Molecular genetics of 22q11.2 deletion syndrome - PubMed (original) (raw)

Review

Molecular genetics of 22q11.2 deletion syndrome

Bernice E Morrow et al. Am J Med Genet A. 2018 Oct.

Abstract

The 22q11.2 deletion syndrome (22q11.2DS) is a congenital malformation and neuropsychiatric disorder caused by meiotic chromosome rearrangements. One of the goals of this review is to summarize the current state of basic research studies of 22q11.2DS. It highlights efforts to understand the mechanisms responsible for the 22q11.2 deletion that occurs in meiosis. This mechanism involves the four sets of low copy repeats (LCR22) that are dispersed in the 22q11.2 region and the deletion is mediated by nonallelic homologous recombination events. This review also highlights selected genes mapping to the 22q11.2 region that may contribute to the typical clinical findings associated with the disorder and explain that mutations in genes on the remaining allele can uncover rare recessive conditions. Another important aspect of 22q11.2DS is the existence of phenotypic heterogeneity. While some patients are mildly affected, others have severe medical, cognitive, and/or psychiatric challenges. Variability may be due in part to the presence of genetic modifiers. This review discusses current genome-wide efforts to identify such modifiers that could shed light on molecular pathways required for normal human development, cognition or behavior.

Keywords: 22q11.2 deletion syndrome; DiGeorge syndrome; birth defect syndrome; chromosome rearrangements; congenital malformation; pharyngeal apparatus; velo-cardio-facial syndrome.

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Figures

Figure 1.. The 22q11.2 region.

This image was modified from a previously published image (McDonald-McGinn et al., 2015). The 3 Mb 22q11.2 region (hg19 assembly, coordinates) is shown as a line that spans the 22q11.2 region, distal to the centromere (Cen) and harbors four sets of low copy repeats (LCR22), termed LCR22A, -B, -C and –D (gray boxes). The position of clinical diagnostic probes, N25 and TUPLE, for clinical fluorescence_in situ_ hybridization (FISH) testing are shown (green boxes). Most of the known coding and non-coding genes that span the interval are shown below the line representing the 22q11.2 region. TBX1 is indicated in blue font. Genes associated with recessive genetic conditions are indicated in red font. Non-coding genes are indicated with a star. The size and position of 22q11.2 deletions are indicated (gray boxes). The frequency of deletions were obtained from McDonald-McGinn and colleagues in the Special AJMG Issue.

Figure 2.. Embryonic development of the pharyngeal apparatus into adult structures.

Cartoon of a lateral view of a mouse embryo at stage day (E) 10.5 in development. The head is shown on top and the tail can be visualized as it twists around the body of the embryo. The pharyngeal apparatus is highlighted in light blue with individual arches (PA) and their derivative structures indicated on the left side (arrows). The outflow tract (OFT), right ventricle (RV), forelimb (FL) and hindlimb (HL) are indicated. Cells migrate from the pharyngeal apparatus into the cardiac OFT to form the aorta and pulmonary trunk during later stages of embryogenesis.

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Molecular genetics of 22q11.2 deletion syndrome - PubMed (original) (raw)