AbstractA boy with the Dandy-Walker syndrome associated with multiple congenital abnormalities is described. Chromosomal analyses revealed an abnormal chromosome 21, inherited from his father who had a balanced translocation involving chromosomes 12 and 21: rcp(12;21)(q24.1;q22.1). The clinical features of this patient are compared with published descriptions for duplication 12q24→qter and a review of the literature pertaining to chromosomal anomalies found in other patients with the Dandy-Walker syndrome is presented.Key Words: Key words: human chromosomesduplication 12qchromosome 12Dandy-Walker syndrome
We used a rapid and inexpensive method for studying the FMR1 CGG-repeat from dried blood spots, prepared from heel pricks, finger pricks, or an aliquot of blood from a venipuncture. The procedure includes a single tube for preparation of template DNA for PCR and minimal handling, avoiding opportunities for mislabelling specimens and loss of template. We extended the protocol to numerous di- and trinucleotide repeat markers and disease loci, including FRAXE, FRAXF, DXS548, DRPLA, and ZFY. The use of a highly reliable and very inexpensive method which employs blood spots as a source for target DNA means that newborn Guthrie cards can be used to establish allele frequencies for linkage disequilibrium studies, that large populations can be screened for genetic disorders, and that mapping studies can proceed rapidly even when only small amounts of blood are available from key family members.
In 3 families with the fragile-X [fra(X)] syndrome, we have identified a minimum of 4 recombinations in 9 meioses between the syndrome locus and the coagulation Factor IX gene. Two Factor IX intragenic restriction fragment length polymorphisms (RFLPs), produced with TaqI and XmnI, were used as markers. In lod score calculations, incomplete penetrance of the fra(X) mutation in males and females was taken into account by the computer program LIPED. The cumulative maximum lod score calculated from these data and from data previously reported was 2.75 at a recombination frequency of 20% (θ = 0.20). This indicates that the genetic distance between the Factor IX gene and the fra(X) locus is too great for Factor IX probes to be used alone for carrier detection in the fra(X) syndrome. Additional polymorphic loci more tightly linked to the fra(X) syndrome locus are required.
Abstract We have previously described a murine mammary tumor cell line (SP1) that metastasizes when transplanted into the mammary gland, but not when injected into the subcutaneous site. We used cytogenetic markers to assess genetic heterogeneity, and to monitor the selection and evolution of karyotypically distinct cell types during primary tumor growth and in metastases. The SPI tumor cells are hypotetraploid (mean chromosome number = 72), and have at least four karyotypically distinct cell types. We found no consistent pattern of selection of tumor cell types in primary tumors. However, metastases were derived from a cell type that was present in the corresponding primary tumor. In addition, novel, karyotypically distinct cell types also appeared in the metastatic nodules. Markers that appeared in metastases included two translocations, t(10; 18) and t(1;19). By injecting a mixture of cells from a metastatic nodule with a non‐metastatic clone into mice, we showed that the new cell types in metastases displayed a stable increased growth and metastatic potential when compared to the non‐metastatic clone, or when compared to the initial cell type from which the metastases derived. These results indicate that metastases are derived from a distinct cell type in the primary tumor, but that additional chromosome and cell evolution occurs, resulting in new cell types that are selected in metastases.
Previous researchers have reported autistic features in children with fragile X syndrome. We compared 21 children with pervasive developmental disorders (autism group) to 15 with fragile X syndrome on the Childhood Autism Rating Scale and the Reiss Scales for Children's Dual Diagnosis. The 7 children (47%) with fragile X who scored above the Childhood Autism Rating Scale cut-off (fragile X-autism group) were more impaired than the remaining children (fragile X-no autism) on Childhood Autism Rating Scale subscales related to emotion, visual and listening responses, and communication. The autism group's Reiss scores were higher than fragile X-no autism group, but not fragile X-autism group. Although the Childhood Autism Rating Scale identified almost 50% of children with fragile X as having autism, qualitative differences may exist in specific autistic-like behaviors between children with autism and children with fragile X.
Recently, unstable trinucleotide repeats have been shown to be the etiologic factor in seven neuropsychiatric diseases, and they may play a similar role in other genetic disorders which exhibit genetic anticipation. We have tested one polymerase chain reaction (PCR)-based and two hybridization-based methods for direct detection of unstable DNA expansion in genomic DNA. This technique employs a single primer (asymmetric) PCR using total genomic DNA as a template to efficiently screen for the presence of large trinucleotide repeat expansions. High-stringency Southern blot hybridization with a PCR-generated trinucleotide repeat probe allowed detection of the DNA fragment containing the expansion. Analysis of myotonic dystrophy patients containing different degrees of (CTG)n expansion demonstrated the identification of the site of trinucleotide instability in some affected individuals without any prior information regarding genetic map location. The same probe was used for fluorescent in situ hybridization and several regions of (CTG)n/(CAG)n repeats in the human genome were detected, including the myotonic dystrophy locus on chromosome 19q. Although limited at present to large trinucleotide repeat expansions, these strategies can be applied to directly clone genes involved in disorders caused by large expansions of unstable DNA.
Abstract One hundred and three individuals in ll unrelated families with the fragile‐X [fra(X)] syndrome were tested for polymorphisms identified bhy probes flanking the fra(X) site at Xq27.3 Two probes distal and 2 proximal to the fra(X) site were used. Thirteen known female carriers were analyzed retrospectively. DNA markers gave probabilities of carrying the mutation of 99% in 1 female, 89% in 8 females, and 10–55% in the other 4 females. We also estimated the probability of having inherited the mutation for 16 individuals of unknown fra(X) status using DNA markers and corrections for imcomplete penetrance. the DNA marker test gave risks for females of 1–6% (7 females), 15% (1 female), and 97% (1 female). In males the risks were 1–3% (6 males) and 91% (1 male). In 3 families, DNA marker data were used to calculate probabilities of ≥98.5% that transmission of the fra(X) mutation had occurred through normal males. In the retrospective studies, only 1 of 7 retarded males could have been diagnosed prenatally as having the fra(X) mutation with a probability of 99% DNA maker analysis was uninformative in 5 of these males. When fra(X) carrier status cannot be established by chromosome analysis, DNA maker studies provide an alternative test that can be used to calculate individual risks more precisely. However, linkage analysis of the probe loci in these 11 families suggests that the recombination frequency between the fra(X)locus and the factor IX gene (F9) and DXS52 may be greater than previously suggested. Until the true recombination frequencies are established and the question of heterogeneity among families is fully analyzed, caution in using DNA markers as a predictive is advised.
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