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Changes in gene dosage are a major driver of cancer, known to be caused by a finite, but increasingly well annotated, repertoire of mutational mechanisms. This can potentially generate correlated copy-number alterations across hundreds of linked genes, as exemplified by the 2% of childhood acute lymphoblastic leukaemia (ALL) with recurrent amplification of megabase regions of chromosome 21 (iAMP21). We used genomic, cytogenetic and transcriptional analysis, coupled with novel bioinformatic approaches, to reconstruct the evolution of iAMP21 ALL. Here we show that individuals born with the rare constitutional Robertsonian translocation between chromosomes 15 and 21, rob(15;21)(q10;q10)c, have approximately 2,700-fold increased risk of developing iAMP21 ALL compared to the general population. In such cases, amplification is initiated by a chromothripsis event involving both sister chromatids of the Robertsonian chromosome, a novel mechanism for cancer predisposition. In sporadic iAMP21, breakage-fusion-bridge cycles are typically the initiating event, often followed by chromothripsis. In both sporadic and rob(15;21)c-associated iAMP21, the final stages frequently involve duplications of the entire abnormal chromosome. The end-product is a derivative of chromosome 21 or the rob(15;21)c chromosome with gene dosage optimized for leukaemic potential, showing constrained copy-number levels over multiple linked genes. Thus, dicentric chromosomes may be an important precipitant of chromothripsis, as we show rob(15;21)c to be constitutionally dicentric and breakage-fusion-bridge cycles generate dicentric chromosomes somatically. Furthermore, our data illustrate that several cancer-specific mutational processes, applied sequentially, can coordinate to fashion copy-number profiles over large genomic scales, incrementally refining the fitness benefits of aggregated gene dosage changes. [ABSTRACT FROM AUTHOR]

Recent studies have identified PRDM9, a zinc finger (ZF) protein, as a key regulator of meiotic recombination. As both recurrent genomic disorders and chromosomal non-disjunction are known to be associated with specific unusual patterns of recombination, we hypothesized a possible link between PRDM9 ZF variation and susceptibility to microdeletion syndromes and/or trisomy. We sequenced the PRDM9 ZF domain in 271 parents of patients with de novo microdeletions of known parental origin (velocardiofacial syndrome, the 17q21.31 microdeletion syndrome, Prader-Willi/Angelman syndrome and Williams-Beuren syndrome), and in 61 parents of individuals with a supernumerary X chromosome. We compared PRDM9 ZF genotype frequencies between parents in whose germ line the de novo rearrangement occurred and their spouses. We observed a significantly increased frequency ( p = 0.006) of PRDM9 variants in parents who transmitted de novo 7q11.23 deletions to their offspring. These data suggest that certain PRDM9 alleles may be associated with an increased susceptibility to recurrent 7q11.23 microdeletions that cause Williams-Beuren syndrome. However, as the majority of parents who transmitted a de novo microdeletion/supernumerary X chromosome to their offspring have the common AA genotype, we conclude that none of the rearrangements we have studied are dependent on specific non-A PRDM9 alleles. [ABSTRACT FROM AUTHOR]

We report a large series of 173 patients with physical and/or neurological abnormalities and a de novo imbalance identified by array CGH. Breakpoint intervals were screened for the presence of low copy repeats (LCRs) to distinguish between rearrangements formed by non-allelic homologous recombination (NAHR) and rearrangements formed by other mechanisms. We identified significant differences in size and parental origin between the LCR-mediated and non-LCR groups. Non-LCR imbalances were evenly distributed among the four size intervals we defined, whereas LCR-mediated rearrangements had a narrow size distribution, predominantly between 1 and 5 Mb (P=0.001). Among the LCR-mediated rearrangements there were equal numbers of maternally and paternally derived cases. In contrast, for the non-LCR rearrangements there was a significant excess of paternal cases (P=0.024) over a wide size range including below 1 Mb. Our results provide novel evidence that unbalanced chromosome rearrangements are not only more frequent in males, but may also arise through different mechanisms than those seen in females. Although the paternal imbalances identified in our study are evenly distributed throughout the four size groups, there are very few maternal imbalances either <1 Mb or >10 Mb. Furthermore, a lower proportion of paternal imbalances are LCR mediated (13/71) compared with the maternal imbalances (12/30). We hypothesise that imbalances of maternal origin arise predominantly through NAHR during meiosis, while the majority of imbalances of paternal origin arise through male-specific mechanisms other than NAHR. Our data suggest that mitotic mechanisms could be important for the formation of chromosome imbalances; however, we found no association with increased paternal age. [ABSTRACT FROM AUTHOR]

The majority of constitutional reciprocal translocations appear to be unique rearrangements arising from independent events. However, a small number of translocations are recurrent, most significantly the t(11;22)(q23;q11). Among large series of translocations there may be multiple independently ascertained cases with the same cytogenetic breakpoints. Some of these could represent additional recurrent rearrangements, alternatively they could be identical by descent (IBD) or have subtly different breakpoints when examined under higher resolution. We have used molecular breakpoint mapping and haplotyping to determine the origin of three pairs of reciprocal constitutional translocations, each with the same cytogenetic breakpoints. FISH mapping showed one pair to have different breakpoints and thus to be distinct rearrangements. Another pair of translocations were IBD with identical breakpoint intervals and highly conserved haplotypes on the derived chromosomes. The third pair, t(4;11)(p16.2;p15.4), had the same breakpoint intervals by aCGH and fosmid mapping but had very different haplotypes, therefore they represent a novel recurrent translocation. Unlike the t(11;22)(q23;q11), the formation of the t(4;11)(p16.2;p15.4) may have involved segmental duplications and sequence homology at the breakpoints. Additional examples of recurrent translocations could be identified if the resources were available to study more translocations using the approaches described here. However, like the t(4;11)(p16.2;p15.4), such translocations are likely to be rare with the t(11;22) remaining the only common recurrent constitutional reciprocal translocation. [ABSTRACT FROM AUTHOR]

A significant proportion of both pericentric and paracentric inversions have recurrent breakpoints and so could either have arisen through multiple independent events or be identical by descent (IBD) with a single common ancestor. Of two common variant inversions previously studied, the inv(2)(p11q13) was genuinely recurrent while the inv(10)(p11.2q21.2) was IBD in all cases tested. Excluding these two variants we have ascertained 257 autosomal inversion probands at the Wessex Regional Genetics Laboratory. There were 104 apparently recurrent inversions, representing 35 different breakpoint combinations and we speculated that at least some of these had arisen on more than one occasion. However, haplotype analysis identified no recurrent cases among eight inversions tested, including the variant inv(5)(p13q13). The cases not IBD were shown to have different breakpoints at the molecular cytogenetic level. No crossing over was detected within any of the inversions and the founder haplotypes extended for variable distances beyond the inversion breakpoints. Defining breakpoint intervals by FISH mapping identified no obvious predisposing elements in the DNA sequence. In summary the vast majority of human inversions arise as unique events. Even apparently recurrent inversions, with the exception of the inv(2)(p12q13), are likely to be either derived from a common ancestor or to have subtly different breakpoints. Presumably the lack of selection against most inversions allows them to accumulate and disperse amongst different populations over time. [ABSTRACT FROM AUTHOR]

Constitutional chromosome deletions result in wide ranging morbidity and often fatality. Information about risks and causes of death in these patients is important for counselling, and may illuminate the functions of the part of the chromosome deleted. There have been no cohort studies analysing mortality risks in persons with specific deletions compared with general population rates. We therefore conducted a cohort study following cause-specific mortality in 2,561 patients with autosomal chromosome deletions diagnosed by light microscopy or fluorescence in situ hybridisation at cytogenetic laboratories across Britain, 1965–2002. The commonest deletions were of 22q (544 patients), 15q (460) and 7q (210) and the least common 19q (0) and 20q (2). The prevalence of visible deletions of different chromosome arms was significantly inversely correlated with gene density of the arm ( p < 0.001). Mortality was 11-fold raised in the cohort compared with the general population (standardised mortality ratio = 11.4 (95% confidence interval 10.0–12.8)), was significantly raised for each deletion with ≥25 subjects in the study, and had a lower confidence limit >10 for deletions of 1p, 1q, 3p, 4p, 5q and 22q. Overall, 29% of deaths were due to congenital anomalies; significantly raised mortality occurred also from many other causes, varying by chromosome and arm of deletion. The data imply that viability of foetuses with visible chromosome deletions may be inversely related to gene density, and that all visible and fluorescence in situ hybridisation-detectable deletions lead to much raised mortality, but the extent and causes of mortality vary according to the specific deletion. [ABSTRACT FROM AUTHOR]

The birth prevalence of sex chromosome trisomies (SCT), that is individuals with an XYY, XXY or XXX sex chromosome constitution, is traditionally based on six surveys of unselected newborns carried out in the 1960s and early 1970s. All three SCTs had a prevalence of 1 in 1000 same sex births. We re-examined these prevalences based on additional cytogenetic studies of newborn surveys, spontaneous abortions, perinatal deaths and prenatal diagnoses. The more recent newborn surveys suggest there has been an increase in the prevalence of XXYs, but not of the other two SCTs since the original newborn series. The prevalence of XXYs has risen from 1.09 to 1.72 per 1000 male births (P=0.023). We suggest that such an increase, in the absence of an increase in the prevalence of XXX, is unlikely to be due to increased maternal age. As XXY is the only chromosome abnormality known where a substantial proportion (∼50%) arise as the result of non-disjunction at the first paternal meiotic division, we speculate that some factor may be interfering with pairing and/or recombination of the sex bivalent at the paternal MI division.European Journal of Human Genetics (2008) 16, 163–170; doi:10.1038/sj.ejhg.5201956; published online 14 November 2007 [ABSTRACT FROM AUTHOR]

Only one X chromosome functions in diploid human cells irrespective of the sex of the individual and the number of X chromosomes. Yet, as we show, more than one X is active in the majority of human triploid cells. Therefore, we suggest that (i) the active X is chosen by repression of its XIST locus, (ii) the repressor is encoded by an autosome and is dosage sensitive, and (iii) the extra dose of this key repressor enables the expression of more than one X in triploid cells. Because autosomal trisomies might help locate the putative dosage sensitive trans-acting factor, we looked for two active X chromosomes in such cells. Previously, we reported that females trisomic for 18 different human autosomes had only one active X and a normal inactive X chromosome. Now we report the effect of triplication of the four autosomes not studied previously; data about these rare trisomies – full or partial – were used to identify autosomal regions relevant to the choice of active X. We find that triplication of the entire chromosomes 5 and 11 and parts of chromosomes 1 and 19 is associated with normal patterns of X inactivation, excluding these as candidate regions. However, females with inherited triplications of 1p21.3–q25.3, 1p31 and 19p13.2–q13.33 were not ascertained. Thus, if a single key dose-sensitive gene induces XIST repression, it could reside in one of these locations. Alternatively, more than one dosage-sensitive autosomal locus is required to form the repressor complex.European Journal of Human Genetics (2008) 16, 153–162; doi:10.1038/sj.ejhg.5201944; published online 31 October 2007 [ABSTRACT FROM AUTHOR]

The mortality and cancer incidence risks among males with Y polysomy are unknown because there have been no large long-term cohort studies carried out of such men. We conducted a cohort study of 667 men diagnosed with the abnormality in Britain since 1959 to compare their mortality and cancer incidence rates with those of the general population. Sixty deaths occurred during follow-up to December 2005, twice the number expected from general population rates (standardised mortality ratio (SMR) = 2.0 (95% confidence interval (CI) 1.5–2.6)). Significantly raised mortality was observed for diseases of the nervous system (SMR = 7.0, 95% CI: 2.3–16.4), circulatory system (SMR = 2.1, 95% CI: 1.3–3.2), respiratory system (SMR = 4.0, 95% CI: 1.8–7.5), genitourinary system (SMR = 10.2, 95% CI: 1.2–36.9), and congenital anomalies (SMR = 11.9, 95% CI: 3.2–30.5). Four of the five nervous system deaths were from epilepsy, the risk of death from this condition being more than 20-fold raised. The rates of cancer incidence and mortality among these men was not significantly different from those in the general population. This study provides evidence that mortality rates from several specific causes are raised among men with Y polysomy. The use of these data in genetic counselling should be cautious particularly for cases of Y polysomy that are detected prenatally. Further investigations are required to confirm these findings and to elucidate the possible role of genes on the Y chromosome in the aetiology of these causes of death. [ABSTRACT FROM AUTHOR]

Using fluorescent in situ hybridization (FISH) with the probe p15 (D15Z1), we investigated the distribution of the polymorphic 15p signal which has been reported to occur on acrocentric chromosomes in addition to chromosome 15. The short arm of chromosome 15 has a characteristic signal pattern when hybridized with the FISH probe D15Z1. However, the D15Z1 signal can occasionally be seen on the short arm of other acrocentric chromosomes. We studied the distribution of the D15Z1 probe in 1657 patients consisting both of individuals with a normal karyotype and those with a variety of chromosome abnormalities involving the acrocentric chromosomes. Our results show that one in six individuals, regardless of their patient ascertainment category or karyotypic status, had one or more additional D15Z1 signals, and that there were no significant differences in the distribution of extra signals among the patient groups.European Journal of Human Genetics (2007) 15, 441–445. doi:10.1038/sj.ejhg.5201780; published online 21 February 2007 [ABSTRACT FROM AUTHOR]

Non-allelic homologous recombination between chromosome-specific LCRs is the most common mechanism leading to recurrent microdeletions and duplications. To look for locus-specific differences, we have used microsatellites to determine the parental and chromosomal origins of a large series of patients with de novo deletions of chromosome 7q11.23 (Williams syndrome), 15q11–q13 (Angelman syndrome, Prader–Willi syndrome) and 22q11 (Di George syndrome) and duplications of 15q11–q13. Overall the majority of rearrangements were interchromosomal, so arising from unequal meiotic exchange, and there were approximately equal numbers of maternal and paternal deletions. Duplications and deletions of 15q11–q13 appear to be reciprocal products that arise by the same mechanisms. The proportion arising from interchromosomal exchanges varied among deletions with 22q11 the highest and 15q11–q13 the lowest. However, parental and chromosomal origins were not always independent. For 15q11–q13, maternal deletions tended to be interchromosomal while paternal deletions tended to be intrachromosomal; for 22q11 there was a possible excess of maternal cases among intrachromosomal deletions. Several factors are likely to be involved in the formation of recurrent rearrangements and the relative importance of these appear to be locus-specific.European Journal of Human Genetics (2006) 14, 831–837. doi:10.1038/sj.ejhg.5201617; published online 12 April 2006 [ABSTRACT FROM AUTHOR]

We report the parental origin, and where possible the chromosomal origin of 115 de novo unbalanced structural chromosome abnormalities detectable by light microscopy. These consisted of 39 terminal deletions, 35 interstitial deletions, 8 rings, 12 duplications and 21 unbalanced translocations. In all categories the majority of abnormalities were of paternal origin, although the proportions varied from a high of 84% in the interstitial deletions and rings to a low of 58% in the duplications. Among the interstitial deletions and duplications, there were approximately equal numbers of intra- and interchromosomal abnormalities, while the majority of unbalanced translocations were isodisomic for the duplicated chromosome. The examination of the parental ages in the four main classes of abnormality showed terminal deletions of maternal origin to be associated with a significantly reduced maternal age. Thus, there is a clear propensity for structural chromosome abnormalities to occur in male germ cells, although the chromosomal origin seems similar irrespective of the parental origin. [ABSTRACT FROM AUTHOR]

About one woman in 1,000 has an extra X chromosome, but such women have no recognised characteristic somatic features and little is known about their long-term health and cancer risks. We conducted a cohort study of mortality and cancer incidence in 542 women diagnosed with X polysomy at 25 cytogenetic centres in Britain since 1959. Fifty-nine deaths occurred during follow-up to mid-2004. Mortality was significantly raised (standardised mortality ratio (SMR) = 2.5 (95% confidence interval (CI) 1.9–3.2)), with excess deaths due particularly to cardiovascular disease (SMR = 2.5 (95% CI 1.5–3.8)) and respiratory disease (SMR = 4.0 (95% CI 1.7–7.9)). Risks of cancer incidence and cancer mortality overall were not raised, but there was significantly raised mortality from non-Hodgkin’s lymphoma (NHL) (SMR = 10.4 (95% CI 1.3–37.6); based on 2 cases). The data indicate that mortality in women diagnosed with X polysomy is considerably raised. The raised risk of NHL is seen also in males with more than one X chromosome, and hence although unexpected and based on small numbers, it might indicate the action of a gene on the X chromosome, possibly in the pseudoautosomal region, that escapes X-inactivation. [ABSTRACT FROM AUTHOR]

To test the hypothesis that translocation breakpoints in normal individuals are simple and do not disrupt genes, we characterised the breakpoints in 13 phenotypically normal individuals incidentally ascertained with an apparently balanced reciprocal translocation. Cases were karyotyped, and the breakpoints were refined by fluorescence in situ hybridisation until breakpoint-spanning clones were identified. 1 Mb array-CGH was performed as a whole genome analysis tool to detect any imbalances in chromatin not directly involved in the breakpoints. Breakpoint-associated imbalances were not found in any of the patients analysed in this study. However, breakpoints which disrupted known genes were identified in two patients, with RYR2 disrupted in one patient and COL13A1 in the other. In a further eight patients, Ensembl mapping data suggested that a gene might be disrupted by a breakpoint. In one further patient, the translocation was shown to be nonreciprocal. This study shows that apparently balanced reciprocal translocations in phenotypically normal patients do not have imbalances at the breakpoints, in contrast to phenotypically abnormal patients where the translocation breakpoints are often associated with cryptic imbalances. However, phenotypically normal individuals, and phenotypically abnormal individuals may have genes disrupted and therefore inactivated by one of the breakpoints. The significance of these disruptions remains to be determined.European Journal of Human Genetics (2005) 13, 1205–1212. doi:10.1038/sj.ejhg.5201488; published online 24 August 2005 [ABSTRACT FROM AUTHOR]

The details of all cytogenetic abnormalities diagnosed in the Wessex Regional Genetics Laboratory (WRGL) since 1967 to the present day have been recorded in the Salisbury Treasury of Interesting Chromosomes (STOIC). From this resource, we identified 137 patients with constitutional autosomal supernumerary marker chromosomes (SMC) ascertained in four principal groups: (i) 37%with abnormal phenotypes; (ii) 7%couples with reproductive difficulties; (iii) 47%antenatal diagnoses and (iv) 9%miscellaneous. Overall, 81 (59%) SMCs were mosaics and 56 (41%) nonmosaics. Of the 109 cases with known parental origins, 70%were de novo, 19%maternally and 11%paternally inherited. The chromosomal origins of 112/137 (82%) of the SMCs have been determined by fluorescence in situ hybridization (FISH). In all, 36/112 (32%) were derived from nonacrocentric autosomes, and 76/112 (68%) from the acrocentric autosomes 13/21, 14, 15 and 22. Of these acrocentric SMCs, 39 (51%) were derived from chromosome 15, so that SMC(15) constituted 39/112 (35%) of all SMCs with known chromosomal origins. The frequencies with which mosaicism was observed varied considerably according to the chromosomal origin of the SMCs and accounted for 8/39 (20%) SMC(15), 13/37 (35%) SMCs from other acrocentrics and 25/36 (69%) of nonacrocentric SMCs. The data were analysed for parental age effects, and only de novo SMC(15)s were found to be associated with a significantly increased maternal age.European Journal of Human Genetics (2005) 13, 154-160. doi:10.1038/sj.ejhg.5201311 Published online 27 October 2004 [ABSTRACT FROM AUTHOR]

Duplications involving the X chromosome, in which the duplicated region is not subject to inactivation, are rare. We describe four distal Xq duplications, in three males and one female, in which the duplicated X chromosomal material is active in all cells. The infantile phenotype bears some resemblance to that of the Prader-Willi syndrome, presenting with initial feeding difficulties, hypotonia and, sometimes, with cryptorchidism. However, the severity of the phenotype is not simply related to the size of the duplication and so variations in gene expression, gene disruption or position effects from breakpoints should be considered as explanations. We have compared the clinical, cytogenetic and molecular findings of our patients with those previously reported. This has enabled us to question the suggestion that duplication of the geneSOX3is the cause of hypopituitarism and that duplication ofFilamin Ais the cause of bilateral periventricular nodular heterotopia/mental retardation syndrome (BPNH/MR). We have also narrowed the putative critical interval forX-linked spina bifida. [ABSTRACT FROM AUTHOR]

Fifty chromosomally normal couples with three or more miscarriages were examined using fluorescent in situ hybridisation (FISH) and a library of subtelomere-specific probes together with alphoid repeats mapping to the acrocentric centromeres. Six abnormalities were found. Firstly, a cryptic reciprocal subtelomere translocation between the long arm of a chromosome 3 and the short arm of a chromosome 10. The other five cryptic abnormalities involved the acrocentric chromosome pericentromeric regions and in one case also Yp. Two patients had a rearranged chromosome 13, where the centromeric region was found to be derived from the short arm, centromere and proximal long arm of chromosome 15. Another two patients had a derived chromosome 22, where the centromere was replaced by two other centromeres, one derived from chromosome 14 and the other from either chromosome 13 or 21, while one patient had the subtelomere region of Yp translocated onto the short arm of a chromosome 21. These abnormalities may be the underlying cause of the recurrent miscarriages, because they may result in abnormal pairing configurations at meiosis leading to non-disjunction of whole chromosomes at metaphase I. The frequency of rearrangements seen in the recurrent miscarriage patient population was significantly different from that in the control group (P=0.0096, Fisher's exact test) due to the acrocentric pericentromeric abnormalities. [ABSTRACT FROM AUTHOR]

Chromosome 15 is frequently involved in the formation of structural rearrangements. We report the molecular characterisation of 16 independent interstitial duplications, including those of one individual who carried a duplication on both of her chromosomes 15, and three interstitial triplications of the Prader-Willi/Angelman syndrome critical region (PWACR). In all probands except one, the rearrangement was maternal in origin. In one family, the duplication was paternal in origin, yet appeared to segregate in a sibship of three with an abnormal phenotype that included developmental delay and a behavioural disorder. Ten duplications were familial, five de novo and one unknown. All 16 duplications, including two not visible by routine G-banding, were of an almost uniform size and shared the common deletion breakpoints of Prader-Willi syndrome and Angelman syndrome. Like deletions, the formation of duplications can occur in both male and female meiosis and involve both inter- and intrachromosomal events. This implies that at least some deletions and duplications are the reciprocal products of each other. We observed no instances of meiotic instability in the transmission of a duplication, although recombination within the PWACR occurred in two members of the same family between the normal and the duplicated chromosome 15 homologues. All three triplications arose de novo and included alleles from both maternal chromosomes 15. Triplication breakpoints were more variable and extended distally beyond the PWACR. The molecular characteristics of duplications and triplications suggest that they are formed by different mechanisms. [ABSTRACT FROM AUTHOR]

We have analysed the spread of X inactivation in an individual with an unbalanced 46,X,der(X)t(X;10)(q26.3;q23.3) karyotype. Despite being trisomic for the region 10q23.3-qter, both the proband and her aunt with the same karyotype presented only with secondary amenorrhoea and lacked any features normally associated with trisomy of distal 10q. Cytogenetic and molecular studies showed that the derivative X;10 chromosome was exclusively inactive. Transcribed polymorphisms were identified in five genes contained within the translocated region of chromosome 10 and were used to perform allele-specific transcription studies. We showed that four of the genes studied are inactive on the derivative chromosome, directly demonstrating the spread of X inactivation over some 30 Mb of autosomal DNA. However, the most distal gene examined remained active, indicating that this spreading was incomplete. In contrast to the gene expression data, replication timing studies showed no spreading of late replication into the translocated portion of 10q. We conclude that silencing of autosomal genes by X inactivation can occur without a delay in the replication timing of the surrounding chromatin. Our findings support the hypothesis that autosomal chromatin lacks certain features present on the X chromosome that are required for the effective spread and/or maintenance of X inactivation. [ABSTRACT FROM AUTHOR]

The incidence of skewed X-inactivation in normal women is controversial, with up to 10-fold differences being reported by different authors. In order to clarify this issue, we have conducted a survey of the X-inactivation patterns in 270 informative females from various age groups, using the androgen receptor gene/polymerase chain reaction assay. Results obtained by using DNA extracted from blood samples show that the incidence of severe skewing (defined here as ratios ≥90:10) is relatively common and increases with age (P<0.05), occurring in 7% of women under 25 years of age, and 16% of women over 60. In order to study tissue-specific patterns of X-inactivation, samples of both buccal and urinary epithelia were also obtained from 88 of the females studied. Although there was a significant association of the X-inactivation ratios between each tissue in most individuals, wide variations were apparent in some cases, making accurate extrapolations between tissues impossible. The degree of correlation between each tissue also fell markedly with age. Our data are consistent with the hypothesis that the major factors in the aetiology of skewed X-inactivation are secondary selection processes. [ABSTRACT FROM AUTHOR]

We have used polymorphisms within the Xp/Yp pseudoautosomal region (PAR 1) to determine the frequency and location of recombination in 80 paternally derived 47, XXY males. Of 64 informative results, there were 10 single cross-overs, one double cross-over and 53 without a cross-over. Therefore 2/3 of 47, XXY males of paternal origin result from meiosis in which the X and Y chromosomes fail to recombine. This failure was not associated with the presence of an increase in recombination in the smaller Xq/Yq pseudoautosomal region (PAR 2) or with the presence of microdeletions within PAR 1. [ABSTRACT FROM AUTHOR]

FRAXE full mutations are rare and appear to be associated with mild mental retardation. As part of a screening survey of boys with learning difficulties to determine the frequency of full and premutations, we have collected data on the frequency of instability at FRAXE for about 4000 transmissions and the haplotype for over 7000 chromosomes. The distribution of FRAXE repeats was similar to other English populations but differed from two North American Caucasian series. Observed instability at FRAXE was rare but increased with increasing repeat number, and there were no expansions into the full mutation range, except in pedigrees ascertained through a full mutation. Haplotype analysis suggested division into five groups with each group having a characteristic distribution of FRAXE repeats. Fourteen of the 15 full mutations occurred on a single haplotype and this haplotype also had a significant excess of intermediate-sized alleles, suggesting that full mutations originate from large normal alleles. However, a related haplotype also had a significant excess of intermediates but we observed no full mutations on this haplotype, suggesting either loss or gain of stability determinants on it. We suggest that whilst triplet repeat size is a significant predisposing factor for expansion at FRAXE other genetic determinants are also likely to be important. [ABSTRACT FROM AUTHOR]

Small ring (X) chromosomes lacking the XIST gene at Xq13.2 have been associated with a severe phenotype that includes mental retardation, facial dysmorphism and congenital abnormalities. It has been hypothesised that the loss of XIST results in functional disomy for the sequences contained in the ring. We studied 47 females with a 45,X/46,r(X) karyotype and found seven to have an XIST-negative ring. Only one of the seven patients had the severe phenotype. The remaining six patients had physical phenotypes consistent with Turner syndrome. The rings were characterised cytogenetically and molecularly. The severe phenotype in one patient can be explained by the absence of XIST expression, the relatively large amount of Xp material in the ring and, possibly, the concomitant maternal uniparental isodisomy. We propose three explanations for the unexpectedly mild phenotypes in the remaining six patients; (1) the rings contained limited amounts of X-chromosome material, and sequences that, when functionally disomic, result in a severe phenotype were absent; (2) mosaicism resulting in the absence of the ring from tissues, such as the brain, which are important in the severe phenotype and (3) the presence of an inactive X in some tissues at some time, exemplified by the demonstration of XIST expression in one patient. [ABSTRACT FROM AUTHOR]

We have determined the parental origin in eight cases of constitutional trisomy 8. In all four cases of spontaneous abortion, the additional chromosome was maternal in origin and there was evidence for nullichiasmate meiosis I occurring in the genesis of this trisomy. In contrast, all four cases of liveborn trisomy 8 appear to have arisen by a mechanism consistent with the post-zygotic mitotic gain of the additional chromosome. [ABSTRACT FROM AUTHOR]

We studied four families each with three trisomy 21 conceptions. In two of the families the trisomy 21 conceptions all occurred when the mothers were under 35 years of age and in the other two families they all occurred when the mothers were over 35 years of age. Cytogenetic studies showed low level mosaic trisomy 21 in the two younger mothers, but not in the two older. In the three families tested using molecular techniques the results were consistent with the additional chromosome 21 in the trisomic conceptuses being maternally derived. Novel alleles were detected in the trisomic offspring of one of the younger mothers, demonstrating that the mother had been conceived as a trisomy with three different chromosomes 21. Therefore the multiple trisomy 21 pregnancies in the two younger mothers resulted from maternal trisomy 21 mosaicism, but may have been due to chance in the older mothers. [ABSTRACT FROM AUTHOR]

The present report summarizes molecular studies on the parent and meiotic stage of origin of the additional chromosome in 432 fetuses or liveborns with an additional chromosome 13, 14, 15, 21, or 22. Our studies suggest that there is little variation in the origin of nondisjunction among the five acrocentric trisomies and that there is no association between the origin of nondisjunction and the likelihood of survival to term of the trisomic conceptus. The proportion of cases of paternal origin was similar among the five trisomies: 12% for trisomy 13, 17% for trisomy 14, 12% for trisomy 15, 9% for trisomy 21, and 11% for trisomy 22. The stage of nondisjunction was also similar among the five trisomies, with the majority of cases of maternal origin being due to nondisjunction at meiosis I, whereas for paternally derived cases, nondisjuction occurred primarily at meiosis II. [ABSTRACT FROM AUTHOR]

We have reviewed 215 published cases of leukaemia and transient leukaemia in Down syndrome. There is an over-representation of mosaic trisomy 21, possibly the result, at least in part, of a survival effect. The most intriguing observation is a bimodal distribution of maternal age, produced largely because cases with true leukaemia have a significantly higher maternal age than cases with transient leukaemia (33.5 versus 29.5 years). In conjunction with evidence that meiosis I non-disjunction is infrequent in transient leukaemia, this suggests different mechanisms for the etiology of leukaemia and transient leukaemia, and favours a locus predisposing to transient leukaemia proximal to the centromere on the long arm of chromosome 21. [ABSTRACT FROM AUTHOR]

Nucleolar organizing region (NOR) variants of parents of karyotyped spontaneous abortions were examined to fest the hypothesis that double NORs are important in the genesis of acrocentric trisomies. We were unable to detect any significant difference in the frequency or types of NOR variants between parents of acrocentric trisomies and parents of other types of spontaneous abortions, nor did we identify a double NOR in either group. Thus, it seems unlikely that double NORs are of major significance in the etiology of acrocentric trisomies. [ABSTRACT FROM AUTHOR]

The fragile (X) chromosome demonstrable in individuals with one type of X-linked mental retardation is seldom, if ever, seen in more than 50% of cells of affected individuals. We have devised a model to explain this apparent 50% maximum, one essential feature of which is that the fragile (X) will not be seen in cells in their first division in thymidine-depleted media. The validity of our model was tested on lymphoblastoid cell lines from affected males by treating the cells with fluorodeoxyuridine (FUdR) to induce the marker and/or bromodeoxyuridine (BrdU) to determine the cell cycle. We have evidence that the fragile (X) is present in cells in the first and subsequent these observations our model is not valid and the 50% expression of the fragile site at Xq(28) and other unusual properties of this region of the X chromosome remain unexplained. [ABSTRACT FROM AUTHOR]

A cytogenetic survey of a population of 274 mentally retarded males on community placement is described. Thirtyfive had an aneuploid chromosome constitution and five had the mar (X) syndrome. The range of clinical variation among the mar(X) probands and their affected relatives is described. Family studies were possible for four of the five mar(X) probands and in two families the mar(X) gene was apparently transmitted through a clinically normal male, suggesting that this type of male transmission may be a not uncommon phenomenon. [ABSTRACT FROM AUTHOR]

Heteromorphisms of chromosomes 3, 4, 13-15, 21-22, and Y were studied in a population of 374 mentally retarded patients from diverse ethnic groups. A significant variation in the size of the Y chromosome was found among different racial groups, those of the Orientals and Filipinos being larger than those of the Caucasians or Polynesians. No other significant variation was found among the different racial groups, although suggestive differences were seen in bands 3 cen, 13p3, and 14p3. Band 13 cen/pl was significantly larger in the category of socio-familial retardation than in the other two categories. However, as the significance was at the 0.05% level and as this was the only heteromorphism whose distribution was different among the three categories of mental retardation, we assign little importance to this observation. [ABSTRACT FROM AUTHOR]

Sixteen patients with unusual heteromorphisms involving alterations of the length and/or position of centromeric heterochromatin are described. Family studies showed that the heteromorphisms were present in other relatives and segregated in the expected 1:1 ratio. There was a significantly greater frequency of unusual heteromorphisms among Orientals than in other races studied. [ABSTRACT FROM AUTHOR]

Heteromorphisms of chromosomes 1,9, and 16 were studied by C-banding in a population of 403 mentally retarded individuals from diverse ethinic groups. A significant difference in the distribution of heteromorphisms was found among the different racial groups. The Orientals had a larger C-band on chromosome 1 and a smaller C-band on chromosome 9 than the other racial groups while the Caucasians had a larger C-band on chromosome 9. The Oriental group also had a significantly greater proportion of inverted C-band. No differences were found in the distribution of C-band heteromorphisms among different etiologic categories of mental retardation. [ABSTRACT FROM AUTHOR]

Human lymphocytes were grown for one replication cycle in BrdU, stained with 33258 Hoechst, exposed to UV light and subsequently treated with 2 x SSC and stained with Giemsa. This technique differentially stains the constitutive heterochromatin of chromosomes 1, 9, 15, 16, and the Y. In the heterochromatin of chromosome 9 both sister chromatids stained darkly and symmetrically but in the other four chromosomes the heterochromatin showed lateral asymmetry, one chromatid being darkly stained while its sister chromatid was as pale or paler than the rest of the chromosome. The lateral asymmetry is presumed to reflect an underlying asymmetry in distribution of thymine between the two strands of the DNA duplex in the satellite DNA component of the chromosomes. In some number 1 chromosomes compound lateral asymmetry was seen; darkly staining material was present on both sister chromatids although at any given point lateral asymmetry was maintained so that if one chromatid stained darkly the corresponding point on the sister chromatid was very pale. The pattern of compound lateral asymmetry varied among the number 1 chromosomes studied but was constant for any one homologue from one individual. This technique reveals a previously unsuspected type of polymorphism within the constitutive heterochromatin of man. [ABSTRACT FROM AUTHOR]

We have developed a new technique of using the scanning probe microscope to measure the marring resistance that is a very desirable characteristic of clearcoats used in the automotive industry. With its high resolution, SPM can also be used to investigate the marring mechanism, and provide useful information in development of highly mar resistant coatings. In this paper, we will report a real time observation of viscoelastic creep which can result in a partial or complete healing of a marred surface. Based on the experimental data, a preliminary analysis of the recovery rate, recoverable deformation, and permanent deformation is presented. [ABSTRACT FROM AUTHOR]

Caffeine has been reported to enhance the expression of the fragile X [fra(X)] and common fragile sites in peripheral blood lymphocyte cultures (PBLC) treated with 5-fluorodeoxyuridine (FUdR). One of the effects of caffeine on replicating cells is inhibition of DNA repair suggesting that fragile sites may be regions of DNA with a high rate of misreplication under the conditions of thymidylate stress induced by FUdR. We have studied the effect of caffeine on the expression of the fra(X) and common folate-dependent fragile sites in PBLC from two fra(X) expressing individuals and in five lymphoblastoid cell lines (LCL) established from individuals in families in which the fra(X) is segregating. Caffeine did not enhance the expression of the fra(X) in the PBLC or in the three LCL from fra(X) expressing individuals nor did it elicit fra(X) expression in LCL from a non-expressing obligate-carrier female and a transmitting male. However, in all cultures there was a marked increase of common fragile site expression due to caffeine treatment. These data suggest that the mechanism of expression of the common fragile sites and the fra(X) may be quite different. [ABSTRACT FROM AUTHOR]

A cytogenetic survey of a population of 278 mentally retarded females on community placement is described. Thirty-five females had an aneuploid chromosome constitution and a single female was found to have the fra(X) syndrome. The frequency of the fra(X) syndrome among female retardates is discussed together with the apparent absence of de novo mutants among this class of fra(X) probands. [ABSTRACT FROM AUTHOR]

Premutations of the fragile-X (FRAXA) gene were thought to have no clinical effects until recent reports of an increased incidence of premature ovarian failure in females and a late-onset neurological disorder in males. These patients were identified from families including typical fragile-X males with a full mutation. By analysing a cohort of patients with neurodegenerative disorders referred for genetic analysis of spinocerebellar ataxia genes, we have found that 3 of 59 males carry the premutation. Our patients extend the phenotype associated with the FRAXA premutation and indicate that it may account for a proportion of undiagnosed neurodegenerative disorders. [ABSTRACT FROM AUTHOR]