Molecular and cytogenetic characterisation of an unusual case of partial trisomy/partial monosomy 13 mosaicism: 46,XX,r(13)(p11q14)/46,XX,der(13)t(13;13)(q10;q14)

A female infant with multiple malformations and mental retardation was noted to have a rare de novo chromosome abnormality involving mosaicism with two cell lines, one with a ring chromosome 13, and the other with partial trisomy 13 owing to a complex rearrangement. Cytogenetic examination excluded the presence of a t(13q;13q) cell line and showed a cell line with a marker chromosome containing two chromosome 13 long arms joined together after deletion of a part (q11→q14) of one of them. In addition, the absence of a cell line with two normal chromosomes 13 or a cell line with a t(13q;13q) implies that the ring (13) and the marker (13) arose from a single event at the first cleavage division.
The two cell lines were present in different proportions in both peripheral blood lymphocytes and skin fibroblasts. The results of microsatellite characterisation clearly indicate the paternal origin and the absence of recombination, supporting the postzygotic origin of both the ring and the marker chromosome.


Keywords: unusual mosaicism; ring 13; partial trisomy 13; partial monosomy 13     

Clinical delineation of proximal and distal partial 13q trisomy

The most relevant phenotypic features seen in both proximal and distal partial trisomy 13 have been identified from a review of 35 cases. Clinical delineation of either proximal or distal partial trisomy 13 has been demonstrated through the use of conspicuous phenotypic differences. The findings of persistent foetal Hb and increased number of nuclear projections on neutrophils are consistent findings associated with partial trisomy of a proximal segment of chromosome 13 and are diagnostic for trisomy of a partial segment of chromosome 13 that contains bands 13q12 and 13q14. The physical features of polydactyly and hemangioma have been mapped to bands 13q31 and 13q32----13qter and provide a differential diagnosis for a distal trisomic segment of chromosome 13 that may include bands 13q22----13qter. A segment of chromosome 13 has been identified that does not produce any detectable phenotypes in the triplicated state. The possible role of a triplicated 13q segment in altering expression of structural and regulatory systems elsewhere in the genome has been examined. Distinct clinical syndromes involving either a partial proximal or partial distal trisomic segment of chromosome 13 may be phenotypically defined.     

13q部分三体的分子细胞检测及其与斜颈体征的可能关系

目的 探讨斜颈与13号染色体部分三体的可能关系。方法 应用染色体显带技术结合荧光原位杂交确诊两个具有13q部份三体典型临床症状病例的核型，并比较他们的临床表型与已报道病例的异同。结果 两例患者均为13q14→qter的部分三体，尽管另一条衍生染色体不同，但他们都有斜颈临床体征。结论 13q14→qter可能与斜颈相关，结合以前报道过的一篇文献，该基因更精确的定位可能为13q32→qter。     

A recognizable phenotype in a child with partial duplication 13q in a family with t(10q;13q)

A case of partial duplication 13q14 → qter is reported in a 9-year-old male with clinical symptoms which include trigonocephaly and synophrys, producing an easily identifiable phenotype. The chromosome duplication resulted from a familial t(10;13)(qter;q14). Subsequently, a normal balanced carrier sibling was diagnosed prenatally.     

Partial deletions of the long arm of chromosome 13 associated with holoprosencephaly and the Dandy‐Walker malformation

Two patients with partial deletions of the long arm of chromosome 13, del(13)(13q21‐q34) and del(13)(13q22‐q33), respectively, multiple congenital anomalies including holoprosencephaly (HPE) and the Dandy‐Walker malformation (DWM) are described. The occurrence of HPE and the DWM in both of these patients suggests that, in addition to ZIC2, which is important for normal development of the forebrain, there is at least one other dosage‐sensitive gene in 13q22‐q33 that plays an important role in brain development. The DWM is anatomically and developmentally distinct from HPE. The presence of a DWM in each of these two patients with partial deletions of the long arm of chromosome 13 suggests that haploinsufficiency at a locus in 13q22‐q33 may cause this anomaly. These findings suggest that microdeletions in 13q22‐q33 may be found in a proportion of patients with an apparently isolated DWM. Therefore, careful high‐resolution cytogenetic analysis (550 band level or greater) of 13q22‐q33 may be considered in these patients. Furthermore, future molecular studies of this region may reveal candidate gene loci for the DWM. © 2002 Wiley‐Liss, Inc.     

Maternal complex chromosome rearrangement ascertained through a del (13)(q12.1q14.1) detected in her mildly affected daughter

A maternal complex chromosome rearrangement (CCR) involving chromosomes 2, 13, and 20 was ascertained in a normal female through the diagnosis of a deletion of 13q in her daughter. The child has mild clinical features and developmental delay consistent with proximal deletions of 13q that do not extend into band q32 and a del(13)(q12q14.1) that does not involve the retinoblastoma locus by FISH. Maternal studies by GTG banding and FISH showed a complex karyotype with bands 13q12.3→13q12.1::20p13 translocated to 2p13 and bands 2pter→2p13::13q12.3→13q14.1 translocated into band 20p13. This would be the first report of an interstitial deletion of 13q inherited from a parental complex chromosome rearrangement. © 2001 Wiley‐Liss, Inc.     

Partial trisomy 13q identified by sequential fluorescence in situ hybridization

We report on a 19-month-old boy with partial trisomy 13q resulting from a probable balanced translocation involving chromosomes 1 and 13. The infant presented with omphalocele, malrotation, microcephaly with overriding skull bones, micrognathia, apparently low-set ears, rocker-bottom feet, and congenital heart disease, findings suggestive of trisomy 13. Karyotypic studies from peripheral blood lymphocytes documented an unbalanced karyotype 46,XY,−1, +der(1). The mother's chromosomes were normal, and the father was not available. Conventional cytogenetic techniques were unable to identify the extra material on the terminal 1q. Using fluorescence in situ hybridization (FISH) on the GTL-banded metaphases, the extra material on 1q was identified as the terminal long arm of 13, thus resulting in partial trisomy 13 (q32–qter). © 1995 Wiley-Liss, Inc.     

Evidence for a critical region for penoscrotal inversion,hypospadias, and imperforate anus within chromosomal region 13q32.2q34

Two unrelated patients with small distal deletions of the long arm of chromosome 13 are described, with shawl scrotum and penoscrotal transposition, penoscrotal hypospadias, a reduced perineum, and anal atresia. The patients have small deletions of 13(q32.2qter) and 13(q32q34), respectively. This report and the literature present evidence for one or possibly more gene(s) within region 13q32.2q34 which regulate the development of the ano-genital structures. The clinical spectrum includes bifid or shawl scrotum, hypospadias, biseptate uterus, malplaced and imperforate anus, and common cloaca. © 1996 Wiley-Liss, Inc.     

Clinical and genetic aspects of trigonocephaly: a study of 25 cases

We reviewed 25 patients ascertained through the finding of trigonocephaly/metopic synostosis as a prominent manifestation. In 16 patients, trigonocephaly/metopic synostosis was the only significant finding (64%); 2 patients had metopic/sagittal synostosis (8%) and in 7 patients the trigonocephaly was part of a syndrome (28%). Among the nonsyndromic cases, 12 were males and 6 were females and the sex ratio was 2 M:1 F. Only one patient with isolated trigonocephaly had an affected parent (5.6%). All nonsyndromic patients had normal psychomotor development. In 2 patients with isolated metopic/sagittal synostosis, FGFR2 and FGFR3 mutations were studied and none were detected. Among the syndromic cases, two had Jacobsen syndrome associated with deletion of chromosome 11q 23 (28.5%). Of the remaining five syndromic cases, different conditions were found including Say-Meyer syndrome, multiple congenital anomalies and bilateral retinoblastoma with no detectable deletion in chromosome 13q14.2 by G-banding chromosomal analysis and FISH, I-cell disease, a new acrocraniofacial dysostosis syndrome, and Opitz C trigonocephaly syndrome. The last two patients were studied for cryptic chromosomal rearrangements, with SKY and subtelomeric FISH probes. Also FGFR2 and FGFR3 mutations were studied in two syndromic cases, but none were found. This study demonstrates that the majority of cases with nonsyndromic trigonocephaly are sporadic and benign, apart from the associated cosmetic implications. Syndromic trigonocephaly cases are causally heterogeneous and associated with chromosomal as well as single gene disorders. An investigation to delineate the underlying cause of trigonocephaly is indicated because of its important implications on medical management for the patient and the reproductive plans for the family.     

Trisomy 4 pter‐q12 and monosomy of chromosome 13 pter‐q12 in a male with deficiency of all blood lymphocyte populations

A six‐year‐old male presented with multiple congenital anomalies, mental retardation, developmental delay, and an increased frequency of upper and lower respiratory infections and deficiency of all blood lymphocyte populations. Chromosome analysis showed an unbalanced translocation involving chromosomes 4 and 13, leading to partial trisomy for 4pter‐q12 and partial monosomy for 13pter‐q13 [karyotype, 46,XY,+der(4)t(4;13)(q12;q12),‐13)]. The mother is the carrier of a balanced translocation involving chromosomes 4 and 13. The translocation is known to be segregating for three generations in this family. The child was found to have deficiency of all blood lymphocyte populations, but other hemopoietic lineages appeared to be normal. In addition, his fresh T cells were principally CD45RA⁺, CD62L⁺, and deficient in the Fas receptor. This deficiency of all blood lymphocyte populations may be due to an overdose of a gene or genes located in the region of chromosome 4 or a partial deficiency of a gene or genes in the region of chromosome 13 that regulate the development of the lymphocyte lineage. Since the mother contributed two copies of chromosomal region 4pter‐q12 and no copy of 13pter‐q12, the deficiency of all blood lymphocyte populations in our patient may be the result of either uniparental disomy or imprinting. A maternal granduncle with dissimilar dysmorphic features was not lymphopenic but was neutropenic. © 2001 Wiley‐Liss, Inc.     

Two different structural abnormalities of chromosome 13 in offspring of chromo-somally normal parents with two fragile sites

Two siblings were found with different structural abnormalities involving their maternally inherited chromosome 13. The proband exhibited a ring 13 and a small fragment: 46, XX, r(13) (pllq34), +f, while her clinically normal brother carried a dicentric Robertsonian translocation: 45, XY, dic(13;15) (pl 1;pl 1). Both parents had normal karyotypes in peripheral blood and skin fibroblasts. The structural abnormalities of chromosome 13 may be due to an unstable gonadal 13; 15 translocation in the mother. In addition, two autosomal fragile sites were segregating in this family. The mother had a fragile (16) (q22) which was inherited by the proband. The father and paternal grandmother possessed a fragile (12)(q13) which was not inherited by either child. The expression of both fragile sites was dependent on culture conditions.     

Partial trisomy 13 plus partial trisomy 4q due to unusual segregation of translocation chromosomes

The cytogenetic analysis of a 7-month-old retarded girl with clinical signs compatible with partial trisomy 13 revealed a translocation t(4;13)(q33;ql4) and an additional derivative chromosome 13. This karyotype probably resulted from 3:1 segregation during meiosis of the patient's mother.     

Preliminary definition of a “critical region” of chromosome 13 in q32: Report of 14 cases with 13q deletions and review of the literature

We report on 14 patients with partial deletions of chromosome 13q. These patients exhibit a wide spectrum of phenotypes. Deletions limited to proximal bands q13–q31 are associated with growth retardation but not with major malformations. We review the literature since 1975 and summarize 13q deletion cases which have a phenotype involving one or more major malformations and mental retardation. Analysis of the breakpoints of these cases, as well as those reported by us, supports the hypothesis that only deletions involving at least part of band q32 are associated with major malformations and digital abnormalities. Patients with more distal deletions have severe mental retardation but do not have major malformations or growth retardation. A group of patients in whom the breakpoint is stated to be within q32 has had an intermediate phenotype. This suggests that it may be possible to define subregions within q32 whose deletion is associated with particular developmental defects. © 1993 Wiley-Liss, Inc.     

Molecular studies of translocations and trisomy involving chromosome 13

Twenty-four cases of trisomy 13 and one case with disomy 13, but a de novo dic(13,13) (p12p12) chromosome, were examined with molecular markers to determine the origin of the extra (or rearranged) chromosome. Twenty-one of 23 informative patients were consistent with a maternal origin of the extra chromosome. Lack of a third allele at any locus in both paternal origin cases indicate a somatic duplication of the paternal chromosome occurred. Five cases had translocation trisomy: one de novo rob(13q14q), one paternally derived rob(13q14q), two de novo t(13q13q), and one mosaic de novo t(13q13q)/r(13). The patient with a paternal rob(13q14q) had a maternal meiotic origin of the trisomy; thus, the paternal inheritance of the translocation chromosome was purely coincidental. Since there is not a significantly increased risk for unbalanced offspring of a t(13q14q) carrier and most trisomies are maternal in origin, this result should not be surprising; however, it illustrates that one cannot infer the origin of translocation trisomy based on parental origin of the translocation. Lack of a third allele at any locus in one of the three t(13q13q) cases indicates that it was most likely an isochromosome of postmeiotic origin, whereas the other two cases showed evidence of recombination. One balanced (nontrisomic) case with a nonmosaic 45,−13,−13,t(13;13) karyotype was also investigated and was determined to be a somatic Robertsonian translocation between the maternal and paternal homologues, as has been found for all balanced homologous Robertsonian translocations so far investigated. Thus, it is also incorrect to assume in de novo translocation cases that the two involved chromosomes are even from the same parent. Despite a maternal origin of the trisomy, we cannot therefore infer anything about the parental origin of the chromosomes 13 and 14 involved in the translocation in the de novo t(13q14q) case nor for the two t(13;13) chromosomes showing a meiotic origin of the trisomy. © 1996 Wiley-Liss, Inc.     

Partial trisomy 1 (q42→ter)

Clinical findings on three closely related, severely malformed infants and a 20-week-old fetus with an identical partial trisomy of chromosome 1 (1q42→ter) have made possible the delineation of a new syndrome. The typical manifestations of this syndrome are: severe intrauterine and postnatal developmental retardation, trigonocephaly with wide sutures and fontanels, characteristic facial features, colobomata of the iris, small hands and feet, and early death.     

Interstitial deletion 13q33 resulting from maternal insertional translocation

A 32-month-old female with a unique interstitial deletion of 13q is presented, including cytogenetic and gene marker studies. The deleted 13 in the patient is a result of malsegregation of a maternal insertional translocation involving chromosomes 7 and 13, 46,XX,ins(7;13)(q22;q32q34). The demonstration of two esterase D alleles in this patient excludes band 13q33 as the site of the ESD locus, previously assigned to the distal long arm of chromosome 13. The BUdR dye studies reveal that the replicative pattern for 13q31 and 13q21 is not altered by deletion of 13q33 and permit precise delineation of the breakpoints of the rearrangement.     

Cryptic subtelomeric translocations in the 22q13 deletion syndrome

Cryptic subtelomeric rearrangements are suspected to underlie a substantial portion of terminal chromosomal deletions. We have previously described two children, one with an unbalanced subtelomeric rearrangement resulting in deletion of 22q13→qter and duplication of 1qter, and a second with an apparently simple 22q13→qter deletion. We have examined two additional patients with deletions of 22q13→qter. In one of the new patients presented here, clinical findings were suggestive of the 22q13 deletion syndrome and FISH for 22qter was requested. Chromosome studies suggested an abnormality involving the telomere of one 22q (46,XX,?add(22)(q13.3)). FISH using Oncor D22S39 and Vysis ARSA probes confirmed a terminal deletion. A multi-telomere FISH assay showed a signal from 19qter on the deleted chromosome 22. Results were confirmed with 19qtel and 22qtel specific probes. The patient is therefore trisomic for 19qter and monosomic for 22qter. The patient''s mother was found to have a translocation (19;22)(q13.42;q13.31). We also re-examined chromosomes from two patients previously diagnosed with 22q deletions who were not known to have a rearrangement using the multi-telomere assay. One of these patients was found to have a derivative chromosome 22 (der(22)t(6;22)(p25;q13)). No evidence of rearrangement was detected in the other patient. Thus we have found the 22q13 deletion to be associated with a translocation in three of four patients. This report illustrates the usefulness of examining patients with hypotonia, severe language delay, and mild facial dysmorphism for this syndrome and suggests that most of these deletions may be unbalanced subtelomeric rearrangements.     

多发性骨髓瘤1q染色体异常与13q缺失的相关性研究

目的 探讨多发性骨髓瘤(multiple myeloma,MM)中13q14的缺失[del(13q14)]和1q染色体异常的相关性.方法 应用CD138单克隆抗体磁珠分选系统纯化48例初治MM患者的骨髓浆细胞,结合SpectrumorangeTM直接标记的位于13q14和1q12的序列特异性DNA探针和间期荧光原位杂交技术检测48例MM患者del(13q14)及1q染色体异常情况.结果 48例MM患者中,用D13S319探针检测,del(13q14)异常22例(45.8%);用CEP1探针检测.23例(47.9%)发现1q染色体异常.其中2例为1q缺失,21例为1q重复.22例伴有del(13q14)MM患者中16例出现1q染色体异常;26例未检测到del(13q14)MM患者中仅7例发现1q染色体异常.经X2检验两者间差异有统计学意义(X2=10.02,P＜0.01).结论 del(13q14)及1q染色体异常在MM中的发生率较高,两者间存在高度相关性.     

Cytogenetic and molecular cytogenetic studies of a case of interstitial deletion of proximal 15q

A 4-month-old child with multiple anomalies was determined to have an interstitial deletion of chromosome 15, i.e., del(15) (q12q14). The deletion appears not to be a typical deletion of 15q12 such as seen in Angelman and Prader-Willi syndromes, but appears to be more distal, involving either loss of all of 15q12 and part of 15q14, or part of 15q12 and most of 15q14. In either case, 15q13 is missing. Fluorescent in situ hybridization with probes for 15 centromere (D15Z), pericentromeric satellite sequences (D15Z1), and chromosome 15 painting probes shows the deleted chromosome to involve only 15 and no other acrocentric chromosome. Hybridization with probes for the AS and PWS loci (D15S11 and GABAB3, Oncor) show both sites to be intact in the deleted 15. The case is compared with two other reports with overlapping interstitial deletions of proximal 15q, neither of which shows typical features of Angelman or Prader-Willi syndromes.     

Diagnosis of chromosome 3 duplication q23→qter,deletion p25→pter in a patient with the C (trigonocephaly) syndrome

The cells of a deceased patient previously reported to have the C (trigonocephaly) syndrome were reinvestigated because his phenotype resembled that of a patient with a duplication-deficiency of chromosome 3. This diagnosis was confirmed using fibroblasts grown from frozen cells, and his mother was shown to carry an inversion of chromosome 3 in her peripheral blood leukocytes. His findings are compared to those of another patient with the C trigonocephaly syndrome with normal chromosomes and to others from the literature. At least one other patient from the literature has a phenotype compatible with “3q duplication syndrome”.