The Genetics and Epigenetics of 22q11.2 Deletion Syndrome

Abstract

Chromosome 22q11.2 deletion syndrome (22q11.2del) is a complex, multi-organ disorder noted for its varying severity and penetrance among those affected. The clinical problems comprise congenital malformations; cardiac problems including outflow tract defects, hypoplasia of the thymus, hypoparathyroidism, and/or dysmorphic facial features. Additional clinical issues that can appear over time are autoimmunity, renal insufficiency, developmental delay, malignancy and neurological manifestations such as schizophrenia. The majority of individuals with 22q11.2del have a 3 Mb deletion of DNA on chromosome 22, leading to a haploinsufficiency of ~106 genes, which comprise coding RNAs, noncoding RNAs, and pseudogenes. The consequent haploinsufficiency of many of the coding genes are well described, including the key roles of T-box Transcription Factor 1 (TBX1) and DiGeorge Critical Region 8 (DGCR8) in the clinical phenotypes. However, the haploinsufficiency of these genes alone cannot account for the tremendous variation in the severity and penetrance of the clinical complications among those affected. Recent RNA and DNA sequencing approaches are uncovering novel genetic and epigenetic differences among 22q11.2del patients that can influence disease severity. In this review, the role of coding and non-coding genes, including microRNAs (miRNA) and long noncoding RNAs (lncRNAs), will be discussed in relation to their bearing on 22q11.2del with an emphasis on TBX1.

Keywords: 22q11.2 deletion syndrome; DiGeorge syndrome; TBX1; epigenetics; haploinsufficiency; microRNAs; noncoding RNAs.

Figure 1

Genetic organization of the human chromosome 22q11.2 locus and synteny on murine chromosome 16. Human chromosome 22 is approximately 51 million base pairs. The region affected by the 22q11.2 chromosomal deletions and duplications spans approximately 4 Mb, with 8 low copy repeats (LCR A-LCR H) causal to this distributed throughout this region. LCR A-LCR D are shown. Recombination of these highly homologous sequences (also called segmental duplications) results in proximal, central, and distal (not shown) deletions affecting both coding and noncoding DNA segments. The proximal deletions are responsible for the classic clinical features of 22q11.2del, which includes DiGeorge syndrome. The location of the coding genes, and noncoding RNAs including miRNAs and lncRNAs, are shown for the proximal region of chromosome 22q11.2. The corresponding genes on the murine locus are connected with lines, which reveals a flipping of the locus and a break containing distinct genes. Three of the more commonly used mouse models of 22q11.2del that replicate many clinical features of 22q11.2del are shown, named as the Df16(A), Df1 and Lgdel lines.

Figure 2

Molecular pathways intersecting with TBX1 with the potential to modulate the clinical severity and penetrance of 22q11.2del. The expression of TBX1, a key gene coupled to the patterning of the pharyngeal apparatus, is positively regulated by members of the Fox-family of transcription factors and MOZ. Negative regulators of TBX1 include the defined teratogens, retinoic acid (RA), gestational diabetes, and miR-96 and miR-451a, the latter two miRNAs that target the 3' untranslated region of TBX1, resulting in its degradation. While most TBX1 resides in the nucleus, wherein it can regulate gene expression, a fraction of TBX1 is localized in the cytosol, where it negatively impacts bone morphogenic protein signaling via a complex with SMAD4.