Correlations between karyotype and phenotype in structural and numerical abnormalities of chromosome 18]

Five cases with different abnormalities of chromosome 18 are described: one case with trisomy 18, two cases with ring 18, one case with partial trisomy 18q and one case with a mosaic 18p-/iso 18q. The karyotypes of the parents were normal. Cytogenetic analysis was performed on PHA stimulated blood lymphocytes. GTG, QFQ, MTX banding techniques were used. Karyotype-phenotype correlations are made. All patients present mental retardation, hypotonia and facial dismorphisms. The different degree of mental retardation and the clinical signs are in relation to the different size of deletions or trisomies of the short or long arm of chromosome 18. In the case with mosaicism 18p-/iso18q the phenotype is determined from the chromosomal abnormality more frequent in the cells (18p-).     

18p- Syndrome resulting from 14q/18q ‘dicentric’ fusion translocation

Summary A child with nasal hypoplasia, growth and developmental delay, and 18p- due to 14q/18q apparent dicentric fusion is reported. Review of ten previously reported patients with 18p- due to fusion translocations involving the long arm of chromosome 18 reveals clinical features ranging from arrhinencephaly to minimal dysmorphic changes and mild retardation. This spectrum of clinical expression is similar to that seen in patients with partial 18p deletions. Since the same range of clinical features is observed whether there is partial or apparent total deletion of 18p, it is suggested that only a distal segment of the short arm of chromosome 18 may be etiologically related to the clinical phenotype in the 18p- syndrome.     

Two new cases of the Christchurch (Ch1) chromosome 21: evidence for clinical consequences of de novo deletion 21P-

We performed an investigation of two unrelated cases with extremal variants of chromosome 21 without visible materials of the short arms (Christchurch or Ch1 chromosome). In the first case chromosome 21p- was initially detected during routine cytogenetic amniocentesis. Chromosomal variant was inherited from phenotypically normal father to phenotypically normal fetus (phenotypically normal boy after the birth). The second case of chromosome 21p- was detected in 7 years old boy, referred to cytogenetic analysis due to mental retardation and mild congenital malformation, including prenatal hypoplasia, microcephaly, low-set dysplastic ears, short nose, micrognatia, short neck. Molecular characterization of 21p-variant chromosomes was performed by the use of FISH with DNA probes specific to the short arm and centromeric region of chromosome 21 (telomeric, beta-satellite, ribosomal, classical satellite and alphoid DNA probes). Chromosomes 21p-hybridized positively only with telomeric DNA at both chromosomal ends and alphoid DNA probes at centromeric region of the first patient. In second case (de novo deletion of 21p), the Ch1 was associated with clinical phenotype and loss of telomeric and subtelomeric DNA in the p-arm of chromosome 21. Therefore, the complete absent of the short arm of chromosome 21 may be considered as abnormal. We propose that de novo deletion 21p- could have negative consequences due to absence of large portion of chromosomal DNA from the p-arm (telomeric, satellite or ribosomal DNAs) and following imbalance in organization and functioning of genome.     

Concordant congenital malformations in twins with inherited translocation: t(9p-;13q+)

Summary Several members of a family with a translocation between the short arm of chromosome 9 and the long arm of chromosome 13 (9p-;13q+) are presented. Although the translocation found in various members of the family looked alike and appeared to be balanced, the clinical features were different. The like-sex twins displayed some features of 9p monosomy syndrome, whereas their mother and maternal grandmother, who apparently had the same translocation, showed only a few features of 9p- syndrome in addition to mild mental retardation. We suggest that a minute deletion of the short arm of chromosome 9 may cause features of 9p- syndrome and that the clinical features of this syndrome in older individuals may be too mild for the clinical diagnosis to be possible.     

Chromosome 18 replaced by two ring chromosomes of chromosome 18 origin

We here describe the first example of the replacement of an autosome by two ring chromosomes originating from the missing chromosome, presented in a patient with a single chromosome 18 and two additional ring chromosomes. Detailed fluorescence in situ hybridization (FISH) analysis revealed the chromosome 18 origin of both ring chromosomes and characterized the small and the large ring chromosome as derivatives of the short and long arm of chromosome 18, respectively. The loss of subtelomeric regions of the short and the long arm of chromosome 18 in the ring chromosomes was confirmed by FISH studies. Molecular studies showed the exclusive presence of the paternal alleles for microsatellite markers located distal to the short and long arm loci D18S843 and D18S474, respectively. This indicates the maternal origin of both rings and provides evidence for substantial deletions of the distal parts of both arms of chromosome 18 in the ring chromosomes. The dysmorphic features of the patient can be explained by these deletions in both chromosome arms, as the clinical findings partly overlap with observations in 18p- and 18q-syndrome and are similar to some cases of ring chromosome 18. Centromere misdivision is suggested as one mechanism involved in the formation of the ring chromosomes.     

Partial trisomy 8q in half-sisters with distinct dysmorphic patterns not similar to the trisomy 8 mosaicism syndrome

Summary Two cases of partial trisomy 8q are presented. Common clinical features included severe mental and physical retardation, a prominent and short forehead, widely set mongoloid eyes, broad, flat nose with short septum, short upper lip, misshapen ears, a funnel chest, hypertrichosis of the back, coxa valga, and short fingers with brachymesophalangy and clinodactyly of the little fingers. Moreover, Case 1 had a frontal meningocele and bilateral talipes equinovarus, and Case 2 had a ventricular septal defect. The chromosome aberration in the two girls arose from a maternal balanced translocation, t(8;18) (q2309;p113). Since the major clinical features of mosaic trisomy 8 are absent in the two girls and in other cases of partial trisomy, both for the distal segment of the lang arm and for the short arm of chromosome 8, it is concluded that trisomy of the proximal part of the long arm of chromosome 8 causes most of the clinical findings of trisomy 8 mosaicism syndrome.     

A case with mosaic partial duplication of 1q: prenatal and postmortem clinical and cytogenetic evaluations

Partial trisomy 1q including different segments of the long arm is a rare cytogenetic anomaly. Especially the cases with mosaic proximal tandem duplication of 1q included a longer fragment are very rare. Cases who have partial 1q trisomy showed large phenotypic variation due to the differences in size of the duplicated segments of 1q. The clinical phenotype of most cases is characterized by multiple congenital anomalies especially including central nervous system and developmental delay. We describe a prenatally diagnosed case with mild cerebral ventriculomegaly and karyotype with mosaic pure trisomy of chromosome 1q [(46,XX/46,XX,dup(1)(q21qter)]. Phenotypic postmortem examination showed cranial asymmetry, flat and broad nasal bridge, anteverted nostrils, hypertelorism, retrognathia, abnormal pinnae, hypoplasic thumbs, long fingers and toes, mediodorsal curvature of the 4th and 5th toes and posterior prominence of the heel was observed. Autopsy confirmed the ventriculomegaly. Postmortem chromosome preparation from skin culture, cord blood and intracardiac blood confirmed the mosaic pure trisomy of chromosome 1q.     

17 long arm isochromosome. A common anomaly in malignat blood disorders.

A cytogenetic anomaly consisting in the replacement of a 17 by its long arm isochromosome was identified as the only alteration in the marrow cells of two patients with acute granulocytic leukemia. In one case, the specific nature of the abnormal chromosome was established by newly available techniques. Since its identification in 1965, this structural anomaly, which implies 17 long arm duplication and short arm deletion, has been observed, as a sole or as an associated finding, in the malignant cells of a spectrum of blood disorders, including acute granulocytic leukemias, the blast crisis of chronic myeloid leukemia and lymphoreticular proliferative disorders. Attention is called to this particular rearrangement for its clinical as well as fundamental implications, as its presence in blood forming cells unfailingly hearalds a fast, fatal course of evolution.     

Hairy cell leukemia: an analysis of the chromosomes of 26 patients.

We studied the chromosomes from 26 patients with hairy cell leukemia (HCL) to ascertain the frequency and types of consistent chromosomal abnormalities. Samples from 21 patients were obtained from peripheral blood cultures grown 24 and 48 h without phytohemagglutinin, or from bone marrow samples. Two male patients had similar, consistent abnormalities; one patient's karyotype was 46, X, +12; that of the second was 46, X, +C marker. In the latter case, the distal long arm of the C marker most closely resembled chromosome No. 12 from band q14 to q terminal, but the short arm and proximal long arm were of undetermined origin. Both karyotypes lacked the Y chromosome. Nine of the 21 patients had abnormalities in single cells. One patient had, in one sample, a single abnormal cell with an extra No. 3 and an extra No. 12 (48, XY, +3, +12), and in a later sample, a second cell of poor morphology which also could have been trisomic for No. 12. Another patient had one cell with an unusually bright short arm, as well as two cells, with different abnormalities, both involving the short arm of chromosome No. 1. The two patients with consistent chromosome abnormalities had rapidly progressive disease in spite of splenectomy, and their clinical course from the time of diagnosis was relatively short (5 and 7 months, respectively).     

Microcell-mediated cotransfer of genes specifying methotrexate resistance, emetine sensitivity, and chromate sensitivity with Chinese hamster chromosome 2.

Many selectable mutants of somatic Chinese hamster cells have been described, but very few of the mutations have been mapped to specific chromosomes. We have utilized the microcell-mediated gene transfer technique to establish the location of three selectable genetic markers on chromosome 2 of Chinese hamster. Microcells were prepared from the methotrexate-resistant MtxRIII line of Flintoff et al. (Somatic Cell Genet. 2:245-261, 1976) and fused to wild-type CHO cells, and microcell hybrids (transferants) were selected in medium containing methotrexate. All transferants were karyotyped and found to contain a marker chromosome from the donor MtxRIII line. This marker chromosome, called 2p-, consisted of a chromosome 2 with a reduced short arm resulting from a reciprocal translocation between 2p and 5q. In experiments utilizing emetine-resistant (Emtr) or chromate-resistant (Chrr) recipient cells it was found that the emt+ and chr+ wild-type genes were cotransferred with the 2p- chromosomes. Karyotype analysis of several transferants with rearranged or broken 2p- markers allowed regional localization of the emt and chr loci to the proximal third of the long arm and localization of the gene or genes conferring methotrexate resistance to the short arm. These results confirm our earlier assignment of the emt and chr loci to chromosome 2 in Chinese hamster.     

Instability of chromosomes in human nerve cells (Normal and with Neuromental Diseases)

It is assumed that the genetic mechanism of pathogenesis of such widely spread neural and mental diseases as schizophrenia (SZ), autism, ataxia-telangiectasia (AT), and Alzheimer’s disease (AD) is associated with structural and functional genomi biological markers of genomic instability. The currently available methods of molecular cytogenetics (I-MFISH, QFISH, and ICS-MCB) facilitate the solution of numerous fundamental biological problems, including analysis of genomic variations in brain cells. Using these methods, we have studied for the first time aneuploidy in human embryo and adult brain cells (normal and with AT, AD, and SZ) as well as in blood cells of children with autism. The level of aneuploidy was increased two- to threefold in the embryo brain with a subsequent reduction of the number of abnormal cells in the adult brain. In the case of SZ, mosaic aneuploidy for chromosomes 1, 18, and X was found. The study of blood cells from children with autism showed chromosomal mosaicism for chromosomes X, 9, and 15. In the case of AT, we observed a global expression of aneuploidy in up to 20–50% of cortex and cerebellum neurons. In addition, a local instability of chromosome 14 was revealed in the degenerating cerebellum in the form of breaks in the 14q12 region. In the case of AD, a tenfold increase was observed in the level of aneuploidy for chromosome 21 in brain sections subjected to neurodegeneration. These data indicate that mosaic genomic instability in nerve cells is one of the mechanism of neurodegenerative and mental diseases.     

Polymorphism of 5-methylcytosine-rich DNA in human acrocentric chromosomes

Summary The acrocentric chromosomes of 18 unrelated individuals were analyzed by sequential staining by the chromomycin A₃/methyl green R-banding technique to identify the chromosomes, followed by an indirect immunoperoxidase technique to detect 5-methylcytosine (5MeC)-rich DNA. The short arms of both chromosomes 15 usually (92% of the chromosomes) had a large collection of 5MeC-rich DNA, which was always rich in AT base pairs. Much less commonly (11% of the possible occasions), a collection of 5MeC-rich DNA was seen on the short arm of a chromosome 13, 14, 21 or 22, and this DNA was always rich in GC base pairs. Sequential distamycin A/DAPI (DA/DAPI) and R-banding studies were carried out in 13 of these 18 individuals. There was bright DA/DAPI fluorescence of the 5MeC-rich region on the short arm of chromosome 15 but not on that of any other acrocentric chromosome. One implication of these findings is that bisatellited or other abnormal chromosomes that are DA/DAPI negative and 5MeC positive cannot be derived from number 15. In the case of a de novo chromosome of this type, the specific origin from any other acrocentric chromosome could be demonstrated by examining 5MeC-binding of the parental chromosomes.     

Partielle Trisomie des kurzen Arms eines Chromosoms Nr. 4 in der Folge einer Translokation t(4p-22p+)

Zusammenfassung Eine partielle Trisomie des kurzen Armes eines Chromosoms 4 wurde bei einem 3 Jahre alten mikrocephalen, in seiner geistigen Entwicklung retardierten Kind festgestellt. Diese Aberration ergab sich bei einer reziproken Translokation t(4p-22p+), die bei der Mutter, dem Großvater und 2 Geschwistern vorliegt.

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Partial trisomy of the short arm of chromosome 4 due to translocation t(4p-22p+)

Summary Partial trisomy of the short arm of chromosome 4 was found in a 3-year-old microcephalic, mentally retarded girl. This aberration resulted from a reciprocal translocation t(4p-22p+) present in the mother, the grandfather and both siblings.

     

Trisomy 3p syndrome. Report of a new case, due to a chromosomal insertion

A new case of the trisomy 3p syndrome is described. The propositus showed mental and growth retardation and many of the congenital anomalies typical of this syndrome. Chromosome analysis in the propositus revealed an enlarged short arm of chromosome 4. In the mother a similar chromosome 4 was found and, in addition, an abnormal chromosome 3 with a deleted short arm. The karyotype of the mother was interpreted as resulting from a balanced insertional translocation. GTG bands p21 and p22 of chromosome 3 were inserted into the short arm of chromosome 4.     

Y;autosome translocations and mosaicism in the aetiology of 45,X maleness: assignment of fertility factor to distal Yq11

Summary Three 45,X males have been studied with Y-DNA probes by Southern blotting and in situ hybridization. Southern blotting studies with a panel of mapped Y-DNA probes showed that in all three individuals contiguous portions of the Y chromosome including all of the short arm, the centromere, and part of the euchromatic portion of the long arm were present. The breakpoint was different in each case. The individual with the largest portion (intervals 1–6) is a fertile male belonging to a family in which the translocation is inherited in four generations. The second adult patient, who has intervals 1–5, is an azoospermic, sterile male. These phenotypic findings suggest the existence of a gene involved in spermatogenesis in interval 6 in distal Yq11. The third case, a boy with penoscrotal hypospadias, has intervals 1–4B. In situ hybridization with the pseudoautosomal probe pDP230 and the Y chromosome specific probe pDP105 showed that Y-derived DNA was translocated onto the short arm of a chromosome 15, 14, and 14, respectively. One of the patients was a mosaic for the 14p+ translocation chromosome. Our data and those reported by others suggest the following conclusions based on molecular studies in eight 45,X males: The predominant aetiological factor is Y;autosome translocation observed in seven of the eight cases. As the remaining case was a low-grade mosaic involving a normal Y chromosome, the maleness in all cases was due to the effect of the testis determing factor, TDF. There is preferential involvement of the short arm of an acrocentric chromosome (five out of seven translocations) but other autosomal regions can also be involved. The reason why one of the derivative translocation chromosomes becomes lost may be that it has no centromere.     

Clinical and cytogenetic studies in a large (4;8) translocation family with pre- and postnatal Wolf syndrome

Partial deletion of 4p (Wolf syndrome) is reported in two cases resulting from paternal balanced t(4;8)(p163;p231). One of them was diagnosed prenatally and aborted. Autopsy revealed dysmorphic face, and malformed heart and kidneys. The other case, the mentally retarded sister, had no clinical signs of internal malformations, only slightly dysmorphic appearance. We concluded that loss of the terminal segment of 4p(4p163) seems sufficient to produce the clinical entity of Wolf syndrome, and partial trisomy of the short arm of chromosome 8 did not mask the 4p- phenotype. Segregation analysis showed risk figures of about 15% for a malformed child comparable to previously given figures concerning the outcome of autosomal reciprocal translocations.     

Silver staining of the supernumerary chromosome in the cat-eye syndrome

A case of the Cat-eye syndrome (CES) with 47,YX, + mar is presented. Silver staining method revealed the marker chromosome to be bisatellited. This abnormal chromosome is interpreted as the product of a Robertsonian translocation between the short arm and satellites of chromosome 22 and short arm of another D-group chromosome, probably No. 13.     

Mosaicism for an ectopic NOR at 8pter and a complex rearrangement of chromosome 8 in a patient with severe psychomotor retardation

We describe a 3-year-old girl with severe delays in mental and motor skills, a history of generalized seizures, and subtle dysmorphic features. Conventional cytogenetics revealed a mosaic karyotype. A de novo ectopic NOR at the telomeric region of the short arm of one chromosome 8 (8ps) was found in 90% of lymphocyte and in 98% of fibroblast metaphases. A small NOR-bearing marker chromosome and a large derivative chromosome 8 without short arm satellites (der(8)) were present in the remaining cells. FISH with a probe specific for centromeres 14 and 22 labeled both the telomeric region of 8ps and the small marker centromere. Der(8) included an inverted duplication of 8p and a rearranged duplication of 8q but lacked a second centromere. A subtelomeric probe for 8p revealed a cryptic deletion in 8ps and der(8). Thus, the karyotype represents a combination of submicroscopic partial monosomy 8pter and mosaic trisomy 8.     

rDNA and acrocentric chromosomes in man

Summary A malformed female infant was found to have a 46,XX complement with a chromosome 8 shorter than normal with a secondary constriction and satellites on the short arm. Chromosome studies on the clinically normal father showed a balanced translocation between chromosome 8 and 13, i.e., 46,XY,t(8;13) (p21 p12). The proposita, carrier of the unbalanced form of the translocation, resulted partially monosomic for short arm of chromosome 8 (8p-) and partially trisomic for short arm of chromosome 13.The levels of DNA complementary to rRNA (normal in the father who had 10 NOR and increased in the proposita who had 11 NOR) confirmed our interpretation of the rearrangement.     

Consistent deficiencies of chromosome 18 and of the short arm of chromosome 17 in eleven cases of human large bowel cancer: a possible recessive determinism

Cytogenetic study of 11 cases of colorectal carcinoma was performed after R-banding. In all instances, there was a rearrangement involving chromosome 17 in its juxtacentromeric region, leading to the loss of its short arm. There was also a relative lack of chromosome 18, unrelated to a rearrangement of this chromosome in all but one case. Other anomalies, involving chromosomes 1 and 8 among others, were frequently but not systematically observed. The consistent lack of chromosome 18 and of the short arm of chromosome 17, leading to a complete or partial monosomy of these chromosomes in near diploid cells suggests that the passage to the hemizygous status of recessive genes carried by these chromosomes may play an important role in the development of colorectal carcinoma.