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Chromosome 22q11.2 deletions are found in almost 90% of patients with DiGeorge/velocardiofacial syndrome (DGS/VCFS). Large, chromosome-specific low copy repeats (LCRs), flanking and within the deletion interval, are presumed to lead to misalignment and aberrant recombination in meiosis resulting in this frequent microdeletion syndrome. We traced the grandparental origin of regions flanking de novo 3 Mb deletions in 20 informative three-generation families. Haplotype reconstruction showed an unexpectedly high number of proximal interchromosomal exchanges between homologs, occurring in 19/20 families. Instead, the normal chromosome 22 in these probands showed interchromosomal exchanges in 2/15 informative meioses, a rate consistent with the genetic distance. Meiotic exchanges, visualized as MLH1 foci, localize to the distal long arm of chromosome 22 in 75% of human spermatocytes tested, also reflecting the genetic map. Additionally, we found no effect of proband gender or parental age on the crossover frequency. Parental origin studies in 65 de novo 3 Mb deletions (including these 20 patients) demonstrated no bias. Unlike Williams syndrome, we found no chromosomal inversions flanked by LCRs in 22 sets of parents of 22q11 deleted patients, or in eight non-deleted patients with a DGS/VCFS phenotype using FISH. Our data are consistent with significant aberrant interchromosomal exchange events during meiosis I in the proximal region of the affected chromosome 22 as the likely etiology for the deletion. This type of exchange occurs more often than is described for deletions of chromosomes 7q11, 15q11, 17p11 and 17q11, implying a difference in the meiotic behavior of chromosome 22.
Hum Mol Genet 2004 Feb 15
PMID:Aberrant interchromosomal exchanges are the predominant cause of the 22q11.2 deletion. 1468 6

Deletion 22q11.2 is a chromosomal abnormality detected in young patients with clinical manifestations of the DiGeorge/velocardiofacial syndrome. Conotruncal heart defects are also associated with del22q11.2. An association of these cardiac malformations with neoplasias has been observed. Our series includes two cases of malignancies, a hepatoblastoma and a renal-cell carcinoma, arising in children with complex cardiac malformations. The aim of the study was to determine if the deletion at 22q11.2 was present and could be responsible for both pathological processes. Del22q11.2 was identified in both cases. Comparative genomic hybridization revealed terminal gains on chromosomes 1q and Xq and terminal loss on 1p in the hepatoblastoma, and gains in 1p, 12q, 16p, 20q, 22q, and whole chromosome 19 and loss of Xq in the renal-cell carcinoma. Our results confirm a common genetic basis for cardiac malformations, and del22q11.2 presents a risk factor for the development of pediatric tumours.
Pediatr Pathol Mol Med
PMID:Neoplastic disease and deletion 22q11.2: a multicentric study and report of two cases. 1469 28

Deletions and duplications of genomic segments commonly cause developmental disorders. The resolution and efficiency in diagnosing such gene-dosage alterations can be drastically increased using microarray-based comparative genomic hybridization (array-CGH). However, array-CGH currently relies on spotting genomic clones as targets, which confers severe limitations to the approach including resolution of analysis and reliable gene-dosage assessment of regions with high content of redundant sequences. To improve the methodology for analysis, we compared the use of genomic clones, repeat-free pools of amplified genomic DNA and cDNAs (single and pooled) as targets on the array. For this purpose, we chose q11.2 locus on chromosome 22 as a testing ground. Microdeletions at 22q11 cause birth defects collectively described as the DiGeorge/velocardiofacial syndrome. The majority of patients present 3 Mb typical deletions. Here, we report the construction of a gene-dosage array, covering 6 Mb of 22q11 and including the typically deleted region. We hybridized DNA from six DiGeorge syndrome patients to the array, and show that as little as 11.5 kb non-redundant, repeat-free PCR-generated sequence can be used for reliable detection of hemizygous deletions. By extrapolation, this would allow analysis of the genome with an average resolution of 25 kb. In the case of cDNAs our results indicate that 3.5 kb sequence is necessary for accurate identification of haploid/diploid dosage alterations. Thus, for regions rich in redundant sequences and repeats, such as 22q11, a specifically tailored array-CGH approach is good for gene copy number profiling.
Int J Mol Med 2004 Feb
PMID:DNA copy-number analysis of the 22q11 deletion-syndrome region using array-CGH with genomic and PCR-based targets. 1471 34

The hypothesis of the existence of one or more schizophrenia susceptibility loci on chromosome 22q is supported by reports of genetic linkage and association, meta-analyses of linkage, and the observation of elevated risk for psychosis in people with velocardiofacial syndrome, caused by 22q11 microdeletions. We tested this hypothesis by evaluating 10 microsatellite markers spanning 22q in a multicenter sample of 779 pedigrees. We also incorporated age at onset and sex into the analysis as covariates. No significant evidence for linkage to schizophrenia or for linkage associated with earlier age at onset, gender, or heterogeneity across sites was observed. We interpret these findings to mean that the population-wide effects of putative 22q schizophrenia susceptibility loci are too weak to detect with linkage analysis even in large samples.
Mol Psychiatry 2004 Aug
PMID:Multicenter linkage study of schizophrenia loci on chromosome 22q. 1500 91

Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) is associated with de novo hemizygous 22q11.2 deletions and is characterized by malformations attributed to abnormal development of the pharyngeal arches and pouches. The main physical findings include aortic arch and outflow tract heart defects, thymus gland hypoplasia or aplasia and craniofacial anomalies. The disorder varies greatly in expressivity; while some patients are mildly affected with learning disabilities and subtle craniofacial malformations, others die soon after birth with major cardiovascular defects and thymus gland aplasia. In addition to the main clinical features, many other findings are associated with the disorder such as chronic otitis media and hypocalcemia. Tbx1, a gene encoding a T-box transcription factor, which is hemizygously deleted on chromosome 22q11.2, was found to be a strong candidate for the equivalent of human VCFS/DGS in mice. Mice hemizygous for a null allele of Tbx1 had mild malformations, while homozygotes had severe malformations in the affected structures; neither precisely modeling the syndrome. Interestingly, bacterial artificial chromosome (BAC) transgenic mice overexpressing human TBX1 and three other transgenes, had similar malformations as VCFS/DGS patients. By employing genetic complementation studies, we demonstrate that altered TBX1 dosage and not overexpression of the other transgenes is responsible for most of the defects in the BAC transgenic mice. Furthermore, the full spectrum of VCFS/DGS malformations was elicited in a Tbx1 dose dependent manner, thus providing a molecular basis for the pathogenesis and varied expressivity of the syndrome.
Hum Mol Genet 2004 Aug 01
PMID:Full spectrum of malformations in velo-cardio-facial syndrome/DiGeorge syndrome mouse models by altering Tbx1 dosage. 1519 12

Catechol-O-methyltransferase (COMT) has been implicated in schizophrenia by its function through its roles in monoamine neurotransmitter metabolism and its impact on prefrontal cognition, and also by its position through linkage scans and a strong cytogenetic association. Further support comes from association studies, especially family-based ones examining the COMT variant, Val(108/158)Met. We have studied eight markers spanning COMT and including portions of the two immediately adjacent genes, thioredoxin reductase 2 and armadillo repeat deleted in velocardiofacial syndrome (ARVCF), using association testing in 136 schizophrenia families. We found nominal evidence for association of illness to rs165849 (P=0.051) in ARVCF, and a stronger signal (global P=0.0019-0.0036) from three-marker haplotypes spanning the 3' portions of COMT and ARVCF, including Val(108/158)Met with Val(108/158) being the overtransmitted allele, consistent with previous studies. We also find Val(108/158)Met to be in linkage disequilibrium with the markers in ARVCF. These findings support previous association signals of schizophrenia to COMT markers, and suggest that ARVCF might contribute to this signal. ARVCF, a member of the catenin family, besides being a positional candidate, is also one due to its function, that is, its potential role in neurodevelopment, which is implicated in schizophrenia pathogenesis by several lines of evidence.
Mol Psychiatry 2005 Apr
PMID:Haplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia. 1534 Mar 58

Several lines of evidence have implicated the catechol-O-methyltransferase (COMT) gene as a candidate for schizophrenia (SZ) susceptibility, not only because it encodes a key dopamine catabolic enzyme but also because it maps to the velocardiofacial syndrome region of chromosome 22q11 which has long been associated with SZ predisposition. The interest in COMT as a candidate SZ risk factor has led to numerous case-control and family-based studies, with the majority placing emphasis on examining a functional Val/Met polymorphism within this enzyme. Unfortunately, these studies have continually produced conflicting results. To assess the genetic contribution of other COMT variants to SZ susceptibility, we investigated three single-nucleotide polymorphisms (SNPs) (rs737865, rs4633, rs165599) in addition to the Val/Met variant (rs4680) in a highly selected sample of Australian Caucasian families containing 107 patients with SZ. The Val/Met and rs4633 variants showed nominally significant associations with SZ (P<0.05), although neither of the individual SNPs remained significant after adjusting for multiple testing (most significant P=0.1174). However, haplotype analyses showed strong evidence of an association; the most significant being the three-marker haplotype rs737865-rs4680-rs165599 (global P=0.0022), which spans more than 26 kb. Importantly, conditional analyses indicated the presence of two separate and interacting effects within this haplotype, irrespective of gender. In addition, our results indicate the Val/Met polymorphism is not disease-causing and is simply in strong linkage disequilibrium with a causative effect, which interacts with another as yet unidentified variant approximately 20 kb away. These results may help explain the inconsistent results reported on the Val/Met polymorphism and have important implications for future investigations into the role of COMT in SZ susceptibility.
Mol Psychiatry 2005 Jun
PMID:Separate and interacting effects within the catechol-O-methyltransferase (COMT) are associated with schizophrenia. 1550 38

Cytogenetic, molecular, and clinical genetic studies have contributed to our understanding of the etiology, pathogenesis, and natural history of DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). Submicroscopic deletions of chromosome 22ql 1.2 are the leading cause of both of these disorders. The 22q 11.2 deletion syndrome is recognized as one of the most common microdeletion syndromes. The clini'cal features are highly variable and include a variety of congenital anomalies, medical problems, and cognitive and neuropsychological difficulties. Infrequently, other chromosomal rearrangements are found in patients with DGS/VCFS, and, rarely, point mutations in the gene TBX1, a transcription factor, that maps to the deleted region. The most sensitive and widely used diagnostic test for detecting the 22ql 1.2 deletion is fluorescence in situ hybridization using probes from the commonly deleted region. Alternatively, polymerase chain reaction can be performed to confirm failure to inherit a parental allele in the region or to determine copy number. Prenatal diagnosis is also available, particularly when a conotruncal cardiac defect is identified during a pregnancy or when a parent carries a deletion. Genetic counseling is recommended before testing to review the natural history of the disorder, testing options, and test sensitivity and limitations.
Methods Mol Med 2006
PMID:Molecular and genetic aspects of DiGeorge/velocardiofacial syndrome. 1693 5

Velocardiofacial syndrome (VCFS) is a relatively common developmental disorder characterized by craniofacial anomalies and conotruncal heart defects. Many VCFS patients present hemizygous deletions on part of chromosome 22q11.2; suggestive that haploinsufficiency in this region is responsible for this etiology. Most 22q11.2 deletions occur sporadically, although in some cases the deletion may be transmitted. A total of 29 VCFS patients and their parents were genotyped using six consecutive polymorphic markers (STS) of the chromosome 22q11.2: D22S420, D22S941, D22S264, D22S306, D22S425, and D22S257. The results revealed that 72% (21/29) of the patients harbored a deletion involving the polymorphic markers D22S420, D22S941, and/or D22S264. Haplotype analysis showed that among the patients studied, the deletions were either of maternal or paternal origin. Our findings demonstrated that independently of their size, any deletion occurring in the VCFS critical region is enough to confer the patient phenotype.
Mol Cell Biochem 2007 Sep
PMID:Typical phenotypic spectrum of velocardiofacial syndrome occurs independently of deletion size in chromosome 22q11.2. 1742 30

Mouse modeling of haploinsufficiency syndromes and, in general, of syndromes caused by gene dosage imbalance, is often unsatisfactory because loss (or gain) of one copy of the gene of interest is insufficient to recapitulate the disease phenotype. In this study, we use Tbx1 mutants, which model one of the most common haploinsufficiency disorders, the 22q11.2DS/DiGeorge/Velocardiofacial syndrome, to test the feasibility of high resolution dosage manipulation to generate mouse models that more closely resemble the human syndrome. We used nine different genotypes at the Tbx1 locus that are associated with progressively lower mRNA levels in vivo. We show that penetrance and expressivity of different phenotypic features became more severe as the dosage diminished, as expected, but the response was strikingly non-linear, with extreme examples such as neonatal lethality, which changed from 2 to 100% after a dosage reduction of just approximately 16%. Furthermore, heart phenotype variability, extreme in the human syndrome but very limited, or absent, in the standard knockout model, was seen when mRNA level was approximately 20% of normal level, suggesting that there is a threshold level associated with unstable balance, which can be perturbed by chance events. Overall, our data suggest that there are developmental process-specific gene dosage thresholds beyond which the phenotype worsens very rapidly with very small mRNA level reductions.
Hum Mol Genet 2008 Jan 01
PMID:In vivo response to high-resolution variation of Tbx1 mRNA dosage. 1791 82


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