Variable Phenotypic Expressivity of Specific Copy Number Variants and Single Gene Mutations in Autism and Other Neurodevelopmental Disorders

Background:  Autism spectrum disorders (ASD), like intellectual disabilities, can be caused by many different highly penetrant genetic abnormalities, including mutations and genomic imbalances.  These variants are individually rare but collectively common; even though no single genetic variant accounts for more than 1-1.5% of ASD, together they currently explain the etiology of approximately 15% of cases.  However, it is also becoming apparent that identical variants may lead to ASD in some individuals and to other neurodevelopmental disorders in other individuals, including members of the same family. 

Objectives:  The objective of this literature review was to examine the variable phenotypic expression of selected DNA copy number variants (CNVs) and single-gene variants that are known to cause autism spectrum disorders (ASD).

Methods:  In a case-control study involving 15,749 cases and 10,118 published controls, the International Standards for Cytogenomic Arrays (ISCA) consortium identified 14 recurrent CNV regions in which pathogenic deletions and/or duplications occur frequently in association with abnormal clinical phenotypes including ASD and developmental delay or intellectual disability (DD/ID) (Kaminsky et al., 2011).  CNVs in 13 of these regions (1q21.1, 3q29, 5q35, 7q11.23, 8p23.1, 15q11.2-q13, 15q13.2-q13.3, 16p11.2, 16p13.11, 17p11.2, 17q12, 17q21.31, and 22q11.2) have been associated with ASD.  We sought to determine how commonly CNVs in these 13 regions have been associated with the following phenotypes in addition to ASD: DD/ID, schizophrenia (SZ), and epilepsy (EP).  We searched the English-language literature pertaining to the 26 distinct recurrent variants (13 deletions and 13 duplications) to determine which of the clinical phenotypes of interest have been associated with each CNV.  In addition to these relatively large CNVs, which contain multiple genes, single gene variants have been implicated in ASD.  To assess whether 6 single gene variants (mutations or CNVs) with robust association with ASD (CNTN4, CNTNAP2, NLGN4X, NRXN1, SHANK2, and SHANK3) have also been implicated in other phenotypes (DD/ID, SZ, EP, and Tourette syndrome [TS]), we again searched the literature.  

Results:  All 26 (100%) of the recurrent CNVs examined have been associated with ASD, some more robustly than others.  The vast majority of these ASD-associated CNVs (21/26 = 81%) have also been reported to be associated with at least 2 of the 3 other phenotypes (DD/ID, SZ, and EP), and 9/26 (35%) have been reported to be associated with all 4 phenotypes.  Among the 6 single gene variants examined, 5/6 (83%) were associated with at least 2 of the 4 other phenotypes (DD/ID, SZ, EP, and TS) in addition to ASD.  2/6 (33%) were associated with at least 3 of the 4 other phenotypes in addition to ASD, and one (17%) was associated with all 5 phenotypes. 

Conclusions:  Recurrent CNVs and mutations that cause autism also cause other neurodevelopmental disorders, including intellectual disability, schizophrenia, epilepsy, and Tourette syndrome.  The substantial etiologic overlap among what have been defined clinically as distinct disorders raises questions about diagnostic classification systems and poses challenges and opportunities for future research.  It is possible that identifying the mechanisms that underlie variable expressivity might lead to novel therapeutic interventions.