Duplication 11 (q22----qter) in an infant. A case report with review

A male infant with partial duplication of the long arm of chromosome 11 (11q22----qter) is described with a hitherto unreported translocation. In most cases 11q trisomy is associated with 11q/22q translocation and a 3:1 meiotic disjunction with 47 chromosomes. In a few cases the 11q translocation is associated with a partial deletion of other autosomes and a total of 46 chromosomes. In the present case, translocation to 9p is involved and no apparent deletion of 9p was noted, providing an opportunity to delineate the phenotypic features due to duplication of 11q. A comparison is made between the findings of partial 11q trisomy and 11q/22q translocation.     

Congenital heart defect and mental retardation in a patient with a 13q33.1-34 deletion

13q deletion syndrome is a rare genetic disorder caused by deletions of the long arm of chromosome 13. Patients with 13q deletion display a variety of phenotypic features. We describe a one-year-old female patient with congenital heart defects (CHD), facial anomalies, development and mental retardation. We identified a 12.75Mb deletion in chromosome region 13q33.1-34 with high resolution SNP Array (Human660W-Quad, Illumina, USA). This chromosome region contains about 55 genes, including EFNB2, ERCC5, VGCNL1, F7, and F10. Comparing our findings with previously reported 13q deletion patients with congenital heart defects, we propose that the 13q33.1-34 deletion region might contain key gene(s) associated with cardiac development. Our study also identified a subclinical deficiency of Factors VII and X in our patient with Group 3 of 13q deletion syndrome.     

A complex rearrangement on chromosome 22 affecting both homologues; haplo-insufficiency of the Cat eye syndrome region may have no clinical relevance

The presence of highly homologous sequences, known as low copy repeats, predisposes for unequal recombination within the 22q11 region. This can lead to genomic imbalances associated with several known genetic disorders. We report here a developmentally delayed patient carrying different rearrangements on both chromosome 22 homologues, including a previously unreported rearrangement within the 22q11 region. One homologue carries a deletion of the proximal part of chromosome band 22q11. To our knowledge, a ‘pure’ deletion of this region has not been described previously. Four copies of this 22q11 region, however, are associated with Cat eye syndrome (CES). While the phenotypic impact of this deletion is unclear, familial investigation revealed five normal relatives carrying this deletion, suggesting that haplo-insufficiency of the CES region has little clinical relevance. The other chromosome 22 homologue carries a duplication of the Velocardiofacial/DiGeorge syndrome (VCFS/DGS) region. In addition, a previously undescribed deletion of 22q12.1, located in a relatively gene-poor region, was identified. As the clinical features of patients suffering from a duplication of the VCFS/DGS region have proven to be extremely variable, it is impossible to postulate as to the contribution of the 22q12.1 deletion to the phenotype of the patient. Additional patients with a deletion within this region are needed to establish the consequences of this copy number alteration. This study highlights the value of using different genomic approaches to unravel chromosomal alterations in order to study their phenotypic impact.     

Constitutional duplication 11q23 de novo involving the MLL gene

We report a child with mental retardation, brain anomalies and congenital heart defect. His karyotype, after G-banding and FISH with a whole chromosome probe for chromosome 11 and a locus-specific probe for the MLL gene, was 46,XY,dup(11)(q23q23).ish dup(11)(q23q23)(wcp11+, MLL++) de novo; i.e., he had a pure partial 11q23 duplication. Clinical and cytogenetic findings of the present case were compared with the 7 previously reported cases with pure partial trisomy 11q; in 6/8 cases the region 11q23 was involved. We conclude that the scarce number of cases and their heterogeneity do not allow to establish a reliable genotype-phenotype correlation.     

A new case with 10q23 interstitial deletion encompassing both PTEN and BMPR1A narrows the genetic region deleted in juvenile polyposis syndrome

We report on a patient with a contiguous interstitial germline deletion of chromosome 10q23, encompassing BMPR1A and PTEN, with clinical manifestations of juvenile polyposis and minor symptoms of Cowden syndrome (CS) and Bannayan–Riley–Ruvalcaba syndrome (BRRS). The patient presented dysmorphic features as well as developmental delay at the age of 5 months. Multiple polyps along all parts of the colon were diagnosed at the age of 3 years, following an episode of a severe abdominal pain and intestinal bleeding. The high-resolution comparative genomic hybridisation revealed a 3.7-Mb deletion within the 10q23 chromosomal region: 86,329,859–90,035,024. The genotyping with four polymorphic microsatellite markers confirmed a de novo 10q deletion on the allele with a paternal origin, encompassing both PTEN and BMPR1A genes. The karyotype analysis additionally identified a balanced translocation involving chromosomes 5q and 7q, and an inversion at chromosome 2, i.e. 46,XY,t(5;7)(q13.3-q36), inv(2)(p25q34). Although many genetic defects were detected, it is most likely that the 10q23 deletion is primarily the cause for the serious phenotypic manifestations. The current clinical findings and deletion of BMPR1A indicate a diagnosis of severe juvenile polyposis, but the existing macrocephaly and PTEN deletion also point to either CS or BRRS, which cannot be ruled out at the moment because of their clinical manifestation later in life and the de novo character of the deletion. The deletion detected in our patient narrows the genetic region deleted in all reported cases with juvenile polyposis by 0.04 Mb from the telomeric side, mapping it to the region chr10:88.5–90.03Mb (GRCh37/hg19), with an overall length of 1.53 Mb.     

Cytogenetic findings in a prospective series of patients with DiGeorge anomaly.

High-resolution cytogenetics analysis of peripheral blood lymphocytes was done prospectively on 27 of 28 patients with features of DiGeorge anomaly. Twenty-two patients (81%) had normal chromosome studies with no detectable deletion in chromosome 22. Five patients (18%) had demonstrable chromosome abnormalities. Three patients had monosomy 22q11, one due to a 4q;22q translocation, one due to a 20q;22q translocation, and one due to an interstitial deletion of 22q11. One patient had monosomy 10p13, and one patient had monosomy 18q21.33, although the latter had subsequent resolution of T-cell defects. These findings are consistent with the heterogeneity of DiGeorge anomaly but confirm the association with monosomy 22q11 in some cases. However, monosomy 10p13 may also lead to this phenotype. Because of these associated chromosome findings, cytogenetic analyses should be done on patients with suspected DiGeorge anomaly. This is particularly important since many of the abnormalities involving chromosome 22 are translocations that can be familial with a higher recurrence risk. Since only one subtle, interstitial deletion of chromosome 22 was observed, it is not clear whether high-resolution cytogenetic analysis is cost beneficial for all such patients.     

Combined deletion 18q22.2 and duplication/triplication 18q22.1 causes microcephaly,mental retardation and leukencephalopathy

Chromosome 18 abnormalities rank among the most common autosomal anomalies with 18q being the most frequently affected. A deletion of 18q has been attributed to microcephaly, mental retardation, short stature, facial dysmorphism, myelination disorders, limb and genitourinary malformations and congenital aural atresia. On the other hand, duplications of 18q have been associated with the phenotype of Edwards syndrome. Critical chromosomal regions for both phenotypes are contentious. In this report, we describe the first case of an 11-year old male with a combined interstitial duplication 18q22.1, triplication 18q22.1q22.2 and terminal deletion 18q22.2q23 with phenotypic features of isolated 18q deletion syndrome and absence of phenotypic features characteristic of Edwards syndrome despite duplication of the suggested critical region. This report allows for reevaluation of proposed critical intervals for the phenotypes in deletion 18q syndrome and Edwards syndrome.     

Decreased DGCR8 Expression and miRNA Dysregulation in Individuals with 22q11.2 Deletion Syndrome

Deletion of the 1.5–3 Mb region of chromosome 22 at locus 11.2 gives rise to the chromosome 22q11.2 deletion syndrome (22q11DS), also known as DiGeorge and Velocardiofacial Syndromes. It is the most common micro-deletion disorder in humans and one of the most common multiple malformation syndromes. The syndrome is characterized by a broad phenotype, whose characterization has expanded considerably within the last decade and includes many associated findings such as craniofacial anomalies (40%), conotruncal defects of the heart (CHD; 70–80%), hypocalcemia (20–60%), and a range of neurocognitive anomalies with high risk of schizophrenia, all with a broad phenotypic variability. These phenotypic features are believed to be the result of a change in the copy number or dosage of the genes located in the deleted region. Despite this relatively clear genetic etiology, very little is known about which genes modulate phenotypic variations in humans or if they are due to combinatorial effects of reduced dosage of multiple genes acting in concert. Here, we report on decreased expression levels of genes within the deletion region of chromosome 22, including DGCR8, in peripheral leukocytes derived from individuals with 22q11DS compared to healthy controls. Furthermore, we found dysregulated miRNA expression in individuals with 22q11DS, including miR-150, miR-194 and miR-185. We postulate this to be related to DGCR8 haploinsufficiency as DGCR8 regulates miRNA biogenesis. Importantly we demonstrate that the level of some miRNAs correlates with brain measures, CHD and thyroid abnormalities, suggesting that the dysregulated miRNAs may contribute to these phenotypes and/or represent relevant blood biomarkers of the disease in individuals with 22q11DS.     

Associated anomalies in asymmetric crying facies and 22q11 deletion

Congenital asymmetric crying facies, a minor congenital anomaly due to unilateral absence or hypoplasia of the depressor anguli oris muscle, is associated at times with major congenital anomalies. A large number of asymmetric crying facies cases with chromosome 22q11 microdeletions have presently been reported. Fluorescence in situ hybridization (FISH) analysis for 22q11 deletion was performed on 8 infants with asymmetric crying facies. Five of our patients had at least one associated systemic anomaly. Two of 5 patients had conotruncal heart disease (Cayler cardiofacial syndrome). In three of the affected infants, we failed to reveal additional congenital malformation. The 22q11 deletion was present in only one patient. This baby had congenital hypoparathyroidism, severe neonatal hypocalcaemia and tetralogy of Fallot. We suggest, a 22q11 deletion should be excluded not in all cases but in cases with Cayler cardiofacial syndrome and in ACF associated with additional congenital anomalies.     

Chromosome deletion at 11q23 in an abnormal child from a family with inherited fragility at 11q23

Summary A neonate with clinical features of the 11q23 deletion syndrome was apparently mosaic with the dominant cell line showing deletion of the chromosomal segment 11q23.3 to 11qter. The presence of a few lymphocytes with a normal karyotype indicates post-zygotic deletion of chromosome 11. The mother and brother of the propositus show folate-sensitive fragility at band 11q23.3. This case indicates in vivo deletion at a folate-sensitive fragile site.     

Partial duplication of 17 long arm

Three subjects from 2 unrelated families with partial duplication of 17q, derived from a reciprocal parental translocation between chromosomes 11 and 17 with different breakpoints, are described. A female patient from one family with a 46,XX,-11,+der(11),t(11;17)(q24;q23.2)pat chromosome complement had died at 2 months of age. In the second family, a male propositus and a subsequent fetus, identified by cytogenetic prenatal diagnosis, showed a 46,XY,-11,+der(11),t(11;17)(q2505,q24.3) mat chromosome complement. Twelve other cases involving partial duplication of chromosome 17 have been reported, 11 of these derived from a balanced translocation, and 1 was a duplication. All these cases showed psychomotor and mental retardation, cranial contour anomalies, micrognathia, bulbous nose, short neck, skeletal anomalies, and CNS defects. The phenotypic and clinical observations in the three subjects of this report are compared with previously reported findings.     

Partial proximal trisomy 10q syndrome: a new case

We report a case of partial proximal trisomy of the long arm of chromosome 10 confirmed by fluorescence in situ hibridization (FISH) performed with whole chromosome 10 specific painting and specific yac clones. The phenotypic findings, compared to those found in other published cases with the same karyotype, support the recognition of a distinctive partial proximal trisomy 10q syndrome (10q11-->q22).     

Molecular analysis of the 18q- syndrome--and correlation with phenotype.

Seven individuals with deletions of the distal long arm of chromosome 18 were evaluated at the clinical, cytogenetic, and molecular levels. The patients had varying degrees of typical clinical findings associated with the 18q- syndrome. Cytogenetic analysis revealed deletions from 18q21.3 or 18q22.2 to qter. Somatic cell hybrids derived from the patients were molecularly characterized using ordered groups of probes isolated from a chromosome 18-specific library. In general, the size of the deletion could be correlated with the severity of the phenotype. Based on the clinical pictures of these seven patients, a preliminary phenotypic map for the clinical features associated with deletions of the distal portion of the long arm has been generated. Furthermore, genes previously localized to 18q21 were mapped relative to the chromosome breakpoints present in these patients.     

Molecular characterization of a ring chromosome 14 showing that the PI locus is centromeric to the D14S1 and IGH loci

Summary Molecular characterization of a ring chromosome 14 was carried out in a patient with the 46,XX,r(14) karyotype. The breakpoints shown by chromosome banding were within bands p11 and q32. Using molecular probes for the immunoglobulin heavy chain (IGH), D14S1 and PI loci located at 14q32, we showed that the IGH and D14S1 loci, located at 14q32.2 and 14q32.2, respectively, were deleted on the ring chromosome 14, but that the PI locus was not. Therefore, the chromosomal break lies between PI and D14S1. These results show that the order of these chromosome 14 markers is cen-PI-D14S1-IGH, in keeping with multipoint linkage data. Further molecular characterization of ring 14 chromosomes should lead to a detailed understanding of the molecular events and clinical consequences of the gene deletion associated with such chromosomal aberrations.     

Der(22) syndrome and velo-cardio-facial syndrome/DiGeorge syndrome share a 1.5-Mb region of overlap on chromosome 22q11

Derivative 22 (der[22]) syndrome is a rare disorder associated with multiple congenital anomalies, including profound mental retardation, preauricular skin tags or pits, and conotruncal heart defects. It can occur in offspring of carriers of the constitutional t(11;22)(q23;q11) translocation, owing to a 3:1 meiotic malsegregation event resulting in partial trisomy of chromosomes 11 and 22. The trisomic region on chromosome 22 overlaps the region hemizygously deleted in another congenital anomaly disorder, velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS). Most patients with VCFS/DGS have a similar 3-Mb deletion, whereas some have a nested distal deletion endpoint resulting in a 1.5-Mb deletion, and a few rare patients have unique deletions. To define the interval on 22q11 containing the t(11;22) breakpoint, haplotype analysis and FISH mapping were performed for five patients with der(22) syndrome. Analysis of all the patients was consistent with 3:1 meiotic malsegregation in the t(11;22) carrier parent. FISH-mapping studies showed that the t(11;22) breakpoint occurred in the same interval as the 1.5-Mb distal deletion breakpoint for VCFS. The deletion breakpoint of one VCFS patient with an unbalanced t(18;22) translocation also occurred in the same region. Hamster-human somatic hybrid cell lines from a patient with der(22) syndrome and a patient with VCFS showed that the breakpoints occurred in an interval containing low-copy repeats, distal to RANBP1 and proximal to ZNF74. The presence of low-copy repetitive sequences may confer susceptibility to chromosome rearrangements. A 1.5-Mb region of overlap on 22q11 in both syndromes suggests the presence of dosage-dependent genes in this interval.     

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).     

Microdissection and reverse painting reveals a microdeletion 6(q26qter) in a de novo r(6) chromosome

Ring chromosomes 6 are rare constitutional abnormalities with inconsistent phenotypic and clinical features. One of the reasons for this variability is the cytogenetically undetectable loss of chromosomal material from the telomeric segments at 6p or 6q. We have therefore used fluorescence in situ hybridization (FISH) to analyse a ring chromosome 6 that was detected in a newborn boy with dysmorphic features. Reverse painting of the microdissected ring chromosome onto normal metaphase spreads revealed a small deletion of the terminal region of the long arm, 6(q26qter). Moreover, the simple all-telomeric sequence (TTAGG)n was lost, whereas the p-specific subtelomeric sequence was still present. Our findings confirm that microdeletions occur during the formation of r(6) chromosomes and, therefore, are an important determinator of the associated phenotype.     

Langer-Giedion syndrome,in a child with complex structural aberration of chromosome 8

A patient with typical features of the Langer-Giedion syndrome (tricho-rhino-phalangeal syndrome, type II) is described. In the karyotype an interstitial deletion of the long arm of chromosome 8 (band 8q22) was observed as the result of a complex rearrangement of chromosomes 1 and 8: 46,XY inv(8)(q23 leads to q242), del(8)(q221 leads to q223), ins(8;1) (q221;p321 p341;q242). Previously reported cases of Langer-Giedion syndrome with deletion of 8q are compared with the present one.