A susceptibility gene for psoriatic arthritis maps to chromosome 16q: evidence for imprinting

Several genetic loci have been reported for psoriasis, but none has been specifically linked to psoriatic arthritis (PsA), a condition that affects >10% of patients with psoriasis. A genetic component for PsA is suggested by segregation within families and high concordance among identical twins. We performed a linkage scan to map genes contributing to PsA. We identified 178 patients with PsA out of 906 patients who were included in our genetic study of psoriasis. Using a comprehensive genealogy database, we were able to connect 100 of these into 39 families. We genotyped the patients using a framework marker set of 1,000 microsatellite markers, with an average density of 3 cM, and performed multipoint, affected-only, allele-sharing linkage analysis using the Allegro program. On the basis of the initial results, we genotyped more markers for the most prominent loci. A linkage with a LOD score of 2.17 was observed on chromosome 16q. The linkage analysis, conditioned on paternal transmission to affected individuals, gave a LOD score of 4.19, whereas a LOD score of only 1.03 was observed when conditioned for maternal transmission. A suggestive locus on chromosome 16q has previously been implicated in psoriasis. Our data indicate that a gene at this locus may be involved in paternal transmission of PsA.     

Equal parental origin of chromosome 22 losses in human sporadic meningioma: no evidence for genomic imprinting.

Inactivation of tumor suppressor genes can occur either by mutation at the gene locus or by loss of part or all of the chromosome region containing the gene. The latter is most frequently detected by DNA markers as loss of heterozygosity in the tumor tissue. In several reports, the paternal homologue was preferentially retained in embryonal tumors associated with loss of particular chromosomal regions, suggesting genomic imprinting of the corresponding tumor suppressor loci. To explore the generality of these findings and the possible role of genomic imprinting in adult tumors of the nervous system, we have determined the parental origin of chromosome 22 loss in sporadic meningioma. Of nine cases studied, five tumors retained the maternally derived chromosome 22 homologue while four retained the paternally derived chromosome 22. Thus, in contrast to the embryonal tumors, the meningioma locus on chromosome 22 is inactivated by random mutation in sporadic adult meningiomas.     

An Fgf8 mouse mutant phenocopies human 22q11 deletion syndrome

Deletion of chromosome 22q11, the most common microdeletion detected in humans, is associated with a life-threatening array of birth defects. Although 90% of affected individuals share the same three megabase deletion, their phenotype is highly variable and includes craniofacial and cardiovascular anomalies, hypoplasia or aplasia of the thymus with associated deficiency of T cells, hypocalcemia with hypoplasia or aplasia of the parathyroids, and a variety of central nervous system abnormalities. Because ablation of neural crest in chicks produces many features of the deletion 22q11 syndrome, it has been proposed that haploinsufficiency in this region impacts neural crest function during cardiac and pharyngeal arch development. Few factors required for migration, survival, proliferation and subsequent differentiation of pharyngeal arch neural crest and mesoderm-derived mesenchyme into their respective cardiovascular, musculoskeletal, and glandular derivatives have been identified. However, the importance of epithelial-mesenchymal interactions and pharyngeal endoderm function is becoming increasingly clear. Fibroblast growth factor 8 is a signaling molecule expressed in the ectoderm and endoderm of the developing pharyngeal arches and known to play an important role in survival and patterning of first arch tissues. We demonstrate a dosage-sensitive requirement for FGF8 during development of pharyngeal arch, pharyngeal pouch and neural crest-derived tissues. We show that FGF8 deficient embryos have lethal malformations of the cardiac outflow tract, great vessels and heart due, at least in part, to failure to form the fourth pharyngeal arch arteries, altered expression of Fgf10 in the pharyngeal mesenchyme, and abnormal apoptosis in pharyngeal and cardiac neural crest. The Fgf8 mutants described herein display the complete array of cardiovascular, glandular and craniofacial phenotypes seen in human deletion 22q11 syndromes. This represents the first single gene disruption outside the typically deleted region of human chromosome 22 to fully recapitulate the deletion 22q11 phenotype. FGF8 may operate directly in molecular pathways affected by deletions in 22q11 or function in parallel pathways required for normal development of pharyngeal arch and neural crest-derived tissues. In either case, Fgf8 may function as a modifier of the 22q11 deletion and contribute to the phenotypic variability of this syndrome.     

Genomic disorders on 22q11

The 22q11 region is involved in chromosomal rearrangements that lead to altered gene dosage, resulting in genomic disorders that are characterized by mental retardation and/or congenital malformations. Three such disorders-cat-eye syndrome (CES), der(22) syndrome, and velocardiofacial syndrome/DiGeorge syndrome (VCFS/DGS)-are associated with four, three, and one dose, respectively, of parts of 22q11. The critical region for CES lies centromeric to the deletion region of VCFS/DGS, although, in some cases, the extra material in CES extends across the VCFS/DGS region. The der(22) syndrome region overlaps both the CES region and the VCFS/DGS region. Molecular approaches have revealed a set of common chromosome breakpoints that are shared between the three disorders, implicating specific mechanisms that cause these rearrangements. Most VCFS/DGS and CES rearrangements are likely to occur by homologous recombination events between blocks of low-copy repeats (e.g., LCR22), whereas nonhomologous recombination mechanisms lead to the constitutional t(11;22) translocation. Meiotic nondisjunction events in carriers of the t(11;22) translocation can then lead to offspring with der(22) syndrome. The molecular basis of the clinical phenotype of these genomic disorders has also begun to be addressed. Analysis of both the genomic sequence for the 22q11 interval and the orthologous regions in the mouse has identified >24 genes that are shared between VCFS/DGS and der(22) syndrome and has identified 14 putative genes that are shared between CES and der(22) syndrome. The ability to manipulate the mouse genome aids in the identification of candidate genes in these three syndromes. Research on genomic disorders on 22q11 will continue to expand our knowledge of the mechanisms of chromosomal rearrangements and the molecular basis of their phenotypic consequences.     

Tertiary trisomy (22q11q),47,+der(22),t(11;22)

Summary We describe a case of tertiary trisomy (22q11q) 47,XX,+der(22),(22pter22q13: : 11q2511qter) in a child with mental retardation, cleft palate, and congenital heart disease resulting from 3: 1 meiotic nondisjunction in a maternal (11;22) translocation carrier. The clinical findings in previously reported cases are reviewed and compared with the features of reported patients with partial trisomy 11q and trisomy 22 syndromes. Half of the ten reported families had additional balanced translocation carriers who may have an increased risk of having a liveborn child with an MCA/MR syndrome, although none have been reported to date.     

Hypocalcemia and chromosome 22q11 microdeletion

This review of the diagnosis, causes, prevention and treatment of hypocalcemia emphasizes the high incidence of this biological alteration in patients with 22q11 microdeletion. It also points out its large spectrum of presentation, from cases where the most prominent feature of the syndrome is hypocalcemia with hypoparathyroidism, to cases with asymptomatic, latent or late-onset hypocalcemia. Hence, the advice to perform genetic analysis of the 22q11 region in patients with late-onset or recurrent hypoparathyroidism and to systematically include serum calcium in the survey of patients with known 22q11 microdeletion, especially during infancy, adolescence and pregnancy and especially during cardiac surgery or sepsis.     

Screening of patients at risk for 22q11 deletion

The aim of this study was to determine whether deletion 22q11.2 studies should become apart of a standardized diagnostic workup for selected groups of at risk patients. We prospectively investigated four cohorts of unselected patients referred because of 1) congenital heart defect (CHD), 2) palatal anomalies, 3) hypocalcaemia, 4) dysmorphic features suggestive of del 22q11.2. Fluorescence in situ hybridization analysis revealed deletion 22q11.2 in 9.4% (6/64) patients with CHD. From 18 patients referred because of the hypocalcaemia, six (33.3%) had 22q11.2 deletion. In the group of 31 children with dysmorphic traits, the diagnosis was confirmed in two (6.4%) patients. None of the 58 children with palatal anomalies showed evidence of 22q11.2 deletion. Conclusions: Testing for the 22q11.2 microdeletion can be recommended in all patients with conotruncal heart defects and in patients with hypocalcaemia. It should be also considered in patients presenting only with dysmorphic traits suggestive of del 22q11.2, while screening in patients with cleft palate is not warranted.     

Microarray analysis of the Df1 mouse model of the 22q11 deletion syndrome

The 22q11 deletion syndrome (22q11DS; DiGeorge/velo-cardio-facial syndrome) primarily affects the structures comprising the pharyngeal arches and pouches resulting in arch artery, cardiac, parathyroid, thymus, palatal and craniofacial defects. Tbx1 haploinsufficiency is thought to account for the main structural anomalies observed in the 22q11DS. The Df1 deleted mouse provides a model for 22q11DS, the deletion reflecting Tbx1 haploinsufficiency in the context of the deletion of 21 adjacent genes. We examined the expression of genes in Df1 embryos at embryonic day (E) 10.5, a stage when the arch-artery phenotype is fully penetrant. Our aims were threefold, with our primary aim to identify differentially regulated genes. Second, we asked whether any of the genes hemizygous in Df1 were dosage compensated to wild type levels, and third we investigated whether genes immediately adjacent to the deletion were dysregulated secondary to a position effect. Utilisation of oligonulceotide arrays allowed us to achieve our aims with 9 out of 12 Df1 deleted genes passing the stringent statistical filtering applied. Several genes involved in vasculogenesis and cardiogenesis were validated by real time quantitative PCR (RTQPCR), including Connexin 45, a gene required for normal vascular development, and Dnajb9 a gene implicated in microvascular differentiation. There was no evidence of any dosage compensation of deleted genes, suggesting this phenomenon is rare, and no dysregulation of genes mapping immediately adjacent to the deletion was detected. However Crkl, another gene implicated in the 22q11DS phenotype, was found to be downregulated by microarray and RTQPCR.     

Tightly clustered 11q23 and 22q11 breakpoints permit PCR-based detection of the recurrent constitutional t(11;22)

Palindromic AT-rich repeats (PATRRs) on chromosomes 11q23 and 22q11 at the constitutional t(11;22) breakpoint are predicted to induce genomic instability, which mediates the translocation. A PCR-based translocation-detection system for the t(11;22) has been developed with PCR primers flanking the PATRRs of both chromosomes, to examine the involvement of the PATRRs in the recurrent rearrangement. Forty unrelated carriers of the t(11;22) balanced translocation, plus two additional, independent cases with the supernumerary-der(22) syndrome, were analyzed to compare their translocation breakpoints. Similar translocation-specific junction fragments were obtained from both derivative chromosomes in all 40 carriers of the t(11;22) balanced translocation and from the der(22) in both of the offspring with unbalanced supernumerary-der(22) syndrome, suggesting that the breakpoints in all cases localize within these PATRRs and that the translocation is generated by a similar mechanism. This PCR strategy provides a convenient technique for rapid diagnosis of the translocation, indicating its utility for prenatal and preimplantation diagnosis in families including carriers of the balanced translocation.     

Translocation 11q;22q: a clinico-cytogenetic study]

Seven families with translocations t(11; 22) identified at our Institute and analysis of the literature showed that the imbalance resulted from such translocations is always due to nondisjunction 3:1. Nondisjunction occurs more often in the 1st meiotic division, and is more rare in the second one. Expressed prezygotic selection against spermia with an additional chromosome greatly increases the risk of having an imbalanced child for the women-carriers as compared to men-carriers. The phenotype of the patients with +der(22)t(11; 22) is composed of the features characteristic for trisomy 22q (cleft lip and palate, preauricular papillomas and fistulas, rectal atresia or stenosis) and trisomy 11q (long philtrum with the upper lip hanging over, renal al; asia and hypoplasia). Diaphragmatic hernias are found to be common for the patients with +der(22)t(11; 22).     

Replication asynchrony between homologs 15q11.2: Cytogenetic evidence for genomic imprinting

Summary Replication kinetics of the Prader-Willi syndrome critical region (15q11.2) was investigated in seven normal healthy adult females using RBG replication bands. Replication asynchrony between homologs 15q11.2 was identified consistently in about 40% of cells in all individuals. It was limited to the stages in which Xp22, Xp11, Xq13 and Xq24/26 were visible in the late-replicating X chromosome. This asynchrony suggested that replication timing overlapped between 15q11.2 and the early replicating R-bands of the late X chromosome in some cells, and that the difference in replication timing between homologs was probably related to genomic imprinting; the latter has been suggested as a pathogenetic basis of Prader-Willi syndrome. As a result of an analysis of the proportions of asynchronous and synchronous cells in each replication stage, two types of cells were deduced providing 11 methylation mosaicism of genomic imprinting was assumed. The first type was composed of cells with normal replication in one homolog and delayed replication in the other. The second type was composed of cells with normal replication in both homologs. Our results provide cytogenetic evidence of methylation mosaicism for mammalian genomic imprinting.     

Microdeletion 22q11 in complex cardiovascular malformations

Besides DiGeorge, velocardiofacial and conotruncal anomaly face syndromes, some of the isolated congenital heart diseases have also been associated with a chromosomal deletion in 22q11. These disease entities, which had originally been considered to have a different genetic background, are now included in the CATCH-22 microdeletion complex. CATCH 22 is an acronym for cardiac defect, abnormal facies, thymic hypoplasia or aplasia and T-cell deficiency, cleft palate, hypoparathyroidism, and hypocalcemia. In the present study, we focused on the complex cardiovascular defects (CCVD) and screened 40 patients for a microdeletion of 22q11 by fluorescence in situ hybridization using the D22S75 DNA probe and for associated CATCH features. The patients were from genetic counseling (n = 15) or fetopathology (n = 3) of the Clinical Genetics Department in Marburg and from the Pediatric Cardiology Department (n = 22) in Mainz. Monosomy 22q11 was detected in 9 cases (= 22.5%). Familial transmission with one mildly affected parent and one affected sib each was proven in two cases. The CCVDs comprised complex conotruncal defects such as tetralogy of Fallot, double outlet right ventricle, transposition of great arteries and truncus arteriosus communis, or anomalies of the derivatives of the branchial arch arteries in association with a ventricular septal defect, including one case of atresia of the ductus arteriosus with pulmonary artery aneurysm and resulting in fetal hydrops. All 13 patients with a deletion of 22q11 showed at least one additional CATCH symptom. Most consistently, facial dysmorphy was apparent (92%), while hypocalcemia, mostly at threshold values, was present in 62% and thymic hypoplasia including borderline low T-lymphocyte numbers was observed in 41%. None of the patients presented with a cleft palate. A high intrafamilial variability in expression was also evident with respect to the CCVD. Our findings indicate that seemingly isolated complex cardiovascular defects associated with a 22q11 microdeletion most probably do not represent a distinct subgroup within the CATCH-22 complex but are syndromal in nature with extracardiac features that are often overlooked. Received: 25 July 1996 / Revised: 15 October 1996     

Analysis of DEXI/Dexi refines the organization of the mouse 7C and human 15q11-->q13 imprinting clusters

Identification of imprinted genes in the Prader-Willi/Angelman syndrome deletion region is complicated by the presence of large flanking repeats. While inactive copies of DEXI are located within the repeats, we have now localized the active DEXI gene to 15q11-->q13 outside the PWS/AS deletion and Dexi to mouse chromosome 16, suggesting complex evolution of this genomic region in both species.     

Predisposition for breast cancer in carriers of constitutional translocation 11q;22q.

A translocation between the long arms of chromosomes 11 and 22, t(11;22)(q23;q11), is the most frequent constitutional reciprocal translocation in man. This chromosome abnormality has not previously been reported to be associated with an increased risk for neoplasia. The observation of one patient with a constitutional translocation t(11q;22q) and breast cancer prompted us to study the relationship between these two conditions. The incidence of breast cancer was determined in carriers of t(11q;22q). The karyotypes were determined by QFQ-banding, and the breakpoints were then further characterized by fluorescent in situ hybridization. Eight families with a total of 22 balanced carriers were found. In five of these families there was one case of breast cancer each. In another family a case of an unknown malignancy was reported in one member. No other malignancies were found among these patients. The number of breast cancer cases was significantly higher than expected among the translocation carriers (P < .001). The chromosomal breakpoints showed the same localization with the markers used, in the seven families studied. The association of constitutional translocation t(11q;22q) and breast cancer identifies a subset of patients with a highly increased risk for breast cancer who would benefit from counseling and screening. It also suggests the involvement of genes on 11q and/or 22q, in the tumorigenesis of breast cancer.     

Abdominal lymphatic dysplasia and 22q11 microdeletion

We report the case of a child with 22q11 microdeletion who presented with abdominal lymphatic dysplasia resulting in exsudative enteropathy. This primitive and localized lymphatic malformation is consistent with the vascular theory in the velocardiofacial syndrome.     

Crkl deficiency disrupts Fgf8 signaling in a mouse model of 22q11 deletion syndromes

Deletions on chromosome 22q11.21 disrupt pharyngeal and cardiac development and cause DiGeorge and related human syndromes. CRKL (CRK-Like) lies within 22q11.21, and Crkl-/- mice have phenotypic features of 22q11 deletion (del22q11) syndromes. While human FGF8 does not localize to 22q11, deficiency of Fgf8 also generates many features of del22q11 syndrome in mice. Since Fgf8 signals via receptor-type tyrosine kinases, and Crk family adaptor proteins transduce intracellular signals downstream of tyrosine kinases, we investigated whether Crkl mediates Fgf8 signaling. In addition to discovering genetic interactions between Crkl and Fgf8 during morphogenesis of structures affected in del22q11 syndrome, we found that Fgf8 induces tyrosine phosphorylation of FgfRs 1 and 2 and their binding to Crkl. Crkl is required for normal cellular responses to Fgf8, including survival and migration, Erk activation, and target gene expression. These findings provide mechanistic insight into disrupted intercellular interactions in the pathogenesis of malformations seen in del22q11 syndrome.     

The deletions of 22q11--the Portuguese experience

The patients with a chromosome 22q11 deletion have a variable phenotype which includes DiGeorge (DG) and Velocardiofacial (VCF) syndromes. The aim of the present study is to characterize the phenotype of DG and VCF using facial biometry in 12 portuguese patients. We found 4/12 patients with the DG phenotype: 3/4 had telecanthus, small mouth and retrognathia; 1/4 had telecanthus, short nose with bulbous tip and a normal mouth. These patients had major cardiac defects associated with hypoplastic or absent thymus and monosomy 22q11. We did not find velopharyngeal insufficiency in patients with the so called DG phenotype 8/12 patients had the VCF phenotype: typical facies with variable features. Four of these had velopharyngeal insufficiency and learning disabilities. Four patients had cardiac defects and 5/8 had monosomy 22q11. Probably this clinical variability is due to mutations in critical genes involved in embryonic development.