Chromosomal Abnormalities and Their Relation to Disease

When human chromosome anomalies were first described in 1959, it appeared that specific abnormalities might be correlated with specific syndromes. Mongolism and the D and E syndromes are examples of specific syndromes associated with the presence of an extra autosome. Klinefelter''s syndrome may be associated with a variety of different sex chromosome anomalies including XXY, XXYY, XXXY and XXXXY. The lastnamed variant is the only one that frequently presents features distinguishing it from the others. An XO sex chromosome complex is found in many women with gonadal dysgenesis. However, a variety of mosaicisms have been described in association with this condition, including XO/XX, XO/XXX, XO/XX/XXX, XO/XY and XO/XYY. Extra X chromosomes in phenotypical females do not seem to impair fertility or be consistently associated with congenital anomalies. Two families are described in which chromosome anomalies were found, but the association with defects was irregular. In one family the abnormality involved one of the number 16 chromosomes and in the other it involved one of the small acrocentric chromosomes.     

Cytogenetic,FISH and DNA studies in 11 individuals from a family with two siblings with dup(21q) Down syndrome

A Spanish family has previously been described with two siblings with dup(21q) Down syndrome. The father has a normal karyotype. The mother has a microchromosome. Cytogenetic, fluorescence in situ hybridization and DNA studies have now been carried out on the family. Findings include that the mother has three different chromosome anomalies, viz. (1) a chromosome 22 with an unusual pericentromeric region that contains alphoid DNA from chromosomes 21/13 and chromosome 22, (2) an isochromosome 21p in the frequent cell line and (3) an isochromosome 21q in a rare second cell line. A possible explanation is that the mother developed from a zygote with trisomy 21 and that mitotic error in early development resulted in the formation of two cell lines with karyotypes of 47,XX,+i(21p) and 47,XX,+i(21q), respectively. The unusual chromosome 22 represents a hitherto undescribed chromosome anomaly and one possible explanation is a translocation of the short arms between chromosomes 21/13 and 22 in the ancestry of the family. The relationship between the unusual chromosome 22 and the isochromosome formation in the mother is not known. However, all three chromosome anomalies involve the alphoid DNA of chromosome 21/13, indicating that this is not a chance finding.     

A cytogenetic survey of men being investigated for subfertility.

A study of 336 men attending a subfertility clinic but otherwise unselected, and a further 12 men studied as a part of the investigation of the female partner, revealed 10 with major chromosome anomaly and 3 with unambiguous chromosomal variants. In addition to those with sex chromosome aneuploidy, an extra, small marker chromosome and D/D Robertsonian translocations, anomalies which have been reported in other studies, there were 7 men with rearrangements, including a paracentric inversion of chromosome 7 and an X/21 reciprocal translocation. These would have been difficult or impossible to identify without good banded preparations, suggesting that such rearrangement may be more frequent in association with subfertility than was appreciated.     

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.     

Human Chromosomes: II. Preparation,Analysis and Diagnostic Implications of Abnormalities

This presentation is designed to show the diagnostic implications of chromosomal abnormalities, and how in some cases chromosome analysis may be helpful in prognosis and counselling. Most males with Klinefelter''s syndrome have chromatinpositive nuclei and an abnormal sex chromosome complex (usually XXY). In Turner''s syndrome many such females have chromatin-negative nuclei and a deficient sex chromosome complex (usually XO). Multiple-X females have unusual chromatin patterns (two or three masses of sex chromatin) and abnormal sex chromosome complexes (XXX, XXXX, XO/XXX, etc.). One of the parents of a translocation mongol may carry a translocation chromosome and pass it to future children. Cytogenetic data are therefore essential for genetic counselling. Mosaic and deletion mongols may show incomplete manifestations of mongolism, which make diagnosis difficult; chromosome analysis is helpful in diagnosis, and in prognosis concerning mental development. Abnormal chromosome numbers result from non-disjunction, usually during gametogenesis. The error may occur, however, during cleavage, producing cells with different chromosome complements (mosaicism). Visible structural abnormalities of chromosomes result from deletions or translocations of chromosome fragments.     

Under what circumstances is the human XY bivalent tangled? A note on chromosomally-derived sterility

A microspread, early-mid diplotene nucleus of a man with a normal karyotype and presumably normal meiosis is compared with a similar, earlier described nucleus of a man with meiotic arrest, heterozygous for a (14;21) Robertsonian translocation (Rosenmann et al., 1985). The axes of the XY bivalent of normal diplotene have an extremely tangled configuration, whereas those of the meiotically-arrested cell are straight, recalling the shape of the XY which is normally found in early pachytene. The morphological reversal from the complex configuration to a simpler shape may be associated with reactivation of the sex chromosome(s). Such a reactivation may be responsible for the sterility of the carrier of the Robertsonian translocation which thus may be considered as chromosomally-derived. The diplotene cells shown here have autosomal bivalents with continuous axes and various degrees of focal separation as is typical for diplotene in general. The observations on axis continuity, bivalent segmental dilatations, and XY tanglement in diplotene are compared with findings by others in human ultrathin sectioned material.     

Abnormal genetic segregation associated with the presence of a Y. w+ chromosome in Drosophila melanogaster

We have observed an abnormal genetic segregation in the progeny of crosses between males of the F71 (y wa/Y.w+) strain and females of various strains carrying marker mutations on their chromosome 2. The Y.w+ chromosome, previously described as possibly being associated with a translocation of the 22D region of chromosome 2, was shown to carry the 21A1-22E4 tip of the 2L chromosome. One chromosome 2 of F71 had a deletion of this region. The abnormal genetic segregation observed in the progeny of different crosses can be explained both by the partial lethality (which becomes severe in some homogeneous genetic backgrounds) due to trisomy of the 21A1-22E4 chromosome 2 fragment and by the lethality associated with monosomy of this 21A1-22E4 segment.     

De novo 21/21 translocation Down syndrome

Summary Among ten families with de novo 21/21 translocation Down syndrome (tDS), four were informative, according to the studies of structural variants of chromosome 21, about the origin of the aberrant chromosome. In three of these, the translocation originated in the paternal and in one in the maternal gametogenesis. The parents with meiotic failure were compared with 20 control individuals (10 males and 10 females). There were no significant differences between them in the association coefficient of chromosome 21 and in the frequency of 21–21 associations. Similar results were obtained previously with the entire sample of tDS parents. The results obtained, unless they reflect too small a sample, suggest that the origin of the aberrant chromosome is not related to an increased chromosome 21 association tendency. It could be supposed that in the case of an apparent 21/21 translocation, the 21q isochromosome, morphologically indistinguishable from the Robertsonian translocation, is in question. The Ag-NoR negative acrocentrics in the tDS parents reappeared in the probands confirming the heritability of that nucleolus organizer regions (NOR) trait.     

Assessment of X bends in patients with atypical X chromosome phenotypes.

Several patients with X chromosome structural abnormalities have been more severely affected clinically than expected. Since bends at Xq13-21 have been associated with inactivation, the authors scored bends retrospectively in 62 patients with X chromosome aneuploidy and 21 cases with structural abnormalities of the X chromosome. They found that patients with 2 X inactivation sites where one X was structurally abnormal had significantly fewer cells with X bends than normal 46,XX. In addition, these patients also showed X bends on the normal X more often than would be expected if non-random X inactivation of the abnormal X chromosome was occurring. Five of the 6 patients with a short or long arm deletion or paracentric inversion of Xq were mentally retarded or had other congenital anomalies not usually associated with Turner syndrome. This suggests to them that these clinical findings may be related to interference with X inactivation patterns in cells with a structurally abnormal X chromosome.     

Reciprocal translocation between Y chromosome long arm euchromatin and the short arm of chromosome 1

A case with an apparently balanced reciprocal translocation between the long arm of the Y chromosome and the short arm of chromosome 1 t(Y;1)(q11.2;p34.3) is described. The translocation was found in a phenotypically normal male ascertained by infertility and presenting for intra-cytoplasmatic sperm injection treatment. Histological examination of testicular biopsies revealed spermatogenic failure. Chromosome painting with probes for chromosome 1 and for the euchromatic part of the Y chromsome confirmed the translocation of euchromatic Y chromosomal material onto the short arm of chromosome 1 and of a substantial part of the short arm of chromosome 1 onto the Y chromosome. Among the Y/autosome translocations, the rearrangements involving long arm euchromatin of the Y chromosome are relatively rare and mostly associated with infertility. Microdeletion screening at the azoospermia locus revealed no deletions, suggesting another mechanism causing infertility in this translocation carrier.     

Choroideremia associated with an X-autosomal translocation

Summary A patient with mild choroideremia has been shown to carry a balanced translocation between chromosome X and 13 – 46,X,t(X;13)(q21.2;p12). Loci (DXY21, DX232, DX233) shown to map to this region on the X chromosome and in some cases to be deleted in other patients with choroideremia are intact in the DNA from this patient. To our knowledge this is the first report of a translocation associated with choroideremia. One of the translocation chromosomes, derivative 13, free of the derivative X and normal X, has been isolated in a somatic cell hybrid. Because of the clinical association of the eye findings with chromosome interchange, we suggest that the breakpoint on the X is at or near the choroideremia locus. Further analysis of this translocation may be useful in cloning the choroideremia gene.     

Pachytene analysis of a man with a 13q;14q translocation and infertility. Behavior of the trivalent and nonrandom association with the sex vesicle

Pachytene analysis was undertaken in a sterile 13q;14q heterozygous translocation carrier in an attempt to follow the segregational behavior of the trivalent and to evaluate the relationship of Robertsonian translocations in man to the impairment of spermatogenesis. Well-spread bivalents from pachytene nuclei were identified by their chromomere patterns. The trivalent was found always in cis configuration. Silver staining demonstrated the loss of nucleolar organizer regions from the translocated chromosomes. A nonrandom association was found between the trivalent configuration and the sex vesicle in 61% of the pachytene nuclei examined. Such an association has been described before in mice heterozygous for Robertsonian or reciprocal translocations, and may thus represent a general phenomenon. As in mice, this contact was restricted to the centromeric region of the trivalent. A hypothesis relating the association of the trivalent with the sex vesicle to impairment of normal X-chromosome inactivation and subsequent spermatogenic breakdown is discussed. Other chromosomal abnormalities in which sex-vesicle anomalies are associated with male sterility (such as X-or Y-autosomal translocations) are also considered. It is proposed that any process interfering with normal X-chromosome inactivation in pachytene spermatocytes could disturb subsequent meiotic or postmeiotic germ cells development.     

Partial trisomy for the short arm of chromosome 2 due to familial balanced translocation

Summary A partial trisomy for the short arm of chromosome 2 (p21pter) was observed in a severely retarded infant with facial, skeletal, genital, renal, and CNS anomalies. The phenotypically normal mother and older brother had a balanced translocation between the short arm of chromosome 2 and the long arm of chromosome 14: 46,XX-XY,t(2;14)(p21;q32).     

Estimates of Incidence and Prevalence of Mongolism and of Congenital Heart Disease in British Columbia

There is a need for accurate ascertainment of incidence and prevalence rates of congenital anomalies. In British Columbia the Registry for Handicapped Children and Adults used in conjunction with vital records has proved a valuable source of information. Birth notifications alone cannot be relied upon for incidence data. It was found that seven times as many cases of congenital heart disease were registered subsequently as were reported at birth. The estimated minimal incidence rates of mongolism and congenital heart disease per 1000 live births were 1.46 and 4.75, respectively. The well-known association of maternal age with mongolism was confirmed. Twice as many babies with congenital heart disease (without mongolism) were born to mothers over 39 years of age as would be expected on the basis of the maternal age distribution for all live births in the population. Prevalence estimates of these two diseases compared favourably with other published estimates.     

Acute promyelocytic leukemia with unusual karyotype

Acute myeloid leukemia (AML-M3) is associated with the translocation t(15;17)(q22;q12-21) which disrupts the retinoic acid receptor alpha (RARA) gene on chromosome 17 and the PML gene on chromosome 15. We report a two-year-old patient with AML-M3 without the usual translocation t(15;17). Cytogenetic studies demonstrated normal appearance of chromosome 15 while the abnormal 17 homologue was apparently a derivative 17, der(17)(17qter-cen-q21:), the rearrangement distinctly shows deletion at 17q21 band and the morphology corresponding to an iso chromosome i(17q-). This case report is a rare cytogenetic presentation of acute promyelocytic leukemia (APML).     

Segregation of acrocentric chromosome association in familial dicentric Robertsonian translocation t(14p;22p), aneuploidy (trisomy-21) and heteromorphism

The frequency and types of acrocentric chromosome association were quantitatively analysed in a Down syndrome child with unusual karyotype, 46, XX, -14, -22, t dic (14p;22p), +21, 21S+. Father and 4 sibs were heterozygous carriers for t dic (14p;22p). The variant 21S+ was inherited from the mother. The occurrence of translocation and trisomy in the same individual is extremely rare. Acrocentric chromosome association was analysed in this interesting family to understand the interrelationship of acrocentric chromosome association, Robertsonian translocation and heteromorphism, as possible predisposing factors for nondisjunction. Our findings suggest that acrocentric chromosome association is a heritable and nonrandom phenomenon. Heterozygous carriers for translocations and variants are likely to be at increased risk of nondisjunction. Long term family studies will enable to ascertain the causal-relationship of these factors more precisely.     

Quantitative studies on the arrangment of human metaphase chromosomes

Summary The pattern of association of acrocentric chromosomes was examined in ten and five carriers of a 15/21 and a 13/14 Robertsonian translocation, respectively, and was compared with that of the same numbers of relatives with normal karyotypes. In the carriers of 15/21 translocation, the number of large associations (involving more than two acrocentrics) and the association frequencies for individual acrocentric chromosomes, were significantly higher than in the control group. The mean number of associations of the single homologs of the translocation chromosomes was much higher than that of the other acrocentrics. In the carriers of 13/14 translocations, only the association frequency for chromosome 13 was higher than in the normal relatives. The uninvolved chromosomes homologous to those involved in translocations showed an insignificant increase in associations in comparison with the other acrocentrics. These results suggest that some mechanism within the cells compensates for the effect of missing acrocentrics or of acrocentrics lacking NORs on the number of associations. The possible relations of this phenomenon to the activity of the nucleolus organizing regions are discussed.     

A 13-15/21 Translocation Chromosome in Carrier Father and Mongol Son

Cytogenetic and dermatoglyphic features were studied in a family in which the mongoloid propositus inherited a 13-15/21 translocation chromosome from his father. Seven other healthy male carriers scattered throughout the pedigree produced nine chromosomally normal children and five carrier children in addition to the mongoloid propositus. These results show that carrier males do not necessarily produce an unusually large proportion of carrier children as previous reports would indicate. Dermatoglyphic studies showed that translocation carriers in this family have neither significantly more centralized nor less centralized palmar axial triradii than non-carrier relatives. No direct evidence was therefore found for the hypothesis that an allele is present on chromosome 21 which influences the height of the triradius.     

Partial trisomy 21 (21q21 - 21q22.2)]

An abnormal chromosome 21 is reported in a child with a phenotype strongly reminiscent of trisomy 21 syndrome. It is shown to result from duplication of the segment 21q21 leads to 21q22.2. Comparison of the phenotype with that of other partial and total trisomics shows that the characteristic features of the trisomy 21 syndrome (mongolism), the mental retardation in particular - is due to trisomy 21q22.2 and perhaps 21q22.2.     

Clinical implications of chromosome abnormalities in acute non-lymphocytic leukemia: current status.

Data currently available on banded chromosome studies on patients with ANLL suggest that the presence of a chromosome abnormality in such patients indicates a poor prognosis, and that different treatment strategies need to be developed for these patients. However, patients with at least one normal metaphase survive nearly as long as those with only normal metaphases. A specific chromosome abnormality in APL [t(15;17)], an unusual association of a translocation [t(8;21)] in association with loss of a sex chromosome, and a rare association of thrombocytosis and a chromosome insertion (3;3 ins), suggest that some chromosome changes in ANLL are specific.