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Three new families are reported for standard gene linkage markers and classical peripheral neurofibromatosis (Von Reckling-hausen disease). Additional data are summarised for the exclusion map. One family gives slight evidence of close linkage with the Gc locus on chromosome 4, raising again the question of possible genetic heterogeneity in NF. [ABSTRACT FROM PUBLISHER]

Objective: To characterize the association between antepartum marijuana exposure and maternal and neonatal outcomes at our institution., Study Design: Retrospective chart review identified an obstetric cohort of singleton gestations. Women with self-reported marijuana use were compared with non-users. Demographic characteristics, risk factors, and maternal-fetal outcomes were evaluated. Associations between outcomes and marijuana use were assessed with regression analysis., Results: Of 2792 deliveries, 5.4% reported marijuana use. Compared to non-users, marijuana users entered prenatal care later, were younger, non-Hispanic, and used other illicit substances. Marijuana users had a higher rate of cesarean delivery (p = 0.01). After adjusting for confounders, marijuana use remained associated with 4.1-fold risk of delivering a small for gestational age (SGA) infant and 2.89-fold risk of neonatal oxygen use., Conclusion: At a safety net hospital, antepartum marijuana use is significantly associated with cesarean delivery, SGA and supplemental oxygen use at birth. Healthcare disparities associated with marijuana use make this a population of critical interest., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier B.V.)

Purpose: To determine if oocyte denudation and ICSI at 36.5 versus 39 h post HCG and/or Lupron trigger (2.5 h versus 5 h post-oocyte retrieval) influences fertilization and blastulation rates in good prognosis couples METHODS: We performed a prospective, randomized controlled trial of 12 patients undergoing IVF with ICSI at an academic fertility center, resulting in 206 MII oocytes analyzed. At time of retrieval, patients with more than 10 oocytes retrieved had their oocytes randomized into two groups-one group for oocyte denudation and ICSI at 36.5 h post HCG and/or Lupron trigger and the other group for these procedures at 39 h post HCG and/or Lupron trigger (2.5 and 5 h after oocyte retrieval). Primary outcomes were fertilization and blastulation rates., Results: No difference was observed in fertilization rate, total blastulation rate, or day of blastulation based on timing of denudation and ICSI (all p > 0.05). Multiple regression analyses for fertilization and blastulation controlling for age and BMI revealed no difference in fertilization based on time of ICSI (p = 0.38, 0.71, respectively). A conditional logistic regression to account for multiple oocytes derived from each patient also found no difference in fertilization or blastulation based on timing of ICSI, even when controlling for age and BMI (p = 0.47, 0.59, respectively)., Conclusion(s): In good prognosis couples, we observed no difference in fertilization or blastulation rates based on timing of ICSI within the currently accepted 2- to 6-h window post-retrieval based on a 34-h trigger. The oocyte appears to have a physiological tolerance for fertilization during this window of time, and variability in the timing of ICSI during this window is unlikely to have an impact on cycle outcome., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Pelvic organ prolapse (POP) affects a significant percentage of women and contributes to major healthcare costs both in the United States and worldwide. This review examines the current understanding of the role of sex steroid hormones (estrogens, androgens, and progesterone) in POP in premenopausal, perimenopausal, and postmenopausal women., Methods: We reviewed the relevant studies on POP related to estrogens, androgens, and progesterone in both animal models and humans., Results: Estrogen has a profound influence on the synthesis and metabolism of pelvic connective tissues, and may have the ability to both prevent POP and improve prognosis if used therapeutically. There is limited research regarding the role of androgens and progesterone and their receptors in POP and results so far have been contradictory, warranting further study to determine whether changes in androgen and progesterone receptor expression are a cause or effect of POP., Conclusions: Because of the role that estrogen plays in maintaining the integrity of pelvic floor connective tissues, we propose that rigorous and well-controlled studies are needed on the role of exogenous estrogen administration as a form of POP prevention. : Video Summary:http://links.lww.com/MENO/A583.

Recent genome-wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified associations with genetic variation at both HLA and non-HLA loci; however, much of heritable HL susceptibility remains unexplained. Here we perform a meta-analysis of three HL GWAS totaling 1,816 cases and 7,877 controls followed by replication in an independent set of 1,281 cases and 3,218 controls to find novel risk loci. We identify a novel variant at 19p13.3 associated with HL (rs1860661; odds ratio (OR)=0.81, 95% confidence interval (95% CI) = 0.76-0.86, P(combined) = 3.5 × 10(-10)), located in intron 2 of TCF3 (also known as E2A), a regulator of B- and T-cell lineage commitment known to be involved in HL pathogenesis. This meta-analysis also notes associations between previously published loci at 2p16, 5q31, 6p31, 8q24 and 10p14 and HL subtypes. We conclude that our data suggest a link between the 19p13.3 locus, including TCF3, and HL risk.

A base substitution in the mouse Dnd1 gene resulting in a truncated Dnd protein has been shown to be responsible for germ cell loss and the development of testicular germ cell tumors (TGCT) in the 129 strain of mice. We investigated the human orthologue of this gene in 263 patients (165 with a family history of TGCT and 98 without) and found a rare heterozygous variant, p. Glu86Ala, in a single case. This variant was not present in control chromosomes (0/4,132). Analysis of the variant in an additional 842 index TGCT cases (269 with a family history of TGCT and 573 without) did not reveal any additional instances. The variant, p. Glu86Ala, is within a known functional domain of DND1 and is highly conserved through evolution. Although the variant may be a rare polymorphism, a change at such a highly conserved residue is characteristic of a disease-causing variant. Whether it is disease-causing or not, mutations in DND1 make, at most, a very small contribution to TGCT susceptibility in adults and adolescents., ((c) 2007 Wiley-Liss, Inc.)

A family history of disease is a strong risk factor for testicular germ cell tumour (TGCT). In order to identify the location of putative TGCT susceptibility gene(s) we conducted a linkage search in 237 pedigrees with two or more cases of TGCT. One hundred and seventy-nine pedigrees were evaluated genome-wide with an average inter-marker distance of 10 cM. An additional 58 pedigrees were used to more intensively investigate several genomic regions of interest. Genetic linkage analysis was performed with the ALLEGRO software using two model-based parametric analyses and a non-parametric analysis. Six genomic regions on chromosomes 2p23, 3p12, 3q26, 12p13-q21, 18q21-q23 and Xq27 showed heterogeneity LOD (HLOD) scores of greater than 1, with a maximum HLOD of 1.94 at 3q26. Genome-wide simulation studies indicate that the observed number of HLOD peaks greater than one does not differ significantly from that expected by chance. A TGCT locus at Xq27 has been previously reported. Of the 237 pedigrees examined in this study, 66 were previously unstudied at Xq27, no evidence for linkage to this region was observed in this new pedigree set. Overall, the results indicate that no single major locus can account for the majority of the familial aggregation of TGCT, and suggests that multiple susceptibility loci with weak effects contribute to the disease.

Testicular germ cell tumor (TGCT) is the most common cancer in young men. Despite a considerable familial component to TGCT risk, no genetic change that confers increased risk has been substantiated to date. The human Y chromosome carries a number of genes specifically involved in male germ cell development, and deletion of the AZFc region at Yq11 is the most common known genetic cause of infertility. Recently, a 1.6-Mb deletion of the Y chromosome that removes part of the AZFc region--known as the "gr/gr" deletion--has been associated with infertility. In epidemiological studies, male infertility has shown an association with TGCT that is out of proportion with what can be explained by tumor effects. Thus, we hypothesized that the gr/gr deletion may be associated with TGCT. Using logistic modeling, we analyzed this deletion in a large series of TGCT cases with and without a family history of TGCT. The gr/gr deletion was present in 3.0% (13/431) of TGCT cases with a family history, 2% (28/1,376) of TGCT cases without a family history, and 1.3% (33/2,599) of unaffected males. Presence of the gr/gr deletion was associated with a twofold increased risk of TGCT (adjusted odds ratio [aOR] 2.1; 95% confidence interval [CI] 1.3-3.6; P = .005) and a threefold increased risk of TGCT among patients with a positive family history (aOR 3.2; 95% CI 1.5-6.7; P = .0027). The gr/gr deletion was more strongly associated with seminoma (aOR 3.0; 95% CI 1.6-5.4; P = .0004) than with nonseminoma TGCT (aOR 1.5; 95% CI 0.72-3.0; P = .29). These data indicate that the Y microdeletion gr/gr is a rare, low-penetrance allele that confers susceptibility to TGCT.

We propose an approach to modelling the joint effects of multiple genes involved in metabolic activation and detoxification of environmental exposures. A physiologically based pharmacokinetic (PBPK) model is used, in which the various person-specific metabolic rates are related to measurements of the genotypes and/or phenotypes at the various stages of the relevant pathways. Markov chain Monte Carlo (MCMC) methods are used to fit the model. We illustrate the approach by application to case-control data on colorectal polyps in relation to consumption of well-done red meat and tobacco smoking via pathways involving heterocyclic amines (regulated by the genes CYP1A2, NAT1 and NAT2) and polycyclic aromatic hydrocarbons (regulated by the genes CYP1A1, EPHX1 (also called mEH) and GSTM3). In this chapter, we focus on the biochemical basis for our conceptual models, deferring detailed mathematical description of the models and simulation results to a separate paper.

We estimated associations between polymorphisms in the gene encoding microsomal epoxide hydrolase (mEH) among 464 cases diagnosed with first occurrence of colorectal adenoma and 510 matched controls. In an analysis controlling only for the matching variables, we found little or no association between adenoma and mEH genotypes defined by polymorphisms at either codon 113 and 139 or mEH activity predicted by both polymorphisms. However, in subsequent analyses, high predicted mEH activity was significantly associated with adenoma among certain subgroups defined by smoking history [odds ratio (OR), 4.27; 95% confidence interval (CI), 1.68-10.81 among current smokers; interaction, P = 0.11], meat consumption (OR, 2.47; CI, 0.99-6.19 among individuals who regularly eat well-done meat; interaction, P = 0.03), and genotypes for the *A/*B polymorphism in the gene encoding glutatione S-transferase M3 (OR, 2.60; CI, 1.28-5.28 among individuals with *A*A genotype; interaction, P = 0.03). These findings are consistent with causal roles for environmental polycyclic aromatic hydrocarbons and genetically encoded variants in enzymes whose actions lead to the production of activated polycyclic aromatic hydrocarbon metabolites.

GAD65 and GAD67, the two forms of GABA-synthesizing enzyme, are usually coexpressed, but their levels are regulated independently. The GAD67 promoter has been described. We have now characterized transcriptional regulatory elements in the 5' flanking region of the GAD65 gene, extending 2.4 kb from the ATG translation initiation site. Primer extension assays revealed that transcription begins at -228 in both adult rat brain and in P19 embryonal carcinoma cells, with additional start sites at -280 in brain and at -360 in P19 cells. These sites are in a GC-rich (72%) region lacking a TATA box. Transient transfection assays revealed that the basal promoter is between -740 and -60, and elements conferring cell-type specificity are further 5'. DNA sequences between -1652 and -1420 can 'silence' transcription from a heterologous promoter. GAD65 and GAD67 promoters share little sequence identity, consistent with differences in their transcriptional regulation.

Recent reports suggest that subjects who are heterozygous for the ataxia-telangiectasia gene are at increased risk of breast cancer. We conducted linkage analyses of 64 families with premenopausal bilateral breast cancer using DRD2, a marker linked to the ataxia-telangiectasia locus at 11q22-23. We assumed a model with dominant transmission of breast cancer. Lod scores summed over all families provided strong evidence against tight linkage (e.g., a lod score of -6.08 at theta = 0.00001), although a single family provides suggestive evidence of tight linkage to DRD2. Evidence against linkage to 11q was strongest among families that may involve the BRCA1 breast cancer susceptibility gene on 17q21. However, we did not observe evidence of linkage to 11q among the remaining subgroup with neither a family history of ovarian cancer nor the appearance of linkage to 17q21.

We report here results of a linkage analysis of a marker in 35 families in which the proband had premenopausal bilateral breast cancer. This group is of particular interest given their high family risk and the question of etiological heterogeneity. Probands were ascertained from cancer registries in Los Angeles County and Connecticut and major hospitals in Montréal and Québec. Assuming no residual heterogeneity and summing lod scores over all families, we obtained strong evidence against tight linkage (e.g., lod score at theta = 0.000001 is -3.39). To address the issue of heterogeneity, we performed admixture and predivided sample analyses. Using an admixture model we were able to reject the hypothesis of no linkage versus that of linkage with homogeneity (P = 0.045). However, we were unable to reject the hypothesis of no linkage versus linkage with heterogeneity (P = 0.119) or to distinguish between linkage with homogeneity and linkage with heterogeneity (P = 0.500). Predivided sample analyses based upon age of onset, pathological characteristics, time between diagnoses of the breast cancers in each bilateral proband, and the span of ages at diagnoses within a family did not discriminate between apparently linked and unlinked families.

We present a Monte Carlo approach to estimation of the recombination fraction theta and the profile likelihood for a dichotomous trait and a single marker gene with 2 alleles. The method is an application of a technique known as 'Gibbs sampling', in which random samples of each of the unknowns (here genotypes, theta and nuisance parameters, including the allele frequencies and the penetrances) are drawn from their posterior distributions, given the data and the current values of all the other unknowns. Upon convergence, the resulting samples derive from the marginal distribution of all the unknowns, given only the data, so that the uncertainty in the specification of the nuisance parameters is reflected in the variance of the posterior distribution of theta. Prior knowledge about the distribution of theta and the nuisance parameters can be incorporated using a Bayesian approach, but adoption of a flat prior for theta and point priors for the nuisance parameters would correspond to the standard likelihood approach. The method is easy to program, runs quickly on a microcomputer, and could be generalized to multiple alleles, multipoint linkage, continuous phenotypes and more complex models of disease etiology. The basic approach is illustrated by application to data on cholesterol levels and an a low-density lipoprotein receptor gene in a single large pedigree.

A human ornithine aminotransferase (OAT) locus has been mapped to the Xp11.2, as has the Norrie disease locus. We used a cDNA probe to investigate a 3-generation UCLA family with Norrie disease; a 4.2-kb RFLP was detected and a maximum lod score of 0.602 at zero recombination fraction was calculated. We used the same probe to study a second multigeneration family with Norrie disease from Utah. A different RFLP of 7.5 kb in size was identified and a recombinational event between the OAT locus represented by this RFLP and the disease loci was observed. Linkage analysis of these two loci in this family revealed a maximum load score of 1.88 at a recombination fraction of 0.10. Although both families have affected members with the same disease, the lod scores are reported separately because the 4.2- and 7.5-kb RFLPs may represent two different loci for the X-linked OAT.

We discuss the effects that a secular trend in incidence would have on estimation of familial relative risk (ratio of observed to expected cumulative incidence among relatives of index cases). For example, when age-specific incidence rates of a condition have increased during the lifetimes of relatives among whom relative risk is to be estimated, familial relative risk will be biased downward if cross-sectional, age-specific incidence data are used to estimate expected cumulative incidence among relatives. The stronger the trend and the older the ages of unaffected relatives, the greater the bias will be. Incorporating different age-specific incidence curves for different birth cohorts into the analysis is an approach we suggest for correcting the bias.

We have identified a family affected with X-linked recessive Norrie disease, in which a recombinational event occurred between the disease locus and the DXS7 locus identified by the probe L1.28. The addition of our family brings the total of published informative families to seven, with a maximum lod score of 7.58 at a recombination frequency of 0.038 +/- 0.036. This finding indicates that the L1.28 probe is useful but may not be completely reliable for prenatal diagnosis and that the gene for Norrie disease is not within the DNA sequence identified by the L1.28 probe.

Previous study has shown that the usual DNA marker for Norrie disease, the L1.28 probe which identifies the DXS7 locus, can recombine with the disease locus. In this study, we used a human ornithine aminotransferase (OAT) cDNA which detects OAT-related DNA sequences mapped to the same region on the X chromosome as that of the L1.28 probe to investigate the family with Norrie disease who exhibited the recombinational event. When genomic DNA from this family was digested with the PvuII restriction endonuclease, we found a restriction fragment length polymorphism (RFLP) of 4.2 kb in size. This fragment was absent in the affected males and cosegregated with the disease locus; we calculated a lod score of 0.602, at theta = 0.00. No deletion could be detected by chromosomal analysis or on Southern blots with other enzymes. These results suggest that one of the OAT-related sequences on the X chromosome may be in close proximity to the Norrie disease locus and represent the first report which indicates that the OAT cDNA may be useful for the identification of carrier status and/or prenatal diagnosis.