Identification of two inherited copy number variants in a male with autism supports two‐hit and compound heterozygosity models of autism

Abstract

Autism is a childhood‐onset neurodevelopmental disorder with complex genetic mechanism underlying its etiology. Recent studies revealed that a few single de novo copy number variants of genomic DNA (copy number variants [CNVs]) are pathogenic and causal in some sporadic cases, adding support to the hypothesis that some sporadic autism might be caused by single rare mutation with large clinical effect. In this study, we report the detection of two novel private CNVs simultaneously in a male patient with autism. These two CNVs include a microduplication of ∼4.5 Mb at chromosome 4q12‐13.1 that was transmitted from his mother and a microdeletion of ∼1.8 Mb at 5q32 that was transmitted from his father. Several genes such as LPHN3, POU4F3, SH3RF2, and TCERG1 mapped to these two regions have psychiatric implications. However, the parents had only mild degree of attention deficit symptoms but did not demonstrate any obvious autistic symptoms or psychopathology. Our findings indicate that each of these two CNVs alone may not be pathogenic enough to cause clinical symptoms in their respective carriers, and hence they can be transmitted within each individual family. However, concomitant presence of these two CNVs might result in the clinical phenotypes of the affected patient reported here. Thus, our report of this family may represent an example to show that two hits of CNV and the presence of compound heterozygosity might be important mechanisms underlying the pathogenesis of autism. © 2012 Wiley Periodicals, Inc.

Chromosomal Microarray versus Karyotyping for Prenatal Diagnosis

“…When encountered in the prenatal setting, this increased range of phenotypic features can make genetic counseling challenging; many of these copy-number variants do not always result in severe impairments. Because of their smaller size and milder phenotypic effects and the possibility that these copy-number variants exert a phenotypic effect only in the presence of other genetic variants, 21-23 these copy-number variants may be inherited from a parent with minimal or no recognizable features. Although data from symptomatic infants evaluated postnatally gives some guidance for prenatal counseling, this group almost certainly represents a biased, more severe, and incomplete characterization of the phenotype.…”

Chromosomal Microarray Versus Karyotyping for Prenatal Diagnosis

“…When encountered in the prenatal setting, this increased range of phenotypic features can make genetic counseling challenging; many of these copy-number variants do not always result in severe impairments. Because of their smaller size and milder phenotypic effects and the possibility that these copy-number variants exert a phenotypic effect only in the presence of other genetic variants, [21][22][23] these copy-number variants may be inherited from a parent with minimal or no recognizable features. Although data from symptomatic infants evaluated postnatally gives some guidance for prenatal counseling, this group almost certainly represents a biased, more severe, and incomplete characterization of the phenotype.…”

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

“…Two recent studies further support the theory of the 'two-hit model' in individuals with ASDs. 19,47 The next challenge in ASDs is therefore to understand the interactions between rare CNVs and other rare variants in individual patients and to take into account environmental interactions that may also modulate the risk for developing ASD. 48 …”