Sherman Elias

HLA and mate choice in humans.

Evidence from studies in rodents suggests that mate selection is influenced by major-histocompatibility-complex haplotypes, with preferences for dissimilar partners. This study was initiated to determine whether avoidance of a mate with the same HLA haplotype as ones own might be occurring in the Hutterites, a North American reproductive isolate of European ancestry, notable for their large sibships, communal lifestyle, and limited number of five-locus HLA haplotypes (HLA-A, -B, -C, -DR, and -DQ). HLA haplotypes were known for 411 Hutterite couples. The number of couples expected to match for a haplotype was calculated in two ways: first, from population genotype frequencies, with account being taken of the nonrandom mating pattern with respect to colony lineages, and, second, from computer simulations using conservative founder assumptions and the exact genealogy of the 411 couples. We observed fewer matches for HLA haplotypes between spouses than expected (first method, P = .005; second method, P = .020-.067). Among couples who did match for a haplotype, the matched haplotype was inherited from the mother in 29 cases and from the father in 50 cases (P = .018). These results are consistent with the conclusion that Hutterite mate choice is influenced by HLA haplotypes, with an avoidance of spouses with haplotypes that are the same as ones own.

Prenatal diagnosis with fetal cells isolated from maternal blood by multiparameter flow cytometry

A long-sought goal of medical genetics has been development of prenatal diagnostic procedures that do not endanger the conceptus. Reliable and universal screening for cytogenetic disorders would require analysis of fetal cells isolated from the maternal circulation. This would be applicable to all pregnant women, irrespective of their ages or histories. In the current study fetal nucleated erythrocytes were flow sorted on the basis of four parameters: cell size, cell granularity, transferrin receptor, and glycophorin-A cell surface molecule. By polymerase chain reaction with oligonucleotide primers flanking single-copy Y-specific deoxyribonucleic acid sequences, male fetuses were correctly identified among flow-sorted samples in 12 of 12 (100%) pregnancies; female fetuses were correctly identified in 5 of 6 (83%) pregnancies. We also achieved the prenatal diagnosis of fetal aneuploidies by use of flow-sorted nucleated fetal erythrocytes and in situ hybridization with chromosome-specific deoxyribonucleic acid probes: one case of trisomy 21 that was detected in maternal blood taken 1 week after chorionic villus sampling and one case of trisomy 18 that was detected in maternal blood taken immediately before chorionic villus sampling. Although our results are promising, additional data on the background sensitivity and specificity of in situ hybridization in flow-sorted fetal cells will be necessary to minimize subjective interpretation and permit clinical application.

23andMe and the FDA

Because of a warning from the FDA, 23andMe has stopped marketing its personal genome service. Now, a dialogue about key issues in genomic testing could result in clear standards for the industry, including requirements for informed consent and disclosure of results.

The politics of transplantation of human fetal tissue.

Research involving human fetal tissue has been the subject of intense political debate in this country for almost two decades, and the use of fetal tissues in transplantation continues this controv...

Endometrial adenocarcinoma: Genetic analysis suggesting heritable site-specific uterine cancer

UNLABELLED Genetic factors are clearly integral to the etiology of neoplasia. A cancer family syndrome (Lynch syndrome II) consisting of uterine, colon, and ovarian cancer is recognized, but the heritability of isolated endometrial adenocarcinoma has not otherwise been thoroughly investigated. We have performed pedigree studies in index cases with endometrial adenocarcinoma, using spouses as controls. Preliminary results from 64 probands showed four families in which endometrial adenocarcinoma was diagnosed in at least one first-degree relative of the proband (mother, daughter, sister); none showed relatives with colon or ovarian cancer. In none of the 34 control pedigrees did either a mother or sister have endometrial adenocarcinoma. In four other families, multiple first- and second-degree relatives of probands had adenocarcinoma of the uterus, colon, or ovary, presumably representing a cancer family syndrome (Lynch syndrome II). CONCLUSION Our preliminary data not only show familial and probably heritable tendencies for endometrial adenocarcinoma, but further suggest that there are at least two distinct forms: (1) the previously described Lynch syndrome II (cancer family syndrome), and (2) a heretofore unemphasized entity characterized by a tendency to endometrial adenocarcinoma alone.

Rare event selection of fetal nucleated erythrocytes in maternal blood by flow cytometry

A noninvasive method of prenatal genetic diagnosis requires fetal cell selection from the maternal circulation that allows efficient recovery for analysis by fluorescence in situ hybridization (FISH). We have solved several problems that negatively affect the isolation and FISH analysis of fetal nucleated red blood cells (nRBCs) in the maternal circulation. The use of glycophorin A (Gly A) antibodies (Abs) for selection is problematic because all five monoclonal antibodies (mAbs) tested caused agglutination of non-nRBCs, thereby changing both light scatter and fluorescence properties of cells by flow cytometry. Because the number of non-nRBCs is variable after Ficoll separation, isolation of nRBCs could be compromised severely by agglutination of nucleated cells with nonnucleated cells, causing them to shift light scatter and fluorescence properties. Several methods for the removal of unwanted maternal white blood cells with CD45 mAbs were also evaluated. Magnetic bead depletion was found to interfere with FISH detection because of residual bead debris after sorting. By contrast, removal of CD45+ cells by a panning technique eliminated this problem. Positive selection methods based on CD71, CD45, and LDS-751 staining and detection of fetal cells by gamma globin expression were also analyzed. Fetal cells were detected by FISH in 11 of 19 (CD71 selection) and in 13 of 15 (gamma selection) random pregnancies. These data support the possibility of a noninvasive method for isolation and analysis of fetal cells for prenatal diagnosis.

Isolated fetal choroid plexus cysts and trisomy 18: A review and meta-analysis

OBJECTIVE Risk of trisomy 18 in a fetus with ultrasonographic diagnosis of choroid plexus cysts and no other anomalies is controversial. Using our data and current literature, we performed a meta-analysis and estimated the positive predictive value of isolated choroid plexus cysts for trisomy 18. STUDY DESIGN Between Jan. 1, 1989, and Dec. 31, 1992, all women undergoing ultrasonographic examination at our institution were prospectively evaluated for fetal choroid plexus cysts and cytogenetic outcome. In addition, all reports dealing with fetal choroid plexus cysts obtained from MEDLINE (1983 through 1992) were assessed. Only prospective studies with > 10 cases of choroid plexus cysts were further evaluated to determine the total number of fetuses with choroid plexus cysts and otherwise normal sonograms. Frequency of aneuploidy was determined by analysis of our data and the included studies. To estimate the positive predictive value of choroid plexus cysts from trisomy 18, a theoretic 2 x 2 table was constructed with values available from the literature. RESULTS Eighty fetuses with choroid plexus cysts were identified in our unit. Of 74 fetuses with isolated choroid plexus cysts, there were no cases of trisomy 18. Meta-analysis identified 2 cases of trisomy 18 among 748 fetuses with isolated cysts (1/374). To derive a positive predictive value of isolated choroid plexus cysts for trisomy 18, we reviewed the literature and found a total of 50 fetuses with trisomy 18 who underwent ultrasonographic examination in the midtrimester. There were 3 cases of isolated choroid plexus cysts, and 12 of 50 (24%) had otherwise normal ultrasonographic results. Using a midtrimester incidence of 1 in 2461 for trisomy 18 (Hsu LYF. In: Milunsky A, ed. Genetic disorders of the fetus. 3rd ed. Baltimore: Johns Hopkins University Press, 1992: 155-210; Hook et al. Am J Hum Genet 1989; 45:855-61) and a prenatal prevalence of 0.95% for choroid plexus cysts (based on a review of the literature), we obtained a positive predictive value of 1 in 390. CONCLUSION On the basis of the risk for trisomy 18 obtained from our meta-analysis (1/374) and its close approximation to the estimated positive predictive value (1/390), our data do not support the routine offering of invasive prenatal cytogenetic testing in cases of isolated choroid plexus cysts.

Point-counterpoint. Patient autonomy and incidental findings in clinical genomics.

Returning genetic incidental findings without patient consent is misguided. Exome and whole-genome sequencing are rapidly moving into clinical application to aid diagnosis and treatment. However, a startling statement by the American College of Medical Genetics and Genomics (ACMG) may prove to be a stumbling block (1). Rather than reconfirming well-established principles of patient autonomy and informed consent that have long applied in medical genetics and in medical practice more broadly, ACMG recommends an abrupt change.

Increased heterogeneity of chromosome 17 aneuploidy in endometriosis

OBJECTIVE Endometriosis is a complex gynecologic disorder that may display features similar to malignancy, including aggressive growth and localized invasion of the myometrium or spread to various organs outside the uterus. Molecular studies of cancer have demonstrated that genomic instability involving chromosome 17 plays a role in the development and progression of various tumor types. These involve gain and/or loss, deletions, and mutations of candidate tumor suppressor genes (eg, BRCA1 and p53 ) on chromosome 17. STUDY DESIGN We used a 2-color fluorescence in situ hybridization method for analysis of endometriotic and normal archival tissue. Centromere-specific and locus-specific p53 probes localized to chromosome 17 were selected to study 8 patients with late-stage (severe) endometriosis. Single cells localized to endometriotic lesions or normal endometrial glands were analyzed and identified as normal or abnormal on the basis of the distribution of fluorescence in situ hybridization signals. RESULTS Overall, chromosome 17 aneuploidy was significantly greater (P <.05) in the endometriosis specimens (mean of 65%) than in normal endometrial cells (mean of 25%). No significant difference (P =.1071) in the distribution of fluorescence in situ hybridization signals was observed among the 5 normal endometrial specimens. However, significant differences (P <. 0001) were observed between the 8 endometriosis tissue specimens. CONCLUSION We found increased heterogeneity of chromosome 17 aneuploidy in endometriosis. These findings support a multistep pathway involving somatic genetic alterations in the development and progression of this common disease.

Detection of chromosomal aneuploidy in endometriosis by multi-color fluorescence in situ hybridization (FISH)

Abstract Endometriosis affects 10–15% of women of reproductive age and is a common cause of infertility and pelvic pain. Although endometriosis is characterized by abnormal growth or turn-over of cells, the genetic changes involved remain unclear. We employed a multi-color fluorescence in situ hybridization (FISH) strategy to determine the incidence of somatic chromosomal numeric alterations in severe/late stage endometriosis. Using alpha-satellite sequence-specific DNA probes for chromosomes 7, 8, 11, 12, 16, 17, and 18, simultaneous two- and three-color FISH were performed to evaluate the frequency of monosomic, disomic, and trisomic cells in normal control and endometriotic tissue specimens. In one of four endometriosis samples studied, a significantly higher frequency of monosomy for chromosome 17 (14.8%, χ24 = 53.3, P < 0.0001) and 16 (8.8%, χ24 = 11.4, P < 0.05) was observed. An increased number of cells with chromosome 11 trisomy (14.8%, χ24 = 96.2, P < 0.0001) were detected in a second case. In a third case, a distinct colony of nuclei with chromosome 16 monosomy (14.1%, χ24 = 21.39, P < 0.005) was detected. Acquired chromosome-specific aneuploidy may be involved in endometriosis, reflecting clonal expansion of chromosomally abnormal cells. That candidate tumor suppressor genes and oncogenes have been mapped to chromosomes 11, 16, and 17 suggests that chromosomal loss or gain plays a role in the development and/or progression of endometriosis.