Disentangling the Myriad Genomics of Complex Disorders, Specifically Focusing on Autism, Epilepsy, and Schizophrenia

Abstract

Analyses of structural genome variation by array-CGH have dramatically enhanced our ability to detect copy number variations (CNVs). De novo CNVs and those co-segregating with disease in a family are generally interpreted as pathogenic. Yet, often CNVs, such as recurrent microdeletions in region 15q13.3, are not so clearly pathogenic. Here we discuss potential confounding mechanisms that may lead to the phenotypic pleiotropy of CNVs, such as unmasking of recessive alleles by hemizygous deletions, interaction of CNVs with other loci and genes, genetic epistasis, allelic exclusion, and somatic mosaicism. We illustrate some of these mechanisms with a detailed analysis of recent studies of CNVs involving MCPH1, AUTS2, CNTNAP2, and mutations in GRIN2B. Next we discuss the clinical ramifications of these findings and urge workers to avoid ‘diagnostic fatalism’ (i.e., halting all genetic investigation after the detection of a single CNV) and address some of the future challenges likely to result from implementations of next generation sequencing techniques.

Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders

“…30,32,34,38 Our results are consistent with this observation as patients 3 and 4 with duplication of exon 5 have ASDs. Both these duplications are not expected to alter the reading frame, but can result in addition of amino-acid residues to the amino terminus of the protein.…”

Discovery of variants unmasked by hemizygous deletions

“…The results of such studies will also present us with novel challenges during genetic counselling of families. [58][59][60][61][62][63] In conclusion, this study suggests that CNVs may contribute to clinical phenotypes by a recessive mode of gene action. We conclude that array-based enrichment of inherited deletions may be a targeted and highly sensitive method to detect SNVs and CNVs, simultaneously.…”

Structural genomic variation in childhood epilepsies with complex phenotypes

“…When CNVs are found that may explain the epilepsy, monogenic causes can easily be overlooked. 20 We found three regions with overlapping CNVs in more than one patient, at 16p13.11, 7q36.3, and 9p23. The CNVs at 16p13.11 further limit the epilepsy candidate genes in this region to ABCC1 and ABCC6.…”