Detection of trisomy 8 in hematological disorders by in situ hybridization

An alphoid repetitive DNA (D8Z2) probe specific for the pericentromeric region of chromosome 8 was used to detect extra copies of chromosome 8 in bone marrow cells obtained from 10 patients with hematological disorders and five controls. Numerical aberrations of chromosome 8 were established by conventional banding techniques. Trisomy 8 was found in four patients with myelodysplastic syndrome (MDS) and three with acute myeloid leukemia (AML). Three additional patients with MDS exhibited an extra chromosome 8 in only one metaphase. In five of the seven trisomy cases, the presence of the trisomy 8 clone was confirmed by in situ hybridization (ISH). In one case of AML with trisomy 8, detected by GTG-banding, no significant numbers of cells containing three spots were found using the alphoid repetitive probe; however, hybridization with a chromosome 8-specific library revealed that the alleged extra chromosome 8 was a translocation chromosome containing only the long arm of chromosome 8. Due to a lack of material, it was not possible to achieve optimal ISH results on the trisomy 8 bone marrow cells of patient 7. In the three MDS patients with a single trisomy 8 metaphase, a slight, albeit significant, increase of trisomy 8 interphase cells was found with ISH. We conclude that this probe is useful for cytogenetic studies. Moreover, ISH, in general, is a powerful tool for precise classification of chromosomal aberrations and can also contribute significantly to the clinical evaluation of patients with hematological disorders.     

Maternal origin of extra marker chromosome 1Q31.1-qter and 13pter-q12.12 in a child with dysmorhic features

Maternal origin of extra marker chromosome Iq31.l-qter and 13pter-q12.12 in a child with dysmorphic features: We describe a twenty-days-old female child with dysmorphic features and chromosomal analysis with GTG-banding revealed an extra marker chromosome. Fluorescence in situ hybridization (FISH) study of extra marker chromosome confirmed to be maternal der(13) chromosome, contained 1q31.1-qter and 13pter-q11 chromosomal material and resulted from a maternal balanced translocation t(1;13)(q31.1; q12.12). The child had the majority of trisomy 1q clinical features: dysmorphic features, micropthalmia, high arched palate, long philthrum, micrognathia, hypertelorism, low set ears, short sternum, overlapping fingers, valgus of wrists, right knee and ankle joints were in flexion contractures. This is the first case of trisomy 1q with an extra marker chromosome which also contained chromosome 13pter-q12.12 material.     

Partial D 15 trisomy. A case and general review.

A profoundly retarded girl with cyanotic congenital heart disease, recurrent myoclonic seizures, an external strabismus and not very unusual facial features was found to have a 47, XX chromosome complement. The extra chromosome is a small G-size chromosome with small projections extending from the ends of the long arms and no satellites observed on the short arms. By Geimsa-trypsin banding techniques this aberrant chromosome appears to be a partially deleted D 15 chromosome. A comparison of the clinical features is made with those described in the nine other reported specifically identifies cases of 'partial trisomy 15'. For clinical and chromosome morphology reasons, this was felt not to be trisomy in the G group nor an extra Y. We speculate that the long arm projections are satellites derived from a ring-type intrachromosomal translocation.     

Gene expression variation increase in trisomy 21 tissues

Congenital development disorders with variable severity occur in trisomy 21. However, how these phenotypic abnormalities develop with variations remains elusive. We hypothesize that the differences in euploid gene expression variation among trisomy 21 tissues are caused by the presence of an extra copy of chromosome 21 and may contribute to the phenotypic variations in Down syndrome. We used DNA microarray to measure the differences in gene expression variance between four human trisomy 21 and six euploid amniocytes. The three publicly available data sets of fetal brains, adult brains, and fetal hearts were also analyzed. The numbers of euploid genes with greater variance were significantly higher in all four kinds of trisomy 21 tissues (p < 0.01) than in the corresponding euploid tissues. Seventeen euploid genes with significantly different variance between trisomy 21 and euploid amniocytes were found using the F test. In summary, there is a set of euploid genes that shows greater variance of expression in human trisomy 21 tissues than in euploid tissues. This change may contribute to producing the variable phenotypic abnormalities observed in Down syndrome.     

Precarious acrocentric short arm in prenatal diagnosis: no chromosome 14 polymorphism, but trisomy 17p

Precarious acrocentric short arm in prenatal diagnosis: no chromosome 14 polymorphism, but trisomy 17p: We report on a girl with multiple congenital abnormalities and a prenatally diagnosed 46,XX,14p+ de novo karyotype. Fluorescence in situ hybridization (FISH) demonstrated that the extra material on the short arm of chromosome 14 was not just a polymorphism, but that it originated from chromosome 17. The phenotypic findings of this patient with pure trisomy 17p are compared with those of ten previously published cases.     

Consequences of trisomy syndromes – 21 and beyond

The mechanisms underlying pathologies in Down syndrome remain poorly understood. In this forum article we compare the cellular phenotypes of chromosome 21 trisomy with other trisomic cells. We argue that both effects of the extra chromosome 21 and the global consequences of chromosome gain must be considered to understand complex pathologies of Down syndrome.     

A clinical and molecular study of mosaicism for trisomy 17

Trisomy 17 has never been reported in a live birth. We present a case of mosaic trisomy 17 in a male presenting with mental retardation, seizures, attention deficit hyperactivity and autistic disorders, hearing loss, growth retardation, microcephaly, and minor anomalies. Although peripheral blood lymphocyte chromosomes were normal, trisomy 17 was present in the skin fibroblasts. The percentage of abnormal cells appears to have increased from 18% in an initial skin biopsy at age 3 years 8 months to 80% at age 8 years 8 months. Molecular analysis using 13 highly polymorphic markers spanning the length of chromosome 17 demonstrated the extra chromosome 17 in the skin to be of paternal origin. Three alleles were never seen in the trisomic cell line, suggesting that the extra chromosome arose through a mitotic duplication error after conception. Uniparental disomy was excluded in the euploid blood sample. Although Smith-Magenis syndrome involves a deletion of proximal 17p, some of the clinical features of this mosaic trisomy 17 patient, such as decreased REM sleep and increased tolerance to pain, are suggestive of phenotypic features observed in Smith-Magenis syndrome. We speculate that there are dosage-sensitive genes located in 17p11.2 that produce these phenotypes for either deficiencies or overexpression of their gene products.     

A trisomic germ cell line and precocious chromatid segregation leads to recurrent trisomy 21 conception

A chromosomally normal 37-year-old woman was referred for preimplantation genetic diagnosis after having several conceptuses with trisomy 21. Segregation of chromosome 21 was assessed in unfertilised meiosis II oocytes and preimplantation embryos from PGD cycles using fluorescent in situ hybridisation (FISH). Of 7 preimplantation embryos, 5 were chromosomally abnormal with 4 having trisomy 21 and one being tetraploid. Of 4 oocytes, 3 had an abnormal chromosomal constitution with either an extra chromosome 21 or an extra chromatid 21. In one oocyte an extra chromatid 21 was detected in both the metaphase II complement and the first polar body providing the first direct evidence of a maternal trisomic germ cell line. Moreover, this result shows that the extra chromosome 21 can precociously divide into its two chromatids at the first meiotic division. Received: 9 September 1998 / Accepted: 26 November 1998     

DNA polymorphism analysis in families with recurrence of free trisomy 21

We used DNA polymorphic markers on the long arm of human chromosome 21 in order to determine the parental and meiotic origin of the extra chromosome 21 in families with recurrent free trisomy 21. A total of 22 families were studied, 13 in which the individuals with trisomy 21 were siblings (category 1), four families in which the individuals with trisomy 21 were second-degree relatives (category 2), and five families in which the individuals with trisomy 21 were third-degree relatives, that is, their parents were siblings (category 3). In five category 1 families, parental mosaicism was detected, while in the remaining eight families, the origin of nondisjunction was maternal. In two of the four families of category 2 the nondisjunctions originated in individuals who were related. In only one of five category 3 families, the nondisjunctions originated in related individuals. These results suggest that parental mosaicism is an important etiologic factor in recurrent free trisomy 21 (5 of 22 families) and that chance alone can explain the recurrent trisomy 21 in many of the remaining families (14 of 22 families). However, in a small number of families (3 of 22), a familial predisposing factor or undetected mosaicism cannot be excluded.     

Trisomy 4q syndrome: presentation of a new case and review of the literature

We describe the 11th case of a de novo partial trisomy of the long arm of chromosome 4, with the extra segment spanning from 4q27 to 4q35. The aberration resulted from an unbalanced translocation of material from 4q to the short arm of chromosome 7, as evident from fluorescent in situ hybridization. Microsatellite analysis revealed the extra material to originate from the father. The karyotype was interpreted as 46,XX,der(7)t(4;7)(q27;p22). The patient is a 13-year-old girl with severe mental retardation, growth retardation, hearing impairment as well as minor foot, thumb and facial anomalies. Although the extent of the aberration varies between the reported patients, there are nevertheless features in common, suggestive of a trisomy 4q syndrome. The clinical findings most frequently reported are: mental retardation, seizures, microcephaly, hearing impairment and growth retardation, as well as epicanthic folds, high/broad/depressed nasal bridge, malformed ears, tooth and thumb anomalies. Almost the entire long arm of chromosome 4, except band q11, has been involved in trisomies/duplications, but 4q27 and 4q31 seem to be preferentially engaged in the trisomy 4q syndrome.     

Telomere lengths at birth in trisomies 18 and 21 measured by Q-FISH

Trisomies 18 and 21 are genetic disorders in which cells possess an extra copy of each of the relevant chromosomes. Individuals with these disorders who survive birth generally have a shortened life expectancy. As telomeres are known to play an important role in the maintenance of genomic integrity by protecting the chromosomal ends, we conducted a study to determine whether there are differences in telomere length at birth between individuals with trisomy and diploidy, and between trisomic chromosomes and normal chromosomes. We examined samples of peripheral blood lymphocytes (PBLs) from 31 live neonates (diploidy: 10, trisomy 18: 10, trisomy 21: 11) and estimated the telomere length of each chromosome arm using Q-FISH. We observed that the telomeres of trisomic chromosomes were neither shorter nor longer than the mean telomere length of chromosomes as a whole among subjects with trisomies 18 and 21 (intra-cell comparison), and we were unable to conclude that there were differences in telomere length between 18 trisomy and diploid subjects, or between 21 trisomy and diploid subjects (inter-individual comparison). Although it has been reported that telomeres are shorter in older individuals with trisomy 21 and show accelerated telomere shortening with age, our data suggest that patients with trisomies 18 and 21 may have comparably sized telomeres. Therefore, it would be advisable for them to avoid lifestyle habits and characteristics such as obesity, cigarette smoking, chronic stress, and alcohol intake, which lead to marked telomere shortening.     

Dysregulation of gene expression in mouse trisomy 16, an animal model of Down syndrome.

In humans, trisomy 21 results in a specific phenotype known as Down syndrome (DS). The mechanism by which an extra copy of normal genes leads to the DS phenotype is unknown. Most studies in DS and other aneuploid organisms have shown that gene dose is proportional to gene expression. To date, most genes examined have encoded either metabolic enzymes or constitutively expressed products. In the trisomy 16 mouse, an animal model of DS, we found marked dysregulation of two developmentally regulated genes, App and Prn-p. Dysregulation varied from tissue to tissue and during development in the same tissue. We conclude that abnormal phenotypes seen in aneuploid conditions may result in part from disordered expression of developmentally regulated genes.     

Parental origin of the extra chromosome in prenatally diagnosed fetal trisomy 21

Trisomy 21 (Down syndrome) is one of the most common chromosomal abnormalities. Of cases of free trisomy 21 causing Down syndrome, about 95% result from nondisjunction during meiosis, and about 5% are due to mitotic errors in somatic cells. Previous studies using DNA polymorphisms of chromosome 21 showed that paternal origin of trisomy 21 occurred in only 6.7% of cases. However, these studies were conducted in liveborn trisomy 21-affected infants, and the possible impact of fetal death was not taken into account. Using nine distinct DNA polymorphisms, we tested 110 families with a prenatally diagnosed trisomy 21 fetus. Of the 102 informative cases, parental origin was maternal in 91 cases (89.2%) and paternal in 11 (10.8%). This percentage differs significantly from the 7.0% observed in previous studies (P<0.001). In order to test the influence of genomic parental imprinting, we determined the origin of the extra chromosome 21 in relation to different factors: advanced maternal age, maternal serum human chorionic gonadotropin (hormone of placental origin), severity of the disease, gestational age at diagnosis and fetal gender. We found that the increased frequency of paternal origin of nondisjunction in trisomy 21-affected fetuses cannot obviously be explained by factors leading to selective loss of paternal origin fetuses.     

Reliability and efficiency of interphase-fish with alpha-satellite probe for detection of aneuploidy

Early diagnosis is very important in pre- and postnatal diagnosis of Down syndrome. This study examines the use of fluorescence in situ hybridization (FISH) to detect trisomy 21 in interphase nuclei and metaphase chromosome obtained from fifty-four Down syndrome patients with a regular type trisomy 21. Three of them showed six hybridization signals on both interphase nuclei and metaphase spreads instead of five signals corresponding to two chromosomes 13 and three chromosomes 21 although they were cytogenetically trisomy 21. Simultaneous application of probe combination revealed that one of the extra signals of chromosomes 13/21 a-satellite probe was located on chromosome 22 in two cases and one extra signal on chromosomes 15 in one case. In addition, another case showed four hybridization signals on both interphase nuclei and metaphase spreads instead of five signals, indicating deletion of the chromosome specific alpha-satellite DNA sequence of chromosome 13/21. These centromeric sequence changes may have pathological significance in the appearance of aneuploidy because they may be involved in the important centromere function.     

Trisomy: Chromosome competition or maternal strategy?: Increase of trisomy incidence with increasing maternal age does not result from competition between chromosomes

Axelrod and Hamilton (Science 211:1390, 1981) suggested that trisomies may result from an end-game strategy between chromosomes competing to get on the gamete as the mother approaches menopause. We tested this hypothesis by reviewing studies of the parental origin of the extra chromosome in trisomy 21 births. These data show that there is no significant rise in trisomy 21 conceptions as the mother ages. The increase in trisomies with maternal age results not from an increase in nondisjunctions, but from a decrease in rejection of trisomy zygotes, which may be adaptive for the mother towards the end of her reproductive life. This decreasing rate of rejection may result from the changing inclusive benefits of two maternal strategies as menopause approaches.     

Chromosome studies in 500 induced abortions.

A survey of the chromosome constitution in 500 induced abortions (5-12 menstrual weeks) was undertaken over a period of 1 1/2 years. There were 34 cases (6.8%) of gross chromosome anomalies: 2 cases of trisomy A; 5 of trisomy C (including XXX and XXY); 1 of mosaic trisomy C; 4 of trisomy D; 2 of trisomy E; 2 of trisomy G; 1 of double trisomy E and G; 1 of XYY; 4 of monosmy C (including XO); 2 of mosaic monosomy C; 1 of mosaicism of ring D chromosome; 1 of extra small metacentric chromosome; 3 of triploidy (including triploidy with double trisomy C and G); and 5 of tetraploidy and its mosaicism. An increased risk for the occurrence of trisomic anomalies was found with advancing age of the mothers. In contrast, the production of monosomies was not age-related. Trisomies were the most common type of anomalies and were found almost at random, regardless of the characteristics of chromosomes. Neither satellited nor small chromosomes were predominantly involved in the formation of chromosome anomalies.     

Trisomy 22.

The existence of a trisomy 22 has been definitely established by newer methods of karyotype analysis which permit distinction between the acrocentric chromosomes of group G. Trisomy 22 is much rarer than trisomy 21. This report presents presumptive evidence that the cat eye syndrome (CES), the so-called "trisomy 22" (T22), the intermediate cases (IM) with cardinal symptoms of CES and T22, and some cases of mental retardation with rather unspecific symptoms are variants of the same disease entity. For T22, CES and one abortive case the extra chromosome was clearly identified as number 22 chromosome with or without partial deletion of the long arm. An interesting and presently not fully understood feature of trisomy 22 is its frequent familial incidence.     

Partial trisomy 15q1

Summary A supernumerary extra chromosome of maternal origin, precisely described from QM- and C-banding patterns, was studied in a mentally defective boy with a severe convulsive disorder. This case is considered to represent a specific phenotype of trisomy 15q1. The suggestion that in cases of partial trisomy 15q different phenotypes are due to the second chromosome involved in interchange is supported by the observation of a tertiary trisomy in 2 sibs. It resulted from a balanced reciprocal translocation in the mother t(8q+15q-) and caused an unusual malformation syndrome (mental deficiency, cleft lip and palate, funnel chest, hypospadias).     

A trisomy 13 case with Robertsonian translocation presenting with atypical findings

A trisomy 13 case with Robertsonian translocation presenting with atypical findings: Trisomy 13 is an autosomal trisomy caused by the presence of an extra copy of chromosome 13. Anomalies associated with this syndrome are severe mental retardation, coloboma, hypotonia, skeletal anomalies, midline anomalies, facial defects, holoprosencephaly, cardiac defects, omphalocele and polydactyly. Here we report a case of trisomy 13 with Robertsonian translocation, 160 day old, presenting with atypical findings like posterior fusion defect of the vertebra, hyperplasia of the right lobe of the liver, dilatation at pelvicalyxial system, scoliosis and complex heart disease including cardiomyopathy.     

Origin of acrocentric trisomies in spontaneous abortuses

Summary A total of 33 spontaneous abortuses with various acrocentric trisomies were studied for the origin of the extra chromosomes using Q- and R-band polymorphisms as markers. Eleven trisomic abortuses were informative: nine trisomic abortuses (one with trisomy 13, three with trisomy 21, and five with trisomy 22 including one with a 46,XX/47,XX,+22 mosaicism) originated at maternal first meiosis; a 21-trisomic abortus resulted from an error at maternal second meiosis (or first mitosis); and a 13-trisomic abortus was of maternal first or second meiotic origin. The abortus with mosaic trisomy 22 started as a 22-trisomic zygote resulting from an error at maternal first meiosis, followed by a mitotic (in vivo or in vitro) loss of the paternally derived chromosome 22.