Recurrent copy number variations as risk factors for autism spectrum disorders: analysis of the clinical implications

Background Autism spectrum disorders (ASD) affect many children with an estimated prevalence of 1%. Array-comparative genomic hybridization (CGH) offers significant sensitivity for the identification of submicroscopic chromosomal abnormalities and it is one of the most used techniques in daily practice. The main objective of this study was to describe the usefulness of array-CGH in the etiologic diagnosis of ASD. Methods Two-hundred fifty-three patients admitted to a neurogenetic outpatient clinic and diagnosed with ASD were selected for array-CGH (4 × 180K microarrays). Public databases were used for classification in accordance with the American College of Medical Genetics Standards and Guidelines. Results About 3.56% (9/253) of copy number variations (CNVs) were classified as pathogenic. When likely pathogenic CNVs were considered, the rate increased to 11.46% (29/253). Some CNVs apparently not correlated to the ASD were also found. Considering a phenotype–genotype correlation, the patients were divided in two groups. One group according to previous literature includes all the CNVs related to ASDs (23 CNVs present in 22 children) and another with those apparently not related to ASD (10 CNVs present in 7 children). In 18 patients, a next-generation sequencing (NGS) panel were performed. From these, one pathogenic and 16 uncertain significance variants were identified. Conclusion The results of our study are in accordance with the literature, highlighting the relevance of array-CGH in the genetic of diagnosis of ASD population, namely when associated with other features. Our study also reinforces the need for complementarity between array-CGH and NGS panels or whole exome sequencing in the etiological diagnosis of ASD.

Download Full-text

Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders

Nature Communications ◽

10.1038/s41467-019-13380-2 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 5

Author(s):

L. D’Abate ◽

S. Walker ◽

R. K. C. Yuen ◽

K. Tammimies ◽

J. A. Buchanan ◽

...

Keyword(s):

Autism Spectrum Disorders ◽

Copy Number ◽

Copy Number Variants ◽

Autism Spectrum ◽

Copy Number Variations ◽

Recurrence Prediction ◽

Common Genetic Variants ◽

Spectrum Disorders ◽

Atypical Development ◽

Research Consortium

AbstractIdentification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically.

Download Full-text

Copy number variations associated with autism spectrum disorders contribute to a spectrum of neurodevelopmental disorders

Genetics in Medicine ◽

10.1097/gim.0b013e3181f0c5f3 ◽

2010 ◽

Vol 12 (11) ◽

pp. 694-702 ◽

Cited By ~ 79

Author(s):

Jill A Rosenfeld ◽

Blake C Ballif ◽

Beth S Torchia ◽

Trilochan Sahoo ◽

J Britt Ravnan ◽

...

Keyword(s):

Autism Spectrum Disorders ◽

Neurodevelopmental Disorders ◽

Copy Number ◽

Autism Spectrum ◽

Copy Number Variations ◽

Spectrum Disorders

Download Full-text

The landscape of copy number variations in Finnish families with autism spectrum disorders

Autism Research ◽

10.1002/aur.1502 ◽

2015 ◽

Vol 9 (1) ◽

pp. 9-16 ◽

Cited By ~ 18

Author(s):

Chakravarthi Kanduri ◽

Katri Kantojärvi ◽

Paula M Salo ◽

Raija Vanhala ◽

Gemma Buck ◽

...

Keyword(s):

Autism Spectrum Disorders ◽

Copy Number ◽

Autism Spectrum ◽

Copy Number Variations ◽

Spectrum Disorders

Download Full-text

High Prevalence of Pathologic Copy Number Variations Detected by Array Comparative Genomic Hybridization in Children with Autism Spectrum Disorders: The Experience of Southern Switzerland

Neuropediatrics ◽

10.1055/s-0035-1550646 ◽

2015 ◽

Vol 46 (S 01) ◽

Author(s):

G. Pellanda ◽

S. Lava ◽

A. Ferrarini ◽

G. Ramelli

Keyword(s):

Autism Spectrum Disorders ◽

Comparative Genomic Hybridization ◽

Copy Number ◽

Array Comparative Genomic Hybridization ◽

Children With Autism ◽

Autism Spectrum ◽

Copy Number Variations ◽

Comparative Genomic ◽

High Prevalence ◽

Spectrum Disorders

Download Full-text

Association of Copy Number Variations in Autism Spectrum Disorders: A Systematic Review

Chinese Journal of Biology ◽

10.1155/2014/713109 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Elif Funda Sener

Keyword(s):

Autism Spectrum Disorders ◽

Complex Traits ◽

Copy Number ◽

De Novo ◽

Genome Structure ◽

Autism Spectrum ◽

Copy Number Variations ◽

Repetitive Behaviors ◽

Wide Range ◽

Spectrum Disorders

Autism spectrum disorders (ASDs) are characterized by language impairments, social deficits, and repetitive behaviors. The onset of symptoms occurs by the age of 3 and shows a lifelong persistence. Genetics plays a major role in the etiology of ASD. Except genetics, several potential risk factors (environmental factors and epigenetics) may contribute to ASD. Copy number variations (CNVs) are the most widespread structural variations in the human genome. These variations can alter the genome structure either by deletion or by duplication. CNVs can be de novo or inherited. Chromosomal rearrangements have been detected in 5–10% of the patients with ASD and recently copy number changes ranging from a few kilobases (kb) to several megabases (Mb) in size have been reported. Recent data have also revealed that submicroscopic CNVs can have a role in ASD, and de novo CNVs seem to be a more common risk factor in sporadic compared with inherited forms of ASD. CNVs are being implicated as a contributor to the pathophysiology of complex neurodevelopmental disorders and they can affect a wide range of human phenotypes including mental retardation (MR), autism, neuropsychiatric disorders, and susceptibility to other complex traits such as HIV, Crohn’s disease, and psoriasis. This review emphasizes the major CNVs reported to date in ASD.

Download Full-text