Fragile X screening: what is the real issue?
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Female↗
Biomedical subjects
P N Howard-Peebles
Publications and source records attributed to P N Howard-Peebles.
Mental retardation and Ullrich-Turner syndrome in cases with 45,X/46X,+mar: additional support for the loss of the X-inactivation center hypothesis.
Four cases having mosaicism for a small marker or ring [45,X/46,X,+mar or 45,X/46,X,+r] chromosome were ascertained following cytogenetic studies requested because of minor anomalies (cases 1, 3, and 4) and/or short stature (cases 2 and 4). While all 4 cases had traits typical of Ullrich-Turner syndrome (UTS), cases 1, 3, and 4 had manifestations not usually present in UTS, including unusual facial appearance, mental retardation/developmental delay (MR/DD) (cases 3 and 4), and syndactylies (case 1). The facial appearances of cases 1 and 3 were similar yet distinct from that of case 4. Using fluorescence in situ hybridization (FISH), each of the markers in these 4 cases was identified as having been derived from an X chromosome. The level of mosaicism for the mar/r(X) cell line in these cases varied from 70% (case 1) to 16% (case 4) but was not apparently correlated with the presence of MR/DD. Replication studies demonstrated a probable early replication pattern for the mar/r(X) in cases 1, 3, and 4, while the marker in case 2 was apparently late replicating. To date, 41 individuals having mosaicism for a small mar/r(X) chromosome have been described. Interestingly, most of the 14 individuals having a presumedly active mar/r(X) demonstrated clinical findings atypical of UTS, including abnormal facial changes (11) and MR/DD (13). MR was noted most frequently in those cases having at least 50% mosaicism for the marker or ring. In contrast, atypical UTS facial appearance or MR/DD was not noted in 14 of the 16 cases with UTS who carried a probable late replicating marker or ring. In conclusion, although the phenotype of 45,X/46,X,mar/r(X) individuals appears to be influenced by the genetic content and degree of mosaicism for the mar/r(X), the most significant factor associated with MR/DD appears to be the activity status of the mar/r(X) chromosome. Thus, our 4 cases provide further support for the hypothesis that a lack of inactivation of a small mar/r(X) chromosome may be a factor leading to the MR and other phenotypic abnormalities seen in this subset of individuals having atypical UTS.
Child↗
Is fragile X syndrome a pervasive developmental disability? Cognitive ability and adaptive behavior in males with the full mutation.
In addition to mental retardation (MR), fragile X [fra(X)] syndrome has been associated with various psychopathologies, although it appears that the link is secondary to MR. It has been proposed that individuals with the full mutation be classified as a subcategory of pervasive developmental disorders (PDD). If fra(X) males are to be categorized as PDD, how do they compare with other types of developmental disabilities? We examined 27 fra(X) males aged 3-14 years, from 4 sites in North America. Measures of cognitive abilities were obtained from the Stanford-Binet Fourth Edition (SBFE), while levels of adaptive behavior were evaluated using the Vineland Adaptive Behavior Scales (VABS). Control subjects were sex-, age-, and IQ matched children and adolescents ascertained from the Developmental Evaluation Clinic (DEC) at Kings County Hospital. At the DEC, control subjects were diagnosed as either MR (n = 43) or autistic disorder (AD; n = 22). To compare subjects' adaptive behavior (SQ) with their cognitive abilities (IQ), a ratio of [(SQ/IQ) x 100] was computed. Results graphed as cumulative distribution functions (cdf) revealed that the cdf for AD males, who by definition are socially impaired, was positioned to the left of the cdf for MR controls, as expected. Mean ratio for AD males (70) was lower than for MR males (84). On the other hand, the cdf for fra(X) males was positioned far to the right of either AD or MR controls (mean ratio = 125). Statistical tests showed that SQ of fra(X) males was significantly higher than controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Adaptation, Psychological↗
Obstetrical and gynecological complications in fragile X carriers: a multicenter study.
We have conducted a multicenter obstetrical and gynecological survey of women in fragile X families. Included in the study were 131 gene carriers (39 with a full mutation and 92 with a premutation) and 109 noncarriers. Analysis indicated that higher numbers of fragile X gene carriers reported having irregular menses and other gynecological complications. As a group they also experienced cessation of menses prior to age 40 years at a significantly higher rate. The data appear to indicate that the FMR1 gene may play a role in the development and proliferation of oogonia.
Abortion, Spontaneous↗
Prenatal diagnosis in known fragile X carriers.
Prenatal diagnosis for fragile X syndrome was performed in 34 pregnancies of 33 known carriers, on 22 chorionic villus samples (CVS), and 15 amniocentesis samples. Fetal and maternal DNA were analyzed by the EagI/EcoRI Southern blot of Rousseau et al. [1991: N Engl J Med 325:1673-1681], with detection of full mutations ensured by a second loading with brief electrophoresis. As a supplemental assay for full mutations, cytogenetic induction was performed in 20 cases. Positive cytogenetic results were helpful in confirming full mutations in CVS cases where the fetal DNA was intermediate in appearance, between a large premutation and a small full mutation. Of 8 mothers with full mutations, the fetal results were 5 full, 2 normal, and 1 premutation (whose mother was a full/pre compound heterozygote). Of 26 mothers with premutations, the fetal results were 5 full, 13 normal, 7 premutation, and 1 uninterpretable (maternal contamination). Maternal premutations were sized in kb by Southern blot and in CGG repeat number by PCR; the predicted correlation between maternal length and penetrance was seen. Follow-up studies include 3 full mutations and 2 premutations confirmed by DNA analysis at birth. Maternal contamination of CVS samples was encountered in 3 of 22 cases, illustrating the value of EagI in detecting maternal (lyonized) chromosomes.
Amniocentesis↗
Characteristics of the transmission of the FMR1 gene from carrier females in a prospective sample of conceptuses.
The Prospective Study of the Fragile X Syndrome is a large collaborative effort designed to collect prospective data on the pregnancy outcomes of individuals who carry the fragile X mutation. The goal of this 5-year study is to obtain empiric recurrence risks and population parameters for the fragile X syndrome in order to characterize the underlying mechanism of the mutation and the factors that influence its expression. This report presents the DNA results on the first 152 cases of female carriers and their pregnancy outcomes. It was found that the sex ratio of conceptuses was not significantly different from 1.0 and was not associated with mutation status. Thus, there was no evidence for selection against zygotes with full mutations. There was a significant association between the form of the mutation in carrier mothers and the frequency of its transmission. Examination of the segregation ratios from premutation mothers showed that there was a deficit of conceptuses that received the fragile X mutation. The segregation ratio from full mutation carrier mothers did not differ from expected. Several explanations for this observation are discussed. Numbers of cases are too small to estimate recurrence risks; however, the general trend of the data confirm the association of recurrence risks and the repeat number carried by the mother.
Female↗
Improved sizing of fragile X CCG repeats by nested polymerase chain reaction.
We have developed an improved method for polymerase chain reaction (PCR)-based sizing of the CCG repeat region at the fragile X locus, FMR-1. This method is designed to optimize denaturation and replication of long repeats with high G + C content, which are otherwise refractory to amplification. The method utilizes nested PCR primers to increase sensitivity and specificity. Alkaline denaturation of the genomic template DNA, combined with addition of glycerol and deaza-dGTP, facilitates strand separation. Labeled PCR products are sized on denaturing polyacrylamide gels. For alleles in the normal-to-premutation size range, strong reproducible signals are routinely obtained from small amounts of rapidly prepared DNA. This allows precise determination of the CCG repeat number, providing data related to the expansion potential of the repetitive segment. Detection of large premutations and some full mutations is also enhanced by the improved procedure.
Base Sequence↗
Population screening for fragile-X syndrome.
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DNA Mutational Analysis↗
Clinical findings in patients with marker chromosomes identified by fluorescence in situ hybridization.
Twenty-seven patients carrying marker chromosomes were previously collected, characterized by cytogenetic techniques, and identified by stepwise fluorescence in situ hybridization (FISH) with alpha-satellite DNA probes. Clinical features of 22 patients are described here and compared to other patients with marker chromosomes similarly identified and reported in the literature.
Adult↗
Uniparental disomy for chromosome 16 in humans.
The association between chromosomal mosaicism observed on chorionic villus sampling (CVS) and poor pregnancy outcome has been well documented. CVS mosaicism usually represents abnormal cell lines confined to the placenta and often involves chromosomal trisomy. Such confined placental mosaicism (CPM) may occur when there is complete dichotomy between a trisomic karyotype in the placenta and a normal diploid fetus or when both diploid and trisomic components are present within the placenta. Gestations involving pure or significant trisomy in placental lineages associated with a diploid fetal karyotype probably result from a trisomic zygote which has lost one copy of the trisomic chromosome in the embryonic progenitor cells during cleavage. Uniparental disomy would be expected to occur in one-third of such cases. Trisomy of chromosome 7, 9, 15, or 16 is most common among the gestations with these dichotomic CPMs. Nine pregnancies with trisomy 16 confined to the placenta were prenatally diagnosed. Pregnancy outcome, levels of trisomic cells in term placentas, and fetal uniparental disomy were studied. Intrauterine growth retardation (IUGR), low birthweight, or fetal death was observed in six of these pregnancies and correlated with high levels of trisomic cells in the term placentas. Four of the five cases of IUGR or fetal death showed fetal uniparental disomy for chromosome 16. One of the infants with maternal uniparental disomy 16 had a significant malformation (imperforate anus). All infants with normal intrauterine growth showed term placentas with low levels of trisomic cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Complementary duplication and deletion of 17 (pcen----p11.2): a family with a supernumerary chromosome comprised of an interstitially deleted segment.
A sister and brother were investigated because both were developmentally delayed although they had somewhat different physical anomalies. The girl was found to have an interstitial deletion of chromosome 17. Her karyotype was 46,XX,del(17) (pter----p11.2::cen----qter). Her brother had normal chromosomes in peripheral lymphocytes. Cytogenetic investigation of the mother showed the presence of the same deletion as in her daughter and a small supernumerary chromosome. The supernumerary chromosome appeared to contain the material deleted from the short arm of 17 since the mother's phenotype was normal. Study of skin fibroblasts in her son showed that he was mosaic for a normal cell line and one that contained the extra small chromosome; thus, he had mosaic partial trisomy 17(cen----p11.2). The origin of the centromere and telomere(s) of the small supernumerary chromosome in this family presents an interesting problem.
Centromere↗
Expression of the fragile-X in the "premutated"/"non-imprinted" state.
Data about the expression of the fragile site at Xq27.3 from 74 daughters of normal transmitting males (NTMs) were collected from 7 different genetic centers. The majority (85.1%) of these obligate female carriers did not show any cytogenetic expression of fra-X. The remaining 14.9% of these females had frequencies below 3%. In cases with a frequency below 3% of fra-X, a "premutated"/"non imprinted" state of a female carrier should be considered. The results of this collaborative study are in accordance with data from DNA studies taking the premutation model into account.
Female↗
Confirmation of CVS mosaicism in term placentae and high frequency of intrauterine growth retardation association with confined placental mosaicism.
About 2 per cent of specimens from chorionic villus sampling (CVS) analysed either on direct preparation of cytotrophoblast cells or after culture of mesenchymal stroma reveal confined placental mosaicism (CPM), most commonly involving chromosomal trisomy. A significantly higher rate of prenatal loss (22 per cent) as well as the presence of intrauterine growth retardation (IUGR) has been reported among pregnancies with CPM. To evaluate more precisely the effect of these aneuploid cell lines confined to the placenta on intrauterine fetal growth and fetal survival, we have studied 34 term placentae from pregnancies with CPM diagnosed on CVS and confirmed identical mosaicism in 17 of these placentae. There was a direct correlation between a high number of aneuploid cells present at CVS and a high likelihood of their detection in term placenta. Also, the proportion of aneuploid cells in the mosaic term placentae correlated with that observed in CVS specimens. Among 17 gestations with confirmed CPM at delivery, there were six cases of IUGR identified, five in liveborns and one associated with intrauterine death.
Amnion↗
Characterization of seven DA/DAPI-positive bisatellited marker chromosomes by in situ hybridization.
Seven dicentric bisatellited marker chromosomes, ascertained at amniocentesis, chorionic villus sampling, and in blood from an abnormal liveborn were characterized cytogenetically. All seven markers demonstrated brilliant bands by the DA/DAPI technique corresponding to C-band positive regions. Although some dicentric DA/DAPI-positive bisatellited markers have been identified as inverted duplicated 15s, recent literature has suggested that DA/DAPI lacks specificity for chromosome 15. Our evaluation of DA/DAPI-positive bisatellited marker chromosomes by in situ hybridization shows that some originate from chromosome 15 whereas DA/DAPI negative bisatellited markers may not be derived from 15. The morphological variations noted in our studies are discussed with respect to nomenclature.
Amniocentesis↗
Childhood chronic lymphocytic leukemia with (2;14) translocation.
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Adolescent↗
Partial deletion of alpha satellite DNA associated with reduced amounts of the centromere protein CENP-B in a mitotically stable human chromosome rearrangement.
A familial, constitutionally rearranged human chromosome 17 is deleted for much of the DNA in its centromeric region but retains full mitotic centromere activity. Fluorescence in situ hybridization, pulsed-field gel electrophoresis, and Southern blot analysis of the residual centromeric region revealed a approximately 700-kb centromeric array of tandemly repeated alpha satellite DNA that was only approximately 20 to 30% as large as a normal array. This deletion was associated with a reduction in the amount of the centromere-specific antigen CENP-B detected by indirect immunofluorescence. The coincidence of the primary constriction, the small residual array of alpha satellite DNA, and the reduced amount of detectable CENP-B support the hypothesis that CENP-B is associated with alpha satellite DNA. Furthermore, the finding that both the deleted chromosome 17 and its derivative supernumerary fragment retained mitotic function and possess centromeric protein antigens suggests that human centromeres are structurally and functionally repetitive.
Autoantigens↗
The parental origin and mechanism of formation of three dicentric X chromosomes.
Cytogenetic and molecular analyses of three dicentric X chromosomes were performed in an attempt to identify the parental origin and mechanism of formation of the aberrant chromosomes. Results indicate that, in these three cases, the dicentric chromosomes were formed by chromatid breakage and reunion of sister chromatids at the breakpoint. In two cases the abnormal chromosomes were paternal in origin; in the third case the dicentric originated from the maternal X chromosome.
Cells, Cultured↗
ReCAP: the Registry of Cytogenetic Abnormalities and Phenylketonuria.
The Registry of Cytogenetic Abnormalities and Phenylketonuria (ReCAP) is a multicenter collaborative registry of information on patients with constitutional cytogenetic abnormalities or hyperphenylalaninemia (HPA). Data are entered by microcomputer at four contributing centers. Records are then electronically transmitted to the coordinating center, where the composite cytogenetic and hyperphenylalaninemia databases are maintained on a mainframe computer. A set of programs, known as the ReCAP ISCN Translator, is used to create additional database records describing in detail the chromosome abnormalities present in each patient. The ReCAP computer system permits rapid and flexible retrieval of cases on the basis of any combination of laboratory, clinical, psychometric, or genetic characteristics contained within the databases. Special procedures protect patient confidentiality and assure that ReCAP data are of consistently high quality. Qualified investigators may use ReCAP as a resource for a variety of scientific studies.
Chromosome Aberrations↗