Play is a critical aspect of children's development, and researchers have long argued that symbolic deficits in play may be diagnostic of developmental disabilities. This study examined whether deficits in play emerge as a function of developmental disabilities and whether our perceptions of play are colored by differences in language and behavioral presentations. Method Ninety-three children participated in this study (typically developing [TD]; n = 23, developmental language disorders [DLD]; n = 24, attention-deficit/hyperactivity disorder [ADHD]; n = 26, and autism spectrum disorder [ASD]; n = 20). Children were videotaped engaging in free-play. Children's symbolic play (imagination, organization, elaboration, and comfort) was scored under conditions of both audible language and no audible language to assess diagnostic group differences in play and whether audible language impacted raters' perception of play. Results Significant differences in play were evident across diagnostic groups. The presence of language did not alter play ratings for the TD group, but differences were found among the other diagnostic groups. When language was audible, children with DLD and ASD (but not ADHD) were scored poorly on play compared to their TD peers. When language was not audible, children with DLD were perceived to play better than when language was audible. Conversely, children with ADHD showed organizational deficits when language was not available to support their play. Finally, children with ASD demonstrated poor play performance regardless of whether language was audible or not. Conclusions Language affects our understanding of play skills in some young children. Parents, researchers, and clinicians must be careful not to underestimate or overestimate play based on language presentation. Differential skills in language have the potential to unduly influence our perceptions of play for children with developmental disabilities.

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