"Two hit" model as an explanation of variable expressivity of recurrent submicroscopic chromosomal rearrangements in children with intellectual disability and developmental delay
|Year of publication
|MU Faculty or unit
|Microarray-based whole genomic analyses of submicroscopic chromosomal rearrangements (CNVs) lead to the identification of pathogenic genetic variants in 15-20% children with intellectual disability, autism spectrum disorders and congenital abnormalities. Using the genotype-first approach more than 250 loci across the human genome related to pathogenic microdeletions and microduplications were identified so far. The significant phenotypic variability among patients with identical pathogenic CNVs results in complications and uncertainty in the genetic counselling for the assessment of prognosis and challenges to additional whole genomic analyses. Based on the results of complex whole genomic analyses the phenomenon of variable expressivity leading to the phenotypic variability among patients with recurrent pathogenic CNVs can be explained using the "two-hit" model.In the 8-year period of array-CGH analyses at the Department of Medical Genetics (University Hospital Brno, Czech Republic) 724 children patients were examined using 4X180K and 8X60K microarray platforms. In our study we present clinical characteristics of 8 patients with two structurally independent submicroscopic pathogenic CNVs (dup 2q12.1-q12.3 + dup 2q13, del 4q12-q13.1 + del 9q21.1, del 2q23.1-q23.3 + dup 7q21.12-q21.13, del 10q26.2-q26.3 + dup 11p14.3-p15.1, del 10p15.1-p15.3 + del 15q13.2-q13.3, del 13q12.12 + dup 13q21.31, dup 1q21.1 + del 1q21.1-q21.2) or one submicroscopic pathogenic CNV and chromosomal aneuploidy (47,XXY + del 7q11.23). The comparison of their phenotypes to the typical phenotypes related to given pathogenic CNVs may help to specify their partial impact on the total phenotypic effect.