Genomic Aberrations Associated with the Pathophysiological Mechanisms of Neurodevelopmental Disorders

Abstract

Genomic studies are increasingly revealing that neurodevelopmental disorders are caused by underlying genomic alterations. Chromosomal microarray testing has been used to reliably detect minute changes in genomic copy numbers. The genes located in the aberrated regions identified in patients with neurodevelopmental disorders may be associated with the phenotypic features. In such cases, haploinsufficiency is considered to be the mechanism, when the deletion of a gene is related to neurodevelopmental delay. The loss-of-function mutation in such genes may be evaluated using next-generation sequencing. On the other hand, the patients with increased copy numbers of the genes may exhibit different clinical symptoms compared to those with loss-of-function mutation in the genes. In such cases, the additional copies of the genes are considered to have a dominant negative effect, inducing cell stress. In other cases, not the copy number changes, but mutations of the genes are responsible for causing the clinical symptoms. This can be explained by the dominant negative effects of the gene mutations. Currently, the diagnostic yield of genomic alterations using comprehensive analysis is less than 50%, indicating the existence of more subtle alterations or genomic changes in the untranslated regions. Copy-neutral inversions and insertions may be related. Hence, better analytical algorithms specialized for the detection of such alterations are required for higher diagnostic yields.

Keywords: classical microdeletion syndrome; contiguous gene deletion syndrome; diagnostic yield; exome sequencing; genome disease; nonallelic homologous recombination (NAHR).

Figure 1

Schematic representation of the mechanism of nonallelic homologous recombination. Deletions and duplications of the regions of interest (grey rectangles) can be caused by nonallelic homologous recombination triggered by the presence of low-copy repeats (LCRs).

Figure 2

Schematic representation of the patterns of deletions. (A) Deletions (black rectangles) caused by nonallelic homologous recombination triggered by surrounding LCRs show the same breakpoints in patients. (B) Deletions (black rectangles) with random breakpoints, however, include specific gene(s).

Figure 3

Schematic representation of diagnostic yields of various methods used for genetic testing. Diagnostic yields of the methods are shown in % plot format.

Figure 4

Possible mechanism of copy-neutral inversion that cannot be detected by chromosomal microarray testing and exome sequencing.

Figure 5

Schematic representation of the stepwise diagnosis for patients with neurodevelopmental disorder.