Deletion Extents Are Not the Cause of Clinical Variability in 22q11.2 Deletion Syndrome: Does the Interaction between DGCR8 and miRNA-CNVs Play a Major Role?

Abstract

In humans, the most common genomic disorder is the hemizygous deletion of the chromosome 22q11.2 region, that results in the "22q11.2 deletion syndrome" (22q11.2DS). A peculiarity of 22q11.2DS is its great phenotypic variability that makes this pathology a classic example of a syndrome with variable expressivity and incomplete penetrance. The reasons for this variability have not been elucidated yet, and the molecular substrates underlying the different clinical features of 22q11.2DS are still debated. A cohort of 21 patients has been analyzed by array CGH in order to detect some of the genetic differences that may influence this variability. Two aspects have been investigated: (1) the precise localization of the deletion breakpoints within the low copy repeats (LCRs), (2) the additional Copy Number Variations (CNVs) elsewhere in the genome, by analyzing their gene content. Both protein-coding genes and miRNAs were considered, in order to discover possible epistatic interactions between genes of the 22q11.2 region and the rest of the genome. Eighteen out of twenty-one patients had a deletion of ∼3 Mb mediated by LCR22-A and D, whereas 3/21 had a smaller deletion. The breakpoints within the LCR22-A and D do not have a major role in the phenotypic variability since they are rather clustered and the small differences concern genes that are not directly related to clinical signs of 22q11.2DS. A detailed analysis of the gene content of 22q11.2 deleted region indicates that this syndrome could be a bioenergetic disorder or consequence of an altered post-transcriptional gene regulation, due to the presence of DGCR8, a major player of the microRNA (miRNA) biogenesis. Only four genes with mitochondrial function are harbored in the additional CNVs, whereas 11 miRNA, all related to biological pathways present in the 22q11.2DS, have been detected in 19/21 patients. CNVs and miRNAs are new entities that have changed the order of complexity at the level of gene expression and regulation, thus CNV-miRNAs (miRNA harbored in the CNVs) are potential functional variants that should be considered high priority candidate Bertini et al. miRNA-CNVs in 22q11.2 Deletion Syndrome variants in genotype-phenotype association studies. Deletion of DGCR8, the main actor in miRNA biogenesis, amplifies this variability. To our knowledge, this is the first report that focus on the miRNA-CNVs in 22q11.2DS, with the aim of trying to better understand their role in the variable expressivity and incomplete penetrance.

Copy number variations in the GATA4, NKX2‐5, TBX5, BMP4 CRELD1, and 22q11.2 gene regions in Chinese children with sporadic congenital heart disease

“…There were eight LCR blocks (LCR22‐A to LCR22‐H) in the 22q11 region, but only LCR22‐A to LCR22‐D were implicated in the 22q11.2 deletion syndrome. Over 90% of the patients in this study shared a deletion between the LCR22‐A and LCR22‐D blocks . In the present study, Patients 2‐5 possessed a 22q11.2 rearrangement and carried the ~2.5 Mb LCR22A‐D deletion.…”

The Genetics and Epigenetics of 22q11.2 Deletion Syndrome

“…Several miRNA target prediction programs have been applied to the 7 miRNAs encoded on chromosome 22q11.1 to identify linked pathways that relate to clinical phenotypes. An overlapping set of these miRNAs can target TBX1, KAT8 regulatory NSL complex subunit 1 (KANSL1), Glucose Transporter 3 (GLUT3, SLC2A3), and Ras Responsive Element Binding protein 1 (RREB1) (Bertini et al, 2017;León et al, 2017). Several of these targets are discussed in a subsequent section in relation to their roles in 22q11.2del.…”

“…KANSL1 is also linked to gene pathways regulated by miRNAs, discussed in a preceding section. In a separate screen for CNVs in miRNAs, deletions and duplications of 11 distinct miRNAs were uncovered in 22q11.2del patients, with at least 1 miRNA affected per individual (Bertini et al, 2017).…”

“…These are referred to as proximal deletions and are causal to the majority of clinical phenotypes ascribed to 22q11.2del. The actual breakpoint location within the LCR does not have a major role in 22q11.2del phenotypes (Bertini et al, 2017). A rare Du et al 22q11.2del Genetics and Epigenetics number of individuals have deletions between LCR B-D or LCR C-D, which are referred to as central deletions.…”

Consequences of 22q11.2 Microdeletion on the Genome, Individual and Population Levels

“…These exchanges involve eight large, paralogous LRC22s (A-H) or segmental duplications that are located along the 22q11.2 region. The location of the breakpoint within an LCR does not have a huge impact on the 22q11.2DS phenotype [ 34 ]. Optical mapping showed the difference between LCR22 structures in normal and deletion-containing haplotypes.…”