Trisomy 20q caused by der (X)t(X;20)(q28;q11.2)

A first case of "pure" trisomy 20q (q11.2-qter) is described in a female child with minor anomalies and developmental delay. This resulted from the inheritance, from a carrier mother, of an abnormal X chromosome: der (X)t(X;20)(q28;q11.2). Involvement of other autosomes has complicated the interpretation of the phenotypic effect of trisomy 20q in previously published case reports. Red cell gene dosage studies using adenosine deaminase (ADA) have confirmed that the proposita is trisomic for 20q. Taken together with RBG staining studies, these results suggest that there is incomplete inactivation, if any, of the autosomal portion of the consistently late-replicating abnormal X. Unexpectedly, ADA gene dosage results in the carrier mother showed a level of gene expression about half that of normal controls.     

Segregation of an insertional chromosome rearrangement in 3 generations.

The interstitial deletion of a segment of chromosome 13, 13q21 leads to 13q22, and its inversion and insertion into the long arm of chromosome 3 at breakpoint q12, was found to segregate in 3 generations of a family. Segregation of this 3 break rearrangement gave rise to individuals monosomic, trisomic, or balanced for the involved segment. Monosomy for 13q21 leads to 13q22 was associated with mental retardation, expressive aphasia, microcephaly, hand abnormalities, and short stature. Partially trisomic individuals had normal mentality, extremely high arched palate, and mild dysmorphic features. There was no evidence for retinoblastoma in the individuals examined. The balanced carriers were normal. Comparison of monosomic individuals with one previous report of a similar deletion reveals marked phenotypic similarities.     

Partial monosomy or trisomy resulting from crossing over within a rearranged chromosome 1

Two sibs, both monosomic for the same portion of lq (q25q32), had similar severe mental and physical retardation. An older sib was found to be trisomic for the same portion of 1q and less severely affected. These partially monosomic and partially trisomic No. 1 chromosomes resulted from meiotic crossover in the mother, who is a balanced hetero-zygote of the type 46.XX, ins (1) (p32q25q32).     

Translocation 1;7 in preleukemic states

A translocation t(1;7) interpreted as t(1;7)(p11;p11) was first reported by Scheres et al. in eight patients with various hematologic disorders. The karyotype of the abnormal cells was trisomic for 1q and monosomic for 7q. Those investigators reported having found four other cases in the literature. We report herein studies of two patients with the same t(1;7).     

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.     

Boy with bilateral retinoblastoma due to an unusual ring chromosome 13 with activation of a latent centromere

We present a patient with bilateral retinoblastoma and developmental delay who has an abnormal male karyotype containing 47 chromosomes, including an acentric derivative chromosome 13. We postulate that the derivative 13 occurred after a break at 13q14, with the proximal portion of the chromosome forming a ring and the distal portion undergoing duplication. Thus, this patient is trisomic for 13q14-->qter. The derivative chromosome with duplicated distal portion (13q14-->qter) lacked the 13 centromere and was negative for chromosome 13 alpha-satellite DNA by low stringency FISH. Nevertheless, this chromosome is stably transmitted in lymphocytes and fibroblasts. A single primary constriction was observed at band 13q21, consistent with activation of a latent centromere (neocentromere) at this band. The neocentromere on der(13) was positive for multiple centromeric proteins, suggesting that it acts as the functional centromere. By FISH, the Rb gene was present on the normal 13, the proximally derived ring chromosome, but not on the derivative chromosome. Although there was no evidence for disruption of the Rb gene, this chromosome rearrangement most likely results in abnormal expression of the Rb gene product. Copyright Wiley-Liss. Inc.     

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.     

Translocation 9q/13q resulting in duplication (trisomy 9pter→9q22) and deficiency (monosomy 13pter→13q12)

A profoundly retarded, 12-year-old female is described. Her phenotype is compatible with the clinical features of the trisomy 9p syndrome. Cytogenetic analyses showed her to be trisomic for 9pter→9q22 and monosomic for 13pter→13q12, as the result of adjacent-2 segregation during meiosis in her mother. The family pedigree shows this (9;13) translocation to be present in at least three generations.     

Esterase D assay in Brazilian retinoblastoma families

The gene related to retinoblastoma (Rb gene) can be considered a model human tumor suppressor gene and was assigned to band 13q14, together with the esterase D (ESD) gene. We studied the ESD activity and phenotype in 40 retinoblastoma patients, 50 unaffected relatives, and 85 nonrelated healthy control individuals. ESD activity from patients is significantly different from that of relatives and control individuals, but there was no significant difference between ESD activity from unaffected relatives and control individuals. Twelve and one-half percent of patients and 4.2% of unaffected relatives with ESD1 phenotype showed a low ESD level. The results showed the importance of ESD studies in all retinoblastoma patients and their relatives.     

Monosomy and trisomy of 15q24→qter in a family with a translocation t(6;15)(P25;q24)

A child with multiple anomalies, including growth retardation, a left-sided diaphragmatic hernia with lung hypoplasia, and cerebral malformations is described. Cytogenetic investigation demonstrated a deletion of the distal part of one chromosome 15, del(15)(q24qter), an aberration not previously described. Family studies revealed that the mother had a balanced translocation, t(6;15)(p25;q24). Two of her subsequent pregnancies resulted in abortions after prenatal diagnosis: one fetus was trisomic for 15q24→qter, while the other had monosomy 15q24→qter and a left-sided diaphragmatic hernia similar to the first child.     

X;14 translocation:an exception to the critical region hypothesis on the human X-chromosome

We report on a family in which an X;14 translocation has been identified. A phenotypically normal female, carrier of an apparently balanced X-autosome translocation t(X;14)(q22;q24.3) in all her cells and a small interstitial deletion of band 15q112 in some of her cells had 2 offspring. She represents a fifth case of balanced X-autosome translocation with the break point inside the postulated critical region of Xq(q13 q26) associated with fertility. The break point in this case is located in Xq22, the same band as in four previously published exceptional cases. In most of her cells, the normal X was inactivated. Her daughter, the proposita, has an unbalanced karyotype 46,X,der(X), t(X;14)(q22;q24.3)mat, del(15)(q11.1q11.3)mat. She is mildly retarded and has some Prader-Willi syndrome manifestations. She has two normal 14 chromosomes, der(X), and deletion 15q11.2. Her clinical abnormalities probably could be attributed to the deletions 15q and Xq rather than 14q duplication. In most of cells, der(X) was inactivated. We assume that spreading of inactivation was extended to the 14q segment on the derivative X. Late replication and gene dose studies support this view. Another daughter, who inherited the balanced X;14 translocation and not deletion 15 chromosome, is phenotypically normal.     

X;14 translocation: An exception to the critical region hypothesis on the human X-chromosome

We report on a family in which an X;14 translocation has been identified. A phenotypically normal female, carrier of an apparently balanced X-autosome translocation t(X;14) (q22;q24.3) in all her cells and a small interstitial deletion of band 15q 112 in some of her cells had 2 offspring. She represents a fifth case of balanced X-autosome translocation with the break point inside the postulated critical region of Xq(q13 q26) associated with fertility. The break point in this case is located in Xq22, the same band as in four previously published exceptional cases. In most of her cells, the normal X was inactivated. Her daughter, the proposita, has an unbalanced karyotype 46,X,der(X), t(X;14)(q22;q24.3)mat, del(15)(q11.1q11.3)mat. She is mildly retarded and has some Prader-Willi syndrome manifestations. She has two normal 14 chromosomes, der(X), and deletion 15q11.2. Her clinical abnormalities probably could be attributed to the deletions 15q and Xq rather than 14q duplication. In most of cells, der(X) was inactivated. We assume that spreading of inactivation was extended to the 14q segment on the derivative X. Late replication and gene dose studies support this view. Another daughter, who inherited the balanced X;14 translocation and not deletion 15 chromosome, is phenotypically normal.     

Prenatal diagnosis of a rare inherited heterochromatic variant chromosome 4

Heterochromatic chromosome polymorphisms have been extensively reported. Most are associated with C-band positive regions located on chromosomes 1, 9, 16, and Y. We report a prenatal case of a rare heterochromatic variant on chromosome 4. Amniocentesis was performed on a 35-year-old white female for AMA. The karyotype was 46,XY,add(4)(q35)?. One chromosome 4 homolog had an additional dark band at the terminus of the long arm. Parental chromosome analyses revealed that the chromosome 4 was maternally inherited. The mother and fetus were both Q and C-band positive and NOR and DAPI Distamycin staining negative. FISH using Y, 4, and 9 whole chromosome paint (WCP), centromere probes for all chromosomes (Cytocell, Chromoprobe Multiprobe-I System, Rainbow Scientific, Inc., Windsor, CT), alpha-satellite probes for 13/21, 14/22 (D13Z1/D21Z1; D14Z1/D22Z1, Oncor, Gaithersburg, MD), and the 15 PWS/Angelman probe (LSI SNRPN, D15Z1, PML, Vysis, Inc., Downers Grove, IL) were negative. The TelVysion 4q telomere probe (D4S2930, Vysis, Inc.) was positive. A phenotypically normal male was born at 37 weeks. Follow up studies on placenta, cord, cord blood, and foreskin confirmed the prenatal results. Based on these findings, it appears that this chromosome 4 was a rare heterochromatic variant. Heterochromatic variants have been demonstrated to have no phenotypic effect on carriers. This case illustrates the importance of reporting unusual variant chromosomes for genetic counseling purposes. To the best of our knowledge, this is the first report of a heterochromatic variant involving part of the long arm of chromosome 4 in a phenotypically normal mother and child.     

Balanced translocation 12/13 and situs abnormalities: homology of early pattern formation in man and lower organisms?

Studies in "lower" organisms have identified a set of homologous sequences expressed in oocytes and early embryos that is critical for pattern formation. Mutations in such genes may exhibit maternal effect--they cause abnormalities in the fetus only when present in the mother. We report on a mother and child with identical, apparently balanced translocations having the breakpoints 12q13.1 and 13p13. The fetus had multiple anomalies including bilateral trilobar lungs, complex heart defect, malrotation of the gut, and asplenia, while the mother was entirely normal. Several hypotheses are advanced to explain this variable expression including transection of a gene with maternal effect--lateral asymmetry in the fetus is influenced by the maternal genotype. This explanation would account for the higher transmission of congenital heart disease to offspring by affected females noted in several studies. The human counterparts of 2 loci (int-1 and HOX 3) involved in Drosophila early pattern formation are located near the translocation breakpoint 12q13.1. If one of these genes is responsible for situs abnormality, then university of positional code (but not of embryologic mechanism) is suggested for higher metazoans.     

Duplication of Xq26.2-q27.1, including SOX3, in a mother and daughter with short stature and dyslalia

Duplications of the distal long arm of the X chromosome are rare and carrier females are usually phenotypically normal. We report on a 14-year-old short statured (height and weight <3rd centile) girl with dup(X)(q26.2q27.1) inherited from a short mother. The proband has minor dysmorphic features, lordosis, lack of menarche, late signs of puberty, low prepuberal levels of gonadotrophins and steroids, but borderline low IGF-1 and normal IGF-Bp3 serum levels. Both the proposita and her mother have severe speech problems with stuttering and dyslalia. The 44-year-old mother with a strikingly aged face and a prominent nose, had menarche at 15 years. Both maternal sisters and the grandmother of the proposita are also short. Karyotyping revealed an additional band at Xq26 in all metaphases from the proband, her mother, and two maternal aunts. Molecular cytogenetic investigations revealed an Xq26.2-q27.1 direct duplication of approximately 7.5 Mb that encompasses or disrupts the SOX3 gene, which maps at the distal border of the duplicated segment. A similar chromosomal duplication was reported recently in five families and in each was associated with an abnormal phenotype in males with short stature [Hol et al., 2000; Solomon et al., 2002, 2004]. Using an androgen-receptor (HUMARA) gene methylation assay and FISH, we show that despite preferential inactivation of the dup(Xq) chromosome a significant proportion of lymphocytes in both mother and daughter carry an active duplicated X chromosome. Our findings further suggest that a dosage effect of SOX3 may to be responsible for a speech disorder in addition to short stature secondary to hypopituitarism.     

Trisomy for the Down syndrome 'critical region' is necessary but not sufficient for brain phenotypes of trisomic mice

Trisomic Ts65Dn mice show direct parallels with many phenotypes of Down syndrome (DS), including effects on the structure of cerebellum and hippocampus. A small segment of Hsa21 known as the 'DS critical region' (DSCR) has been held to contain a gene or genes sufficient to cause impairment in learning and memory tasks involving the hippocampus. To test this hypothesis, we developed Ts1Rhr and Ms1Rhr mouse models that are, respectively, trisomic and monosomic for this region. Here, we show that trisomy for the DSCR alone is not sufficient to produce the structural and functional features of hippocampal impairment that are seen in the Ts65Dn mouse and DS. However, when the critical region is returned to normal dosage in trisomic Ms1Rhr/Ts65Dn mice, performance in the Morris water maze is identical to euploid, demonstrating that this region is necessary for the phenotype. Thus, although the prediction of the critical region hypothesis was disproved, novel gene dosage effects were identified, which help to define how trisomy for this segment of the chromosome contributes to phenotypes of DS.     

Three cases of partial trisomy 9q in one generation due to maternal reciprocal t(6;8;9) translocation

A family is described in which three siblings had congenital abnormalities consistent with partial trisomy 9q syndrome. Karyotyping indicated that the mother was a carrier of two separate balanced reciprocal translocations involving three chromosomes (46,XX,t (6;8;9)(6q27;8p23;9q32;9q13] resulting from four breakpoints. The three siblings had inherited the der(8) from their mother and hence were partially trisomic for 9q32----9qter and partially monosomic for 8p23----8pter (46,XX,der(8),t(8;9)(p23;q32)mat). The clinical features of the three cases were comparable to those reported in the literature.     

Meiotic consequences of an intrachromosomal insertion of chromosome No. 1: a family pedigree

In three generations of the proband's patrilineal relatives, 14 subjects were found to be carriers of a "shift" insertional chromosome No. 1 (46XX or XY, ins(1)(p32q25q31)). The proband and three female relatives, who were mild to moderate mental retardates with minor congenital anomalies, were trisomic for the insertional segment, (1)q25q31. Another subject, who was a markedly immature female abortus with congenital abnormalities, was found to be monosomic for this same chromosomal segment. The cytogenetic evidence suggests that each of these unbalanced recombinant progeny was the result of a single crossing over in the noninsertional loop of a paternal pachytene bivalent of the balanced insertional chromosome No. 1.