A palindrome-mediated mechanism distinguishes translocations involving LCR-B of chromosome 22q11.2

Two known recurrent constitutional translocations, t(11;22) and t(17;22), as well as a non-recurrent t(4;22), display derivative chromosomes that have joined to a common site within the low copy repeat B (LCR-B) region of 22q11.2. This breakpoint is located between two AT-rich inverted repeats that form a nearly perfect palindrome. Breakpoints within the 11q23, 17q11 and 4q35 partner chromosomes also fall near the center of palindromic sequences. In the present work the breakpoints of a fourth translocation involving LCR-B, a balanced ependymoma-associated t(1;22), were characterized not only to localize this junction relative to known genes, but also to further understand the mechanism underlying these rearrangements. FISH mapping was used to localize the 22q11.2 breakpoint to LCR-B and the 1p21 breakpoint to single BAC clones. STS mapping narrowed the 1p21.2 breakpoint to a 1990 bp AT-rich region, and junction fragments were amplified by nested PCR. Junction fragment-derived sequence indicates that the 1p21.2 breakpoint splits a 278 nt palindrome capable of forming stem-loop secondary structure. In contrast, the 1p21.2 reference genomic sequence from clones in the database does not exhibit this configuration, suggesting a predisposition for regional genomic instability perhaps etiologic for this rearrangement. Given its similarity to known chromosomal fragile site (FRA) sequences, this polymorphic 1p21.2 sequence may represent one of the FRA1 loci. Comparative analysis of the secondary structure of sequences surrounding translocation breakpoints that involve LCR-B with those not involving this region indicate a unique ability of the former to form stem-loop structures. The relative likelihood of forming these configurations appears to be related to the rate of translocation occurrence. Further analysis suggests that constitutional translocations in general occur between sequences of similar melting temperature and propensity for secondary structure.     

The phenotypic effects of chromosome rearrangement involving bands 7q21.3 and 22q13.3.

We report a family in which the proband has a direct insertion of band 7q21.3 into chromosome 22 at 22q13.3, karyotype 46,XX,dir ins(22;7)(q13.3;q21.2q22.1). Two of her children have unbalanced chromosome rearrangements involving 7q21.3, with one girl monosomic for the region and a boy trisomic for the region. The child monosomic for band 7q21.3 has a split hand/split foot (SHSF) anomaly and her clinical features are consistent with the 7q21-q22 contiguous gene deletion syndrome. In situ hybridisation studies have shown that the proband and her son have a submicroscopic deletion of chromosome band 22q13.3. Interstitial deletions of this chromosome band have rarely been reported.     

Novel translocations in acute nonlymphocytic leukemia. Two cases involving chromosome 21, band q22

We present two cases in which translocations involving 21q22 were found at presentation in acute nonlymphocytic leukemia (ANLL). The first of these translocations, t(3;21)(q26-q27;q22), is previously unknown in ANLL, but appears indistinguishable from that reportedly associated with Philadelphia-positive chronic myelogenous leukemia. The second case involves t(15;21)(q21-q22;q22), a translocation previously undescribed in ANLL. Both of these exchanges involve 21q22 plus another chromosome region associated with leukemogenesis. We attempted to interrelate these cytogenetic data with the oncogenic significance of 21q22.     

Sclerocornea associated with the chromosome 22q11.2 deletion syndrome

Reported ocular findings in the 22q11.2 deletion syndrome (which encompasses the phenotypes of DiGeorge, velocardiofacial, and Takao (conotruncal-anomaly-face) syndromes) have included posterior embryotoxon (prominent, anteriorly displaced Schwalbe's line at the corneal limbus or edge), retinal vascular tortuosity, eyelid hooding, strabismus, and astigmatism. We present seven 22q11.2 patients from multiple centers with sclerocornea, an eye finding previously unreported in the literature. Four boys and three girls were identified with sclerocornea, systemic DGS/VCFS findings, and fluorescence in situ hybridization (FISH)-confirmed microdeletion at chromosome 22q11.2. FISH diagnosis was perinatal in six patients but at 2 years of age in one child. Sclerocornea was bilateral in five patients. Findings included descemetocele (five eyes), microophthalmos (one eye), iridocorneal adhesions (one bilateral case), and severe anterior segment dysgenesis (one eye). Two patients underwent bilateral corneal transplantation; another two were scheduled for possible unilateral transplant. Sclerocornea is a static congenital condition in which the cornea is opaque and vascularized and resembles the sclera. The novel finding of sclerocornea suggests that a genetic locus at 22q11.2 may be involved in anterior segment embryogenesis. In most of our patients, the diagnostic process was underway, but in one patient 22q11.2 deletion was not suspected until after the child had already been undergoing treatment for sclerocornea for 2 years. Sclerocornea should be added to the clinical manifestations of the 22q11.2 deletion syndrome. Ophthalmologists diagnosing sclerocornea in children with systemic findings suggestive of 22q11.2 deletion should ensure appropriate genetic referral.     

Deletion of chromosome 22q11 and pseudohypoparathyroidism

A newborn boy with complex congenital heart disease, unilateral renal agenesis, and hypocalcemia was found to have a submicroscopic deletion of 22q11.2 (DiGeorge anomaly). In evaluating the pathogenesis of the hypocalcemia, repeatedly elevated or normal levels of parathyroid hormone were found, consistent with a diagnosis of pseudohypoparathyroidism. Pseudohypoparathyroidism can be due to mutation of a GTP binding protein (Gs-α protein) located on chromosome 20. Since there is another G protein locus (Gz alpha) adjacent to the DiGeorge critical region of chromosome 22, we hypothesized that a more extensive deletion may lead to pseudohypoparathyroidism. Fluorescence in situ hybridization was performed using a probe containing the Gz alpha gene, but no deletion was detected. This patient emphasizes the importance of determining the pathogenesis of the hypocalcemia in cases of DiGeorge anomaly. Am. J. Med. Genet. 72:63–65, 1997. © 1997 Wiley-Liss, Inc.     

Cortical dysgenesis in 2 patients with chromosome 22q11 deletion

Two patients with chromosome 22q11 deletion and cortical dysgenesis (gyral abnormalities) are reported in this study. One had unilateral clubfoot in addition to multiple features suggestive of the Di George syndrome (DGS), and the other presented with leg asymmetry and seizures, with subsequent recognition of the velo-cardio-facial syndrome (VCFS). In each patient, gyral abnormalities were identified in the hemisphere contralateral to the limb abnormality. A wide range of central nervous system abnormalities have been reported in DGS and VCFS, including three prior reports of gyral abnormalities (lissencephaly, microgyria). The 2 patients reported herein strengthen the association between the 22q11 deletion spectrum and cortical dysgenesis, but the underlying pathogenetic mechanism (primary neural migration vs. vascular disruption) remains unclear.     

Vasomotor instability in neonates with chromosome 22q11 deletion syndrome

Approximately 70% of individuals with chromosome 22q11 deletion syndrome (22q11DS) have congenital heart defects. A host of other vascular problems in these patients, such as tortuous carotid arteries, Raynaud's phenomenon, unexplained hypotension, hypertension, and hypothermia, raise the possibility that there may be abnormal autonomic regulation of the vascular system. So far, however, there has been no formal report of autonomic dysfunction in patients with 22q11 deletion. We present two infants with 22q11DS, who had profound hypotension after uncomplicated surgeries for congenital heart disease. The hypotension was not responsive to vasopressor treatment (and extracorporeal membrane oxygenation in one infant) and resulted in death, due to multiorgan system failure. Obvious causes, such as poor cardiac contractility, prolonged circulatory arrest, neurological abnormality, sepsis and blood loss were excluded. On autopsy, no abnormalities were found that could explain the hypotension. We hypothesize that these infants died of severe hypotension due to abnormal vascular tone and that this is a variable feature in individuals with 22q11 deletion. The autonomic nervous system, which is responsible for the regulation of vasomotor tone, may be variably affected in 22q11DS. This could have implications for the surgical management of patients with 22q11DS. Further studies on this topic would establish or refute the association between 22q11DS and dysautonomia.     

Ventricular septal defect associated with microdeletions of chromosome 22q11.2

Microdeletions of chromosome 22q11.2 (del.22q11) cause DiGeorge syndrome, velo-cardio-facial syndrome, and conotruncal anomaly face syndrome, which are commonly associated with conotruncal heart anomalies. Approximately 15% of the patients manifest ventricular septal defect (VSD), and the conal septal type of VSD has been proposed to be associated with del.22q11, since it is categorized as a conotruncal anomaly. However, the types of VSD associated with del.22q11 remain poorly studied. The purpose of this study is to assess whether conal septal VSD or other types of VSDs are associated with del.22q11. We analyzed the chromosomes of 22 consecutive patients with conal-septal VSD, prospectively, and evaluated the types of VSD observed in 3 patients with del.22q11, retrospectively. Del.22q11 was not detected in any of the 22 patients with conal septal VSD. All the VSDs observed in the 3 patients with del.22q11 were a perimembranous type of VSD, which is not a conotruncal anomaly. Our results suggest that perimembranous VSD can be associated with del.22q11, but del.22q11 is not a common cause of conal-septal VSD.     

Radial aplasia and chromosome 22q11 deletion.

We report on a neonate with deletion 22q11 (del22q11) presenting with facial dysmorphism, ocular coloboma, congenital heart defect, urogenital malformations, and unilateral radial aplasia. This malformation complex includes features frequently occurring in velocardiofacial syndrome as well as findings described in the CHARGE and VACTERL associations. To our knowledge, the present case is the first report of radial aplasia in del22q11. This observation further supports and extends the clinical variability of del22q11.     

Specific cerebellar reductions in children with chromosome 22q11.2 deletion syndrome

Children with chromosome 22q11.2 deletion syndrome commonly are found to have morphological brain changes, cognitive impairments, and elevated rates of psychopathology. One of the most commonly and consistently reported brain changes is reduced cerebellar volume. Here, we demonstrate that, in addition to the global cerebellum reductions previously reported, volumetric reductions of the anterior lobule and the vermal region of the neo-cerebellum in the mid-sagittal plane best differentiate children with the deletion from typically developing children. These results suggest that the morphological changes of specific portions of the cerebellum may be an important underlying substrate of cognitive impairments and increased incidence of psychopathology in this group.     

Monozygotic twins with chromosome 22q11 deletion and discordant phenotype.

We report monozygotic twins concordant for 22q11.2 deletion but discordant for clinical phenotype. Both boys show the typical dysmorphic features with short palpebral fissures, square nasal tip, small mouth, and both have nasal speech, but only one twin had a heart defect. They show that the phenotypic variability seen in this microdeletion syndrome cannot be explained on the basis of genotypic differences alone.     

Phenotypic heterogeneity in a family with a small atypical microduplication of chromosome 22q11.2 involving TBX1

The chromosome 22q11.2 region is commonly involved in non-allelic homologous recombination (NAHR) events. Microduplications of 22q11.2, usually involving a 3 Mb or 1.5 Mb region constitute the 22q11 microduplication syndrome. Both microdeletions and microduplications of 22q11.21 are reported to share several phenotypic characteristics, including dysmorphic facial features, velopharyngeal insufficiency, congenital heart disease, urogenital abnormalities, and immunologic defects. We report a child who presented at 8 months of age for evaluation of microcephaly and mild motor delay. Head circumference at birth, at 8 months, and at 19 months of age was below the 3rd centile. Other findings included left-sided cryptorchidism and developmental dysplasia of the left hip. In addition, echocardiography revealed a restrictive patent ductus arteriosus. Chromosomal microarray analysis using Affymetrix Genome-Wide Human SNP Array 6.0 revealed a novel 437 kb interstitial duplication at 22q11.21, involving TBX1, whose breakpoints did not coincide with known low copy repeat (LCR) regions. The same duplication was confirmed by fluorescent in situ hybridization (FISH) in the patient's mother and an older sister. The mother has a history of anxiety disorder and depression. The sister had a history of delayed motor milestones. None of the three duplication carriers has any documented renal anomalies or other significant medical problems. This report demonstrates the clinical heterogeneity associated with microduplications of 22q11.2 and illustrates the difficulties related to providing prognostic information and accurate genetic counseling to families when this finding is detected. The described microduplication is the smallest in this genomic region reported to date and further implicates abnormal gene dosage of TBX1 in disorders resulting from 22q11.2 rearrangements.