VEGF: a modifier of the del22q11 (DiGeorge) syndrome?

Hemizygous deletion of chromosome 22q11 (del22q11) causes thymic, parathyroid, craniofacial and life-threatening cardiovascular birth defects in 1 in 4,000 infants. The del22q11 syndrome is likely caused by haploinsufficiency of TBX1, but its variable expressivity indicates the involvement of additional modifiers. Here, we report that absence of the Vegf164 isoform caused birth defects in mice, reminiscent of those found in del22q11 patients. The close correlation of birth and vascular defects indicated that vascular dysgenesis may pathogenetically contribute to the birth defects. Vegf interacted with Tbx1, as Tbx1 expression was reduced in Vegf164-deficient embryos and knocked-down vegf levels enhanced the pharyngeal arch artery defects induced by tbx1 knockdown in zebrafish. Moreover, initial evidence suggested that a VEGF promoter haplotype was associated with an increased risk for cardiovascular birth defects in del22q11 individuals. These genetic data in mouse, fish and human indicate that VEGF is a modifier of cardiovascular birth defects in the del22q11 syndrome.     

Analysis of CD38 and ZAP70 mRNA expression among cytogenetic subgroups of Iranian chronic-lymphocytic-leukemia patients

Chromosomal abnormalities and ZAP70 expression profile are two major independent prognostic markers in B-cell chronic lymphocytic leukemia. We investigated a possible correlation between these two markers. ZAP70 expression using real-time RT-PCR was examined in 20 B-cell chronic lymphocytic leukemia patients with del13q14, 13 patients with del11q22, 15 patients with trisomy 12, and 16 patients with no detected chromosomal abnormalities. Molecular analysis revealed that ZAP70 expression in the del13q subgroup was the same as in the control group, while it increased 2.78-fold in the del11q subgroup and 2.95-fold in the trisomy 12 subgroup, compared to the 15 cases in the control group. Comparison of the mean and standard deviation of the ZAP70 expression profile within the subgroups showed it to be highly variable among the individuals of the del11q and trisomy 12 subgroups, versus tight clustering for the del13q subgroup. Therefore, there is a correlation between del13q aberration, which has good prognosis with normal levels of ZAP70 expression. Due to a high degree of variation, no conformity is seen for del11q and trisomy 12 subgroups, making this grouping poor for prognostic discrimination. As a result, neither of these markers can serve as sole discriminators to determine the course of the disease; the use of both markers improves prognostic assessment.     

Low prevalence and independent prognostic role of del(11q) in Chinese patients with chronic lymphocytic leukemia

The 11q deletion (del(11q)) is a conventional cytogenetic aberration observed in chronic lymphocytic leukemia (CLL) patients. However, the prevalence and the prognostic value of del(11q) are still controversial. In this research, we retrospectively explored the prevalence, association, and prognostic significance of del(11q) in 352 untreated and 99 relapsed/refractory Chinese CLL patients. Totally 11.4% of untreated and 19.2% of relapsed/refractory patients harbored del(11q). Del(11q) was more common in patients with β2-microglobulin > 3.5 mg/L, positive CD38, positive zeta-chain associated protein kinase 70, unmutated immunoglobulin heavy variable-region gene and ataxia telangiectasia mutated mutation. Kaplan-Meier method and univariate Cox regression indicated that del(11q) was an independent prognostic factor for overall survival (OS). Based on the results of univariate Cox regression analysis, two nomograms that included del(11q) were established to predict survival. Desirable area under curve of receiver operating characteristic curves was obtained in the training and validation cohorts. In addition, the calibration curves for the probability of survival showed good agreement between the prediction by nomogram and actual observation. In summary, the prevalence of del(11q) is relatively low in our cohort and del(11q) is an unfavorable prognostic factor for untreated CLL patients. Besides, these two nomograms could be used to accurately predict the prognosis of untreated CLL patients.     

Congenital heart defects in patients with DiGeorge/velocardiofacial syndrome and del22q11

Congenital heart defects (CHDs) are found in 75% of patients with DiGeorge/velocardiofacial (DG/VCF) syndromes with deletion 22q11.2 (del22q11). The purpose of this study was to analyse clinical features and, particularly, types and subtypes of CHDs associated with del22q11 in our series of patients and in those reported in other studies. All patients with CHD and del22q11 present major or minor clinical features of DG/VCF syndrome. Many children, particularly in the neonatal age, have only a "subtle" phenotype, so that accurate phenotypical evaluation is mandatory for selecting patients with CHD at risk for del22q11. Conotruncal cardiac defects are the most common CHDs in patients with DG/VCF syndrome, but other defects can also occur. Peculiar anatomical subtypes are found in patients with del22q11. They are frequently complex, consisting in malalignment with deficiency of the infundibular septum and anomalies of the aortic arch and pulmonary arteries.     

The phenotypic spectrum of the 10p deletion syndrome versus the classical DiGeorge syndrome

We reviewed 36 patients with a deletion of the short arm of chromosome 10 and a partial DiGeorge syndrome. We compared the phenotypes observed in these del(10p) patients with the classical DiGeorge phenotype associated with del(22q11), pointing out both similarities and differences. Some features, such as sensorineural hearing loss, seem to be highly associated with a deletion of 10p but are absent in the classical DiGeorge spectrum caused by del(22q11).     

Molecular definition of de novo and genetically transmitted WAGR-associated rearrangements of 11p13

We describe a family in whom the phenotypically normal father carries a balanced insertional translocation, ins(14;11)(q23;p12p14). This individual fathered three mentally retarded children, two with a del(11)(p13) and one with a dup(11)(p13). Two other cases of a de novo del(11)(p13) are also described. All four del(11)(p13) cases presented with WAGR, a complex syndrome associated with a predisposition to Wilms' tumor (WT), aniridia (A), genitourinary abnormalities (G), and mental retardation (R). Using an approach combining karyotype analysis, determination of the gene copy number, and RFLP studies employing five 11p13 DNA markers, we were able to define the chromosomal rearrangement involved in each case. Analysis of these WAGR deletions provides further subdivision of band p13 on chromosome 11.     

Children with a 22q11 deletion versus children with a speech-language impairment and learning disability: behavior during primary school age

Children with a 22q11 deletion versus children with a speech-language impairment and learning disability: behavior during primary school age: Common behavioral features described in children with the Velo-Cardio-Facial syndrome (VCFS) (del 22q11) are problems with attention and concentration, extremes in behavior and social problems, especially in relationship with peers. At present, it is unclear whether these behavioral manifestations are directly related to the chromosomal anomaly or related to other manifestations of the syndrome such as developmental delay and speech-language delay. This study describes for the first time the behavior of young primary school aged children with a del22q11 compared to a control group of children matched for age, sex and mental level, with similar developmental problems (speech-language impairment plus learning disability: SLI + LD) but without a del22q11 or any other known genetic condition. Parents and teachers evaluated the children's behavior with standardized questionnaires (CBCL; TRF). Results indicate that most of the behaviors are similar across both groups. The only differences found are in the field of and . Children with a del22q11 have a stronger tendency to withdraw from others, whereas children with a SLI+LD seem to be more aggressive.     

Deletion - translocation del (12) (p11) leads to (t10;12) (p13;pII).

Renewed examinatinon with improved banding techniques of a boy previously reported to have the karyotype 46, XY,del(12)(p11) revealed a translocation 46, XY,t(10;12)(p13;p11), and reexamination of a boy previously reported to have the karyotype 46,XY/46,XY,del(5)(p13) showed the same mosaicism, but with a significantly lower frequency of cells with del(5)(p13), 8% compared with 23% at the time of birth. The decrease of the frequency of cells with chromosome abnormality in mixoploids during the first years of life as found in the present case as well as in prevously reported cases is discussed.     

Physical mapping of Streptomyces coelicolor A3(2) actinophage DNA. II. Transposon-like structure in DNA molecules of phiC43 phage DNA, localization of region responsible for establishment of the lysogenic state

Structural properties of DNA molecules of phages phi C43, phi C43del and mutant phage phi C311yg33 were studied. Actinophages phi C43del and phi C311yg33 have been isolated and shown to have a phenotype characteristic of phages defective in integration, i. e. turbid plaques and inability to establish the lysogenic state. By means of heteroduplexing, deletions were mapped in the genomes of these phages. DNA molecules of phi C43del and phi C11yg33 are devoid of the common fragment, which suggests that the mutant phenotypic character is associated with structural alterations in DNA molecules. The presence of transposon-like structure in phi C43 DNA molecules has been inferred from the analysis of phi C43/phi C43del heteroduplexes and phi C43 homoduplexes. Also, a deletion in phi C43 genome has been detected covering the same region where deletions in phi C43del and phi C11yg33 DNAs were located.     

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.     

Placental alkaline phosphatase types in Germany

Summary Two children with autosomal deletion (46,XY,del(12)(p11) and 46,XY/46,XY, del(5)(p13)) and normal phenotype were found among 5049 consecutive newborn children. The mother of the proband with deletion short arm 5 had the karyotype 46,XX,9qh+, but the parents had otherwise normal chromosome constitution.

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Zusammenfassung Zwei Kinder mit autosomaler Deletion (46,XY,del(12)(p11) und 46,XY/46,XY,del(5)(p13)) bei normalem Phänotyp wurden unter 5049 auslesefrei gewonnenen Neugeborenen entdeckt. Die Mutter des Probanden mit der Deletion am kurzen Arm von Nr. 5 hatte den Karyotyp 46,XX,9qh+; sonst hatten die Eltern normale Chromosomen.

     

Two cases of del(13q)-retinoblastoma and two cases of partial trisomy due to a familial insertion

A del(13)(q13q21.1) was found in a patient with bilateral retinoblastoma and mental retardation. The father was carrier of an ins(16;13)(q12.2;q13q21.1) which also was present in several other family members, and responsible for another case of del (13q)-retinoblastoma and two cases of trisomy for the inserted segment. This second del(13q) patient was also carrier of a balanced t(11;22).     

An unexpected recurrence of Angelman syndrome suggestive of maternal germ-line mosaicism of del(15)(q11q13) in a Finnish family

Angelman syndrome is a neuro-developmental disorder caused by genetic abnormalities affecting the maternal gene expression in the chromosome region 15q11-q13. In a study group of 45 Finnish Angelman patients, a recurrence of a del(15)(q11q13) was detected in one family. The mother's chromosomes 15 were structurally normal, whereas the patients and their unaffected brother shared an identical maternally derived haplotype outside the deletion region. These findings are suggestive of maternal germ-line mosaicism of del(15)(q11q13).     

Retinitis pigmentosa-associated rhodopsin mutations in three membrane-located cysteine residues present three different biochemical phenotypes

A large number of mutations in rhodopsin are associated with autosomal dominant retinitis pigmentosa (ADRP). We analyzed the biochemical phenotypes of the ADRP-associated cysteine mutants C167R, C222R, and C264del. C222R behaved as wild type in every aspect testable and is classified as a class I mutant. C167R produced intact protein but did not regenerate with 11-cis retinal and was not transported to the plasma membrane. We confirm its classification as a class IIa mutant. C264del represents a novel phenotype, which we propose to call class III. It produced a truncated protein of 27kDa that failed to regenerate with 11-cis retinal and was not targeted to the plasma membrane.     

Deletion of the short arms of chromosome 20

Summary A 46, XX, del(20) (p11) karyotype (Paris Conference, 1971) was identified in an 11-month-old French-Canadian girl with a dysmorphic syndrome, multiple congenital anomalies, psychomotor and growth retardation. Both parents had normal phenotype and karyotype.     

Differences in the expression of the ASIP gene are involved in the recessive black coat colour pattern in sheep: evidence from the rare Xalda sheep breed

Here we have tested the hypothesis of association between different levels of agouti signalling peptide (ASIP) mRNA and the recessive black coat colour in the rare Xalda breed of sheep. To deal with this task, we first tested the possible action of both the dominant black extension allele (E(D)) and a 5-bp deletion (X99692:c.100_104del; A(del)) in the ovine ASIP coding sequence on the black coat colour pattern in 188 Xalda individuals. The E(D) allele was not present in the sample and only 11 individuals were homozygous for the A(del)ASIP allele. All Xalda individuals carrying the A(del)/A(del) genotype were phenotypically black. However, most black-coated individuals (109 out of 120) were not homozygous for the 5-bp deletion, thus rejecting the A(del)/A(del) genotype as the sole cause of recessive black coat colour in sheep. Differences in expression of ASIP mRNA were assessed via RT-PCR in 14 black-coated and 10 white-coated Xalda individuals showing different ASIP genotypes (A(wt)/A(wt), A(wt)/A(del) and A(del)/A(del)). Levels of expression in black animals were significantly (P < 0.0001) lower than those assessed for white-coated individuals. However, the ASIP genotype did not influence the ASIP mRNA level of expression. The consistency of these findings with those recently reported in humans is discussed, and the need to isolate the promoter region of ovine ASIP to obtain further evidence for a role of ASIP in recessive black ovine pigmentation is pointed out.     

Monosomy 11Q: report of new phenotypic manifestations.

We present a case of new phenotypic findings not previously reported associated with a partial deletion of chromosome 11 with a break point at 23q - (46,XY,del(11)(q23). Partial deletion of chromosome 11q was first described by Jacobsen et al(4). Forty-eight patients have been reported during the last 30 years, with variable break points between 11q11 and 11qter. New phenotypic findings in our patient with the associated 11q deletion are imperforate anus, bilateral cataracts, and hypoplastic, multilobed lungs.     

Mosaic 13 trisomy due to de novo 13/13 translocation with subsequent fission karyotype: 46,XX,-13,+t(13;13)(p11;q11)/46,XX,del(13)(p11)

Summary A severely retarded child with multiple malformations was found to present a mosaic karyotype 46,XX,-13,+t(13;13)(p11;q11)/46,XX,del (13)(p11), which probably originated as the result of a de novo 13/13 translocation in a parental gamete, followed by postzygotic fission of the translocation chromosomse.