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Chromosomal microdeletions: dissecting del22q11 syndrome

Key Points

  • The most common chromosomal microdeletion syndrome in humans is the chromosome 22 deletion (del22q11). It comprises DiGeorge syndrome, velocardiofacial syndrome and conotruncal anomaly face syndrome, which share a common microdeletion (del22q11) in the proximal long arm of chromosome 22.

  • Approximately 90% of patients have a typically deleted region (TDR) of 3Mb, which encompasses 30 genes. The lack of variety in deletion size is probably due to the presence of intrachromosomal low-copy repeats (LCRs) flanking the deleted region, which mediate aberrant homologous recombination and unequal crossing-over events between LCR sequences.

  • Despite the genetic homogeneity of the syndrome, the distinct clinical features of the disorder are incompletely penetrant and show variable expressivity. The rare patients who have different deletions or rearrangements in the 22q11 region have not aided the localization of disease genes because some of their rearrangements are non-overlapping.

  • To overcome this paucity of informative human material, mouse models of del22q11 syndrome have been generated using chromosome-engineering techniques to generate deletions in the mouse genome that encompass subsets of the genes deleted in patients. These studies have pointed to genes that might be involved in the del22q11-like cardiovascular defects seen in mice that harbour some of these.

  • Cardiovascular defects in mice carrying del22q11-like deletions were rescued by a transgene that contains Tbx1. Targeted inactivation of Tbx1 showed that its loss produces a phenotype that is similar to a severe del22q11 syndrome phenotype.

  • These chromosome-engineering and gene-knockout studies have identified Tbx1 as a gene that is vital for cardiovascular and pharyngeal development in the mouse.

  • Mutations in the human TBX1 gene have not yet been found in patients that have the clinical features of del22q11 syndrome but not the characteristic deletion, so TBX1 remains a candidate disease gene for the disorder, albeit a tantalizing one.

  • Together these studies have shed light on how disturbed pharyngeal tissue development might underlie many of the clinical features of the del22q11 syndrome, and of the role of Tbx1 in pharyngeal tissue growth and patterning. They indicate that neural crest cells do not have a principal role in the Tbx1 mutant phenotype in the mouse, and are therefore possibly not involved in the pathogenesis of del22q11, although they might be targets of Tbx1 signalling.

Abstract

Identifying the genes that underlie the pathogenesis of chromosome deletion and duplication syndromes is a challenge because the affected chromosomal segment can contain many genes. The identification of genes that are relevant to these disorders often requires the analysis of individuals that carry rare, small deletions, translocations or single-gene mutations. Research into the chromosome 22 deletion (del22q11) syndrome, which encompasses DiGeorge and velocardiofacial syndrome, has taken a different path in recent years, using mouse models to circumvent the paucity of informative human material. These mouse models have provided new insights into the pathogenesis of del22q11 syndrome and have established strategies for research into chromosomal-deletion and -duplication syndromes.

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Figure 1: Human del22q11 region.
Figure 2: The mouse chromosome 16 region that is in conserved synteny with 22q11.
Figure 3: Cardiovascular defects in mutant embryos.
Figure 4: Tbx1 expression in early mouse embryogenesis.

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Related links

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DATABASES

Locuslink 

Arvcf

Cdc45l

Cldn5

Comt

CRKL

Crkol

Dgcr2

Dgcr6

Dgsi

Gnb1l

Gp1bb

Gscl

Hira

PAX6

Prodh

Ranbp1

Slc25a1

Stk22a

Tbx1

TBX1

Tsk2

Txnrd2

Ufd1l

Vpreb2

WT1 

OMIM 

Alagille syndrome

Angelman syndrome

campomelic dysplasia

cat eye syndrome

Charcot–Marie–Tooth disease, type 1A

conotruncal anomaly face syndrome

DGS

Down syndrome

Friedriech ataxia

HNPP

Langer–Giedion syndrome

Prader–Willi syndrome

Rubinstein–Taybi syndrome

Smith–Magenis syndrome

spinocerebellar ataxia type 10

VCFS

WAGR

Williams syndrome

Glossary

HAPLOINSUFFICIENCY

When loss of function of one gene copy leads to an abnormal phenotype.

SEGMENTAL ANEUSOMY

Disorder that results from the inappropriate dosage of crucial genes in a genomic segment.

EXPRESSIVITY

The extent to which a particular organ or structure is affected by a particular genotype. Del22q11 syndrome is characterized by variable expressivity because apparently identical deletions can result in mild or severe disease.

PENETRANCE

The proportion of affected individuals among the carriers of a particular genotype. If all individuals with a disease genotype show the disease phenotype, then the disease is said to be completely penetrant.

SCHIZOAFFECTIVE DISORDER

A psychotic illness that comprises both schizophrenia and affective (mood) disorder.

BIPOLAR DISORDER

A mood disorder that is characterized by periodic swings between exaggerated elation and depression.

PHARYNGEAL ARCHES

The tissue that lies between the paired pharyngeal pouches.

PHARYNGEAL POUCHES

Paired embryonic structures formed by the folding of the endodermal lining of the primitive foregut.

LOW-COPY REPEATS

1–200-kb blocks of genomic sequence that are duplicated in one or more locations on a chromosome, and thought to be of recent evolutionary origin because they have very high sequence identity and are absent in closely related species.

PERSISTENT TRUNCUS ARTERIOSUS

A severe heart defect in which a single vessel exits the heart instead of the normal two (the aorta and pulmonary trunk). It reflects the abnormal persistence of an earlier embryonic state.

POSITIVE SELECTION

When a specific chemical is added to a culture medium, the cells that express a positive selectable marker gene, such as the neomycin- or puromycin-resistance genes, survive and are selected for.

HPRT MINIGENE

(hypoxanthine phosphoribosyl transferase (Hprt)). This is divided into two complementary, but non-functional, fragments: 5′Hprt contains exons 1–2 and 3′Hprt contains the remaining exons, 3–9. Each Hprt fragment is linked to a loxP site, and Cre-mediated recombination between them unites the 5′ and 3′ cassettes and restores Hprt activity, which is required for purine biosynthesis and allows desired recombination events to be selected for in HAT (hypoxanthine, aminopterin and thymidine) medium.

NEGATIVE SELECTION

When a specific chemical is added to a culture medium to kill the cells that still express a negative selectable marker gene, such as the herpes simpex virus thymidine kinase gene (HSVtk). Cells that no longer express the marker gene survive.

HSVTK

Herpes simplex virus thymidine kinase (HSVtk) is essential for thymidine-nucleotide biosynthesis by means of a salvage pathway, and is often used as a negative selectable marker in gene targeting.

AORTICOPULMONARY SEPTUM

In early heart development, the heart outflow tract comprises a single tube, the truncus arteriosus, which is later divided into two separate vessels, the aorta and the pulmonary trunk, by the formation of the aorticopulmonary septum.

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Lindsay, E. Chromosomal microdeletions: dissecting del22q11 syndrome. Nat Rev Genet 2, 858–868 (2001). https://doi.org/10.1038/35098574

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