Molecular Definition of 22q11 Deletions in 151 Velo-Cardio-Facial Syndrome Patients

Abstract

Velo-cardio-facial syndrome (VCFS) is a relatively common developmental disorder characterized by craniofacial anomalies and conotruncal heart defects. Many VCFS patients have hemizygous deletions for a part of 22q11, suggesting that haploinsufficiency in this region is responsible for its etiology. Because most cases of VCFS are sporadic, portions of 22q11 may be prone to rearrangement. To understand the molecular basis for chromosomal deletions, we defined the extent of the deletion, by genotyping 151 VCFS patients and performing haplotype analysis on 105, using 15 consecutive polymorphic markers in 22q11. We found that 83% had a deletion and >90% of these had a similar approximately 3 Mb deletion, suggesting that sequences flanking the common breakpoints are susceptible to rearrangement. We found no correlation between the presence or size of the deletion and the phenotype. To further define the chromosomal breakpoints among the VCFS patients, we developed somatic hybrid cell lines from a set of VCFS patients. An 11-kb resolution physical map of a 1,080-kb region that includes deletion breakpoints was constructed, incorporating genes and expressed sequence tags (ESTs) isolated by the hybridization selection method. The ordered markers were used to examine the two separated copies of chromosome 22 in the somatic hybrid cell lines. In some cases, we were able to map the chromosome breakpoints within a single cosmid. A 480-kb critical region for VCFS has been delineated, including the genes for GSCL, CTP, CLTD, HIRA, and TMVCF, as well as a number of novel ordered ESTs.

The recurrent distal 22q11.2 microdeletions are often de novo and do not represent a single clinical entity: a proposed categorization system

“…Based on the mediating LCR22s, about 90% of patients with the DG/VCFs microdeletion have the common ~3.0 Mb deletion between LCR22-A and D, whereas ~7% of the patients have a smaller nested ~1.5 Mb deletion between LCR22-A and B. 5 These microdeletions in the proximal portion of the 22q11.2 region are the most common recurrent, pathogenic microdeletions in humans with a frequency of approximately 1:4,000 to 1:8,000 live births. 6 Recently, others and we demonstrated that the five telomeric LCR22s, namely LCR22-D to H, at the distal portion of 22q11.2 are causally implicated in the recurrent distal 22q11.2 microdeletion-associated phenotype(s) (OMIM 611867), and their reciprocal microduplications in the region immediately distal to the DG/VCFs typically deleted region (Figure 2).…”

Developmental trajectories of brain structure in adolescents with 22q11.2 deletion syndrome: A longitudinal study

“…The 22q11.2 deletion syndrome (22q11.2DS), also known as velocardiofacial and DiGeorge syndromes, is caused by a microdeletion in the long arm of chromosome 22 (Carlson et al, 1997). The exact incidence of the syndrome is not yet certain but is estimated to be at least 1 in 5,000 live births (Botto et al, 2003).…”

Catechol-O-methyltransferase haplotypes are associated with psychosis in Alzheimer disease

“…COMT is located on chromosome 22q11.2, proximate or within the site of microdeletions found in patients with Velocardiofacial syndrome, a disorder in which up to 30% of sufferers have schizophrenia. [15][16][17][18] In addition, COMT is a functional candidate gene for schizophrenia and other psychotic disorders because it encodes a protein that enzymatically inactivates dopamine among other catecholamine neurotransmitters. 19 The most frequently examined COMT polymorphism in subjects with schizophrenia has been a G-A substitution at codon 108/158 of COMT resulting in a Val-Met substitution.…”