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Joe Leigh Simpson

Publications and source records attributed to Joe Leigh Simpson.

49 records · Page 3Linked to original sources
PubMed2002

Genetic counseling in translocations.

Advances in the treatment of male infertility-specifically intracytoplasmic sperm injection have now resulted in greater recognition of the clinical significance of genetic translocations. This article focuses on the different types of translocations (Robertsonian, reciprocal) as well as on the prevalence and incidence of translocations in infertile and other populations. The authors contrast theoretical and empiric meiotic segregation patterns in the different clinical settings of traditional prenatal genetic diagnosis and preimplantation genetic diagnosis. In particular, the significance of a higher prevalence of unbalanced blastomeres is discussed.

Female↗
PubMed2002

A general approach to genetic counseling.

Genetic counseling can best be performed if a systematic approach is taken. The geneticist or genetic counselor has the difficult task of conveying complex information to patients in an understandable form. At the same time, this must be done in a nondirective manner, affording the patient the right to make his or her own decisions. Obtaining accurate family and medical history information is crucial to the genetic counseling process. Given the nature of genetic information, multiple sessions may be necessary to ensure that the patient understands the risks involved in his or her particular situation.

Clinical Laboratory Techniques↗
PubMed2002

Genetic screening for cystic fibrosis.

The importance of the recent recommendations that address cystic fibrosis carrier screening cannot be overemphasized. For the first time, a systematic approach to offering or making screening available to all pregnant women in the hopes of providing refined risk estimates for a genetic disease has been established. Caucasian of European or Ashkenazi-Jewish descent should be offered screening. Within the proposed guidelines are ethnic-specific carrier frequencies (1/29) used to establish who should be offered testing and to whom testing should be made available. Recent recommendations have made clear that in a pan-ethnic population a frequency of 1/1,000 is required for inclusion into the cystic fibrosis mutation panel. A general framework for screening during pregnancy has been established (either concurrent or sequential). It will be interesting to watch as the fruits of the human genome project are inspected and applied to everyday clinical practice. No doubt the cost of screening will be reduced through advances in technology. The combined efforts of NIH, ACOG, and ACMG have provided the first set of comprehensive standards for screening of recessive diseases. How time changes these guidelines deserves following.

Cystic Fibrosis↗
PubMed2002

Molecular approach to common causes of female infertility.

Pivotal genetic information has been derived for a host of rare genetic disorders, but progress has been much slower in relation to the common causes of female infertility. In this chapter, we shall illustrate the approaches being applied in elucidating conditions causing infertility that are inherited in a polygenic/multifactorial fashion. The task is to determine the number of genes responsible and their chromosomal location(s). The first approach is to use genome-wide quantitative linkage analysis, searching throughout the genome with no prior expectation that a given gene or chromosomal region is casually involved. A second approach is to search across the genome for altered gene expression, for example comparing endometriosis and normal (non-endometriosis)cells. The third approach is less indiscriminate and more focused, depending upon identifying specific candidate genes. Aromatase, calhedrin, oestrogen receptor, galactose-1-phosphate uridyl transferase (GALT) and tumour suppressor genes such as p53 are attractive candidate genes for endometriosis. Endometriosis, which has long been suspected to possess a familial tendency, has been subjected to genome-wide linkage analysis in Oxford, UK, where sib-pair analysis uses polymorphic DNA markers and fluorescence-based automated analysis. Several regions of exclusion have been found, but no linkages have so far been reported. A candidate gene approach focuses on the presence of chromosomal aberrations, the assumption being that endometriosis parallels neoplasia. At Baylor College of Medicine, we thus began by showing chromosome alterations involving trisomy 11, monosomy 16 and monosomy 17 in late-stage endometriosis. A loss of only the p53 tumour suppressor gene, rather than a loss (monosomy) of chromosome 17 per se, however, seems to be the pivotal event. A second representative polygenic/multifactorial disorder causing female infertility is polycystic ovarian syndrome. Both quantitative linkage analysis and candidate gene approaches are being pursued. In the far more commonly observed 'idiopathic' variety (non-adrenal polycystic ovarian syndrome and hirsutism), consensus has long existed that one or more dominant genes causes the condition. Although the mode of inheritance in 'essential' polycystic ovarian syndrome remains uncertain, dominant tendencies are clearly more pertinent than recessive ones. Genes for adrenal biosynthetic enzymes, insulin receptors, leptin and leptin receptors, follistatin, activin and inhibins are attractive candidates for polycystic ovarian disease. A linkage to 37 candidate genes was sought using affected sib-pair analysis and transmission/disequilibrium methods.

Endometriosis↗
PubMed2002

Heritability and molecular genetic studies of endometriosis.

Endometriosis is well established as a condition showing heritable tendencies. Polygenic/multifactorial etiology appears far more likely to be the etiology than Mendelian inheritance. The current task is to determine the number and location of genes responsible for endometriosis. This paper shall review the basis for concluding that endometriosis is a genetic disorder of polygenic/multifactorial inheritance and outline selected strategies for identifying the number and location of causative genes. It shall also illustrate our approach to testing the hypothesis that endometriosis bears similarity to neoplasia and, hence, is a multistep phenomenon of clonal origin.

DNA↗
PubMedDate not supplied

Somatic DNA alterations in endometriosis: high frequency of chromosome 17 and p53 loss in late-stage endometriosis.

PROBLEM: Genetic predisposition to endometriosis is well established, but the gene(s) involved largely remain unknown. Although endometriosis is considered a benign disease, it displays several features similar to malignancy: altered morphology, disregulated growth, invasion. We hypothesize endometriosis arises as result of somatic DNA alterations occurring in a multi-step process, analogous to origin of neoplasia. Since chromosome 17 and TP53 tumor suppressor gene (TSG) alterations occur frequently in premalignant and malignant tissues, including endometrial and ovarian epithelial carcinomas, we sought to determine if similar somatic changes occur in late stage endometriosis. METHOD OF STUDY: To determine the frequencies of monosomy for chromosome 17, as well as for perturbations of p53 and other loci on 17, two different approaches were used. Fluorescent in situ hybridization (FISH) analysis was used to detect monosomy for the 17 centromere and for the p53 locus. For FISH, archival tissue (n=6) and fresh endometriotic touch preparations were prepared from women (n=8) undergoing extirpation of advanced stage endometriosis. Direct-labeled probes specific for p53 (17p13.1) and for the chromosome 17 alpha-satellite centromere region (1711.1-q11.1) were used to compare single glandular and stromal cells from endometriosis and normal tissue. DNA analysis of polymorphic DNA loci were used to detect loss of heterozygosity (LoH) for other loci on 17. We assessed matched endometriotic and normal DNA (peripheral blood) from women with severe/late stage disease (n=15), studying these dinucleotide markers: HGH (located on 17q22-24), D17S250 (17q11.2-q12) and CHRNB1 (17p13.1). RESULTS: Loss of the chromosome 17 centromere (monosomy) was shown by FISH in some cells from all 14 endometriosis specimens, although in no case did every cell show monosomy 17. In 12 of 14 specimens, significant proportions of cells not only were monosomic for the chromosome 17-centromere (8 to 42% of cells) but also showed loss of p53 locus. In the two remaining cases, p53 loss alone was observed in 8 and 14%. LoH for other alleles on chromosome 17 was observed less often, namely only 3 of 15 specimens for HGH, 1 of 15 for D17S250, and 0 of 15 for CHRNB1. CONCLUSIONS: Our study indicates that perturbations of chromosome 17 in general and the p53 locus in particular occur frequently in severe/late stage endometriosis. That not all cells show loss of whole chromosome 17 or the p53 locus suggests somatic mutation, perhaps occurring late in the pathogenesis of endometriosis. Clonal evolution of endometriosis must depend not only on somatic mutations for p53 but also on other oncogenes or TSG. Alternatively, the clone could begin with a germline or somatic mutation involving a nonneoplastic process, followed by one or more somatic mutations involving an oncogene or TSG like p53. Additional candidate genes clearly must be evaluated in order to determine the precise role chromosome 17 and p53 alterations play in endometriosis; however, additional genes seem unlikely to involve region connoted by HGH, D17S250 or CHRNB1.

Chromosomes, Human, Pair 17↗
PubMedDate not supplied

Detecting fetal DNA from dried maternal blood spots: another step towards broad scale non-invasive prenatal genetic screening and feasible testing.

Both intact fetal cells and cell-free fetal DNA are present in the maternal circulation and have been used for non-invasive prenatal genetic diagnosis. However, broad clinical application awaits development of robust methods for collecting, transporting and enriching maternal blood samples to recover rare fetal cells. To circumvent this impediment, we have devised a reliable method of fetal DNA detection using dried maternal blood spots and real-time polymerase chain reaction. Fetal Y-specific (DYS1) sequences were detected in all 19 (100%) maternal blood specimens from women carrying male fetuses, in genome equivalents of 4.20-24.68 per ml of blood; the ubiquitous glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene, reflecting both maternal and fetal DNA, concurrently showed 43,684 to 680,357 genome equivalents per ml of blood. The results demonstrate that fetal DNA detection using dried maternal blood spots is highly feasible and easily adaptable for population screening.

Adult↗
PubMedDate not supplied

Cell-free fetal DNA and intact fetal cells in maternal blood circulation: implications for first and second trimester non-invasive prenatal diagnosis.

Both intact fetal cells as well as cell-free fetal DNA are present in the maternal circulation and can be recovered for non-invasive prenatal genetic diagnosis. Although methods for enrichment and isolation of rare intact fetal cells have been challenging, diagnosis of fetal chromosomal aneuploidy including trisomy 21 in first- and second-trimester pregnancies has been achieved with a 50-75% detection rate. Similarly, cell-free fetal DNA can be reliably recovered from maternal plasma and assessed by quantitative PCR to detect fetal trisomy 21 and paternally derived single gene mutations. Real-time PCR assays are robust in detecting low-level fetal DNA concentrations, with sensitivity of approximately 95-100% and specificity near 100%. Comparing intact fetal cell versus cell-free fetal DNA methods for non-invasive prenatal screening for fetal chromosomal aneuploidy reveals that the latter is at least four times more sensitive. These preliminary results do not support a relationship between frequency of intact fetal cells and concentration of cell-free fetal DNA. The above results imply that the concentration of fetal DNA in maternal plasma may not be dependent on circulating intact fetal cells but rather be a product of growth and cellular turnover during embryonic or fetal development.

Aneuploidy↗
PubMedDate not supplied

Klinefelter syndrome: expanding the phenotype and identifying new research directions.

PURPOSE: The purpose of this study is to summarize new data on etiology and clinical features of Klinefelter syndrome in order to derive research priorities. METHODS: This study was conducted using critical reviews of selective topics, emphasizing less well-recognized clinical findings. RESULTS AND CONCLUSIONS: The phenotype of the prototypic 47,XXY case is well recognized: seminiferous tubule dysgenesis and androgen deficiency. Less well appreciated is the varied expressivity of 47,XXY Klinefelter syndrome, in particular neurological/cognitive perturbations like language and behavioral problems. Effective therapies are available. Reproductive technologies allow 47,XXY men to sire offspring through intracytoplasmic sperm injection (ICSI); however, genetic counseling is complex and success is low. Behavioral and expressive language difficulties are amenable to treatment by androgen therapy and psychological help. Early treatment may be imperative for optimal outcome.

Biomedical Research↗
PubMedDate not supplied

Evaluation of a culture system for enrichment of CD34+ hematopoietic progenitor cells present in maternal blood.

BACKGROUND: Clonogenic expansion of fetal cells in maternal blood is one approach to overcome the very low number of target cells available for prenatal genetic analysis. However, efficient methods of enrichment, culturing conditions and subsequent analysis of fetal cells are lacking. Optimization of this technique requires more detailed evaluation of the composition and distribution of fetal cells that cross the placenta into the maternal circulation. Previous studies by others have shown that fetal blood is rich in CD34+ progenitor cells capable of expansion in cultures supplemented with hematopoeitic growth factors. Moreover, CD34+ fetal cells have been recovered from maternal blood following enrichment. OBJECTIVE: In this study, we examine the type and frequency of hematopoietic progenitor cells detected in maternal (n = 13) and non-pregnant control (n = 4) peripheral blood specimens. METHODS: A methylcellulose-based culture system was used to perform colony assays on CD34+-enriched or non-enriched cells. Overall, a total of 2,249 colonies were scored for colony type among the 17 samples. To determine whether fetal cells were present and expanded, all colonies present in each of the 10 confirmed male-cases (n = 1,525 colonies) were examined either by PCR or FISH. RESULTS: With CD34+-enriched maternal samples, we observed a significantly higher number of burst-forming unit-erythroid (BFU-E) and a reduced number of colony-forming unit-granulocyte, macrophage (CFU-GM) colonies compared to the non-enriched samples. Of 1,067 colonies analyzed by PCR for the amelogenin locus on X and Y, none were found positive for the 250-bp Y-specific sequences. Of 458 colonies tested by FISH for presence of X and Y probe signals, no XY-male cells were detected. CONCLUSION: We conclude that hematopoiesis is enhanced during pregnancy, but the number of fetal progenitor cells is either very low or fail to expand using the enrichment techniques and culturing conditions described in this study. Further development of methods is warranted before considering this approach for prenatal diagnosis.

Antigens, CD34↗