Frequency of the fragile X syndrome in institutionalized mentally retarded females in Japan

Summary The fragile X [fra(X)] syndrome was screened on 190 Japanese institutionalized females with moderate to severe mental retardation. Two inmates with severe mental retardation (IQ 20) had the fra(X) chromosome in 26% and 15% of the cells examined, indicating that the prevalence of the fra(X) syndrome was about 1% in all female inmates and was about 3.27% in severely mentally retarded females with known causes. However, no female with fra(X) syndrome was found in 35 moderately retarded females. Both had brothers with the fra(X) syndrome and the prevalence was 10% in females with a family history of mental retardation. In addition, the replication study of the fra(X) chromosome in the patients supported the proposal that an excess of the early replicated fra(X) chromosome is related to the mental capacity in heterozygous females. Therefore, the fra(X) syndrome should not be ignored even in severely mentally retarded females with a family history, though the heterozygotes are commonly normal to subnormal in their mental development. in addition, the replication study of the fra(X) chromosome may help to estimate mental development in the carrier children.     

Inherited pericentric inversion of Y-chromosome with trisomy 21. A case report

A 13-year-old boy with clinical features of Down syndrome was investigated. His karyotype was 47,X,inv(Y),+21. The proband's father and two elder brothers were also found to have the inv(Y). A spontaneous chromatid break was observed in the long arm of the X chromosome[? fra (X)] in 2% of the cells. The mother had two spontaneous abortions. This is the first case of trisomy-21 with inv(Y) in our population. This finding might be fortuitous. The frequency of inv(Y) in Down syndrome is not known.     

A cytogenetic study of a population of retarded females with special reference to the fragile(X) syndrome

Summary 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.     

A Somatic Origin of Homologous Robertsonian Translocations and Isochromosomes

One t(14q14q), three t(15q15q), two t(21q21q), and two t(22q22q) nonmosaic, apparently balanced, de novo Robertsonian translocation cases were investigated with polymorphic markers to establish the origin of the translocated chromosomes. Four cases had results indicative of an isochromosome: one t(14q14q) case with mild mental retardation and maternal uniparental disomy (UPD) for chromosome 14, one t(15q15q) case with the Prader-Willi syndrome and UPD(15), a phenotypically normal carrier of t(22q22q) with maternal UPD(22), and a phenotypically normal t(21q21q) case of paternal UPD(21). All UPD cases showed complete homozygosity throughout the involved chromosome, which is supportive of a postmeiotic origin. In the remaining four cases, maternal and paternal inheritance of the involved chromosome was found, which unambiguously implies a somatic origin. One t(15q15q) female had a child with a ring chromosome 15, which was also of probable postmeiotic origin as recombination between grandparental haplotypes had occurred prior to ring formation. UPD might be expected to result from de novo Robertsonian translocations of meiotic origin; however, all de novo homologous translocation cases, so far reported, with UPD of chromosomes 14, 15, 21, or 22 have been isochromosomes. These data provide the first direct evidence that nonmosaic Robertsonian translocations, as well as isochromosomes, are commonly the result of a mitotic exchange.     

Nucleolar organizer region heteromorphism associated with trisomy-21: a risk factor for non-disjunction?

An unusual nucleolar organizer region (double NOR) on chromosome 13 was observed in a Down syndrome child [47, XY, +21, dNOR(13)]. The variant chromosome was inherited from the mother [46, XX, dNOR(13)]. The extra chromosome 21 in the proband was maternal origin. The frequency of NOR chromosome association showed relatively high frequency in the mother and proband as compared to the controls. The result suggest that chromosome variants involving extra copies of NOR may indeed be involved in the meiotic nondisjunction of chromosome-21.     

Folate-sensitive fragile sites on the X-chromosome heterochromatin of the Indian mole rat, Nesokia indica

Folate-sensitive fragile sites have been demonstrated on the X chromosome of the Indian mole rat, Nesokia indica (subfamily Murinae), utilizing peripheral blood lymphocyte cultures. All normal female individuals expressed fragile sites on the constitutive heterochromatic long arm of one of their two X chromosomes (heterozygous expression); in contrast, no fragile sites were found on the single X chromosome of normal males. Preferential transmission of the maternal fragile X to the daughters is therefore suggested. Four sites have been detected so far: fra Xq1, fra Xq2, fra Xq3, and fra Xc (centromeric). It is significant that their location corresponds to the regions where constitutive heterochromatic deletions occur that result in a variety of polymorphic X chromosomes in natural populations of Nesokia. Thus there is a correlation between fragile sites, deletion sites, and karyotypic changes. In individuals that did not reproduce in the laboratory, there were more fragile sites on both X chromosomes of the females (homozygous/double heterozygous expression) and also on the X of the males (hemizygous expression). This difference in fragile site expression from the normal situation could be attributed to one or more new mutations. However, the mechanism by which fragile sites influence reproductive performance is unclear.     

Female fetal cells in maternal blood: use of DNA polymorphisms to prove origin

The nucleated erythrocyte (NRBC) is one of the target fetal cell types for noninvasive genetic diagnosis using maternal peripheral blood. However, it is now known that pregnancy can stimulate the production of maternal NRBCs. When isolating female gamma-positive NRBCs, fluorescence in situ hybridization (FISH) analysis may show two X chromosome signals per nucleus, and therefore it cannot be conclusively determined whether the isolated cells are fetal or maternal in origin. The purpose of this study was to develop a means of verifying that a female cell is fetal on the basis of polymorphic short tandem repeat markers. Peripheral blood samples were obtained from women who had just undergone termination of pregnancy. Nucleated candidate fetal cells were isolated by flow-sorting using antibody to the gamma-chain of fetal hemoglobin and Hoechst 33342. FISH analysis was performed using X and Y chromosome specific probes. Female gamma-positive cells and leukocytes were micromanipulated separately and subjected to fluorescent polymerase chain reaction amplification of chromosome 21 and/or 18 STR markers (D21S11, D21S1411, D21S1412, and D18S535). In all ten cases analyzed, the gamma-positive female candidate fetal cells were determined to be fetal in origin by the presence of shared and nonshared DNA polymorphisms when compared with maternal leukocytes. These results show that genetic analysis can be performed on all fetal NRBCs, including female fetal cells that cannot be distinguished from maternal cells based on FISH analysis alone.     

Sex chromosome inactivation in the male

Mammalian females have two X chromosomes, while males have only one X plus a Y chromosome. In order to balance X-linked gene dosage between the sexes, one X chromosome undergoes inactivation during development of female embryos. This process has been termed X-chromosome inactivation (XCI). Inactivation of the single X chromosome also occurs in the male, but is transient and is confined to the late stages of first meiotic prophase during spermatogenesis. This phenomenon has been termed meiotic sex chromosome inactivation (MSCI). A substantial portion (~15-25%) of X-linked mRNA-encoding genes escapes XCI in female somatic cells. While no mRNA genes are known to escape MSCI in males, ~80% of X-linked miRNA genes have been shown to escape this process. Recent results have led to the proposal that the RNA interference mechanism may be involved in regulating XCI in female cells. We suggest that some MSCI-escaping miRNAs may play a similar role in regulating MSCI in male germ cells.     

Uniparental disomy of the entire X chromosome in a female with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a severe, progressive, X-linked muscle-wasting disorder with an incidence of approximately 1/3,500 male births. Females are also affected, in rare instances. The manifestation of mild to severe symptoms in female carriers of dystrophin mutations is often the result of the preferential inactivation of the X chromosome carrying the normal dystrophin gene. The severity of the symptoms is dependent on the proportion of cells that have inactivated the normal X chromosome. A skewed pattern of X inactivation is also responsible for the clinical manifestation of DMD in females carrying X;autosome translocations, which disrupt the dystrophin gene. DMD may also be observed in females with Turner syndrome (45,X), if the remaining X chromosome carries a DMD mutation. We report here the case of a karyotypically normal female affected with DMD as a result of homozygosity for a deletion of exon 50 of the dystrophin gene. PCR analysis of microsatellite markers spanning the length of the X chromosome demonstrated that homozygosity for the dystrophin gene mutation was caused by maternal isodisomy for the entire X chromosome. This finding demonstrates that uniparental isodisomy of the X chromosome is an additional mechanism for the expression of X-linked recessive disorders. The proband's clinical presentation is consistent with the absence of imprinted genes (i.e., genes that are selectively expressed based on the parent of origin) on the X chromosome.     

Meiotic crossing-over in nondisjoined chromosomes of children with trisomy 21 and a congenital heart defect.

We have used DNA polymorphisms to study meiotic crossovers of chromosome 21q in 27 nuclear families. Each family had a child with Down syndrome and a congenital heart defect. Twenty DNA polymorphisms on chromosome 21 were used to determine parental and meiotic origin of nondisjunction and to identify crossovers. Twenty-four cases were of maternal origin, and three were of paternal origin. Twenty-two unequivocal crossover events were identified. Sixteen crossovers were observed in 22 chromosome pairs nondisjoining at the second meiotic division. Fifty percent of crossover events in MI nondisjunction are detectable by molecular genetic means. Thus, the results suggest that, in this sample, each nondisjoined chromosome 21 pair has been involved in at least one crossover event.     

Coincidence of familial systemic lupus erythematosus and the fragile X syndrome

The coincidence of fragile X syndrome (fra(X] and systemic lupus erythematosus (SLE) in the same family is reported here for the first time. A 16-year-old boy with typical fra(X) had a severe SLE with multiple organ involvement. His 12-year-old sister of normal intelligence had circulating antinuclear antibodies and proliferative glomerulonephritis. The fra(X) was not found in her karyotype. Except for abnormalities due to immunosuppressive treatment during pregnancy, the association of SLE and chromosome abnormalities has been only reported in Klinefelter's syndrome. The possible pathogenic role of sex hormonal abnormalities due to an extra X chromosome has been suggested in the occurrence of SLE.     

Chimerism and multiple numerical chromosome imbalances in a spontaneously aborted fetus

We report on a case of chimerism and multiple abnormalities of chromosomes 21, Xand Yin spontaneous abortion specimen. To the best our knowledge the present case is the first documented chimera in a spontaneously aborted fetus. The application of interphase fluorescence in situ hybridization (FISH) using chromosome enumeration and site-specific DNA probes showed trisomy X in 92 nuclei (23 %), tetrasomy X in 100 nuclei (25 %), pentasomy of chromosome X in 40 nuclei (10 %), XXY in 36 nuclei (9 %), XXXXXXYY in 12 nuclei (3 %), XXXXXYYYYY in 8 nuclei (2 %), trisomy 21 and female chromosome complement in 40 nuclei (10 %), normal female chromosome complement in 72 nuclei (18 %) out of 400 nuclei scored. Our experience indicates that the frequency of chimerism coupled with multiple chromosome abnormalities should be no less than 1 : 400 among spontaneous abortions. The difficulties of chimerism identification in fetal tissues are discussed.     

Neuroanatomy in fragile X females: the posterior fossa.

The relative homogeneity of the neuropsychiatric phenotype in individuals with fragile (fra) X syndrome suggests that there are consistent central nervous system (CNS) abnormalities underlying the observed cognitive and behavioral abnormalities. In this study, the neuroanatomy of the posterior fossa and other selected CNS regions in 12 young fra X females were compared with those of a group of 12 age-, sex-, and IQ-matched females without evidence of the fra X syndrome. Fra X females were shown to have decreased size of the posterior cerebellar vermis and increased size of the fourth ventricle, findings that are identical to those previously reported for fra X males. When compared with fra X male and nonfra X control groups, the distribution of the posterior-vermis and fourth-ventricle variables for the fra X female group was intermediate. These results support the hypothesis that the fra X genetic abnormality leads to hypoplasia of the posterior cerebellar vermis, a neuroanatomical variation of potential importance to both developmental and neuropsychiatric syndromes.     

The ratio of de novo unbalanced translocation to 47, trisomy 21 Down syndrome. A new method for human mutation surveillance and an apparent recent change in mutation rate resulting in human interchange trisomies in one jurisdiction.

The Down syndrome phenotype may be associated with, among other genotypes, an unbalanced Robertsonian translocation producing an "interchange trisomy" with 46 chromosomes, or 47, trisomy 21. Translocations, like specificlocus point mutations, result from a direct change in structural chromosome elements. In contrast 47, trisomy 21 results from meiotic non-disjunction. Mutation rates for interchange trisomies may be followed indirectly by determining the ratio of instances of Down syndrome associated with a new translocation mutation to those produced by 47, trisomy 21, which accounts for the bulk of the Down syndrome phenotype. This genotypic ratio can be analyzed in data from cytogenetic laboratories, clinics, and chromosome registries and does not depend upon intensive chromosome screening of newborn populations. A similar approach can be adopted to follow trends in Patau syndrome. The genotypic ratio, stratified by maternal age, may in addition, provide a sentinel index for changes in human specific-locus mutations and perhaps other adverse health consequences. Analysis of data from the New York State-North-eastern chromosome registry revealed a two- to three-fold increase in the genotypic ratio for both Down syndrome and Patau syndrome for individuals born in 1973, 1974 and 1975 compared to those born in earlier years.     

Low frequencies of apparently fragile X chromosomes in normal control cultures: a possible explanation

Low frequencies of apparently fragile X [fra(X)] chromosomes have been reported in normal control, short-term, whole blood cultures, and they have been noted in both amniocyte and fetal blood cultures. However, there is currently no universal agreement on the lowest frequency for fra(X)(q27) that is diagnostic for the fragile X syndrome. Here, we present our observations on low levels of apparently fra(X) chromosomes in normal samples. We observed frequencies of 0.5% in short-term whole blood cultures and 0.9% in amniotic fluid cell cultures. In 1982, Steinbach et al. described nonspecific telomeric structural changes (TSC) and suggested that such low frequencies of apparently fra(X) chromosomes in normal material may be occurring by the same mechanism that is responsible for TSC formation. To determine if TSC formation can explain the significant baseline frequencies of fra(X) in normal controls, 10,457 cells were screened from 178 individuals referred for fra(X) analysis. Our findings indicated that TSC are not randomly distributed across chromosomes but tend to occur at specific sites. Based on our observations, we offer the hypothesis that the low frequency of apparent fra(X) in normal individuals may be due to nonrandom TSC distribution.     

High efficiency in the attribution of parental origin of non-disjunction in trisomy 21 by both cytogenetic and molecular polymorphisms

Summary The precise origin of the supernumerary chromosome can be defined in the majority of trisomy 21 cases. This is achieved by evaluating the chromosome 21 short arm polymorphism and analysing restriction fragment length polymorphisms (RFLPs) of multiple chromosome 21 loci. We report a study on 37 Italian families with Down's syndrome. In 35 cases (94.6%) both the parental and the meiotic stage of non-disjunction could be established. Knowledge of the origin of the extra chromosome 21 is a pre-requisite for investigations of genetic or environmental factors that may affect the meiotic process.     

Joubert syndrome co-existing with partial Xp trisomy: review of the literature

We report a five-year-old girl who has been clinically diagnosed as Joubert syndrome. Her cytogenetic analysis showed 46,XX,der(2)add(2q37) karyotype. Cytogenetic analysis of her mother and maternal grandmother revealed a karyogram designated as 46,X,t (X;2)(p11.2;q37). The proband's derivative chromosome was further confirmed to be a translocation chromosome 2 carrying segments from chromosome X, which originated from a segregation event of the maternal grandmother's balanced translocation passed on as a balanced translocation to the proband's mother either. So far, a number of candidate genes including EN1 on 2q were analyzed for Joubert syndrome. Based on our proband's abnormal karyotype, we suggest that further mapping studies for the syndrome should also be directed towards the chromosome X segments present on the derivative chromosome 2 of our proband.     

Insights into the meiotic behavior and evolution of multiple sex chromosome systems in spiders

A characteristic feature of spider karyotypes is the predominance of unusual multiple X chromosomes. To elucidate the evolution of spider sex chromosomes, their meiotic behavior was analyzed in 2 major clades of opisthothele spiders, namely, the entelegyne araneomorphs and the mygalomorphs. Our data support the predominance of X(1)X(2)0 systems in entelegynes, while rare X(1)X(2)X(3)X(4)0 systems were revealed in the tuberculote mygalomorphs. The spider species studied exhibited a considerable diversity of achiasmate sex chromosome pairing in male meiosis. The end-to-end pairing of sex chromosomes found in mygalomorphs was gradually replaced by the parallel attachment of sex chromosomes in entelegynes. The observed association of male X univalents with a centrosome at the first meiotic division may ensure the univalents' segregation. Spider meiotic sex chromosomes also showed other unique traits, namely, association with a chromosome pair in males and inactivation in females. Analysis of these traits supports the hypothesis that the multiple X chromosomes of spiders originated by duplications. In contrast to the homogametic sex of other animals, the homologous sex chromosomes of spider females were already paired at premeiotic interphase and were inactivated until prophase I. Furthermore, the sex chromosome pairs exhibited an end-to-end association during these stages. We suggest that the specific behavior of the female sex chromosomes may have evolved to avoid the negative effects of duplicated X chromosomes on female meiosis. The chromosome ends that ensure the association of sex chromosome pairs during meiosis may contain information for discriminating between homologous and homeologous X chromosomes and thus act to promote homologous pairing. The meiotic behavior of 4 X chromosome pairs in mygalomorph females, namely, the formation of 2 associations, each composed of 2 pairs with similar structure, suggests that the mygalomorph X(1)X(2)X(3)X(4)0 system originated by the duplication of the X(1)X(2)0 system via nondisjunctions or polyploidization.     

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.