Women's attitudes towards disclosure of genetic information in pregnancy with varying levels of penetrance.

BACKGROUND: Chromosomal-microarray-analysis (CMA) may reveal susceptibility-loci (SL) of varied penetrance for autism-spectrum-disorder (ASD) and other neurodevelopmental conditions. Attitudes of women/parents to disclosure of SL during pregnancy are understudied. METHODS: A multiple-choice questionnaire was distributed to postpartum women. Data were collected on women's interest to receive prenatal genetic information with various levels of penetrance. RESULTS: Women's (n = 941) disclosure choices were dependent on the magnitude of risk: approximately 70% supported disclosure of either full or 40% penetrance, 53% supported disclosure at a 20% risk threshold, and 40% supported disclosure at 10% or less. Although most women supported, rejected or were indecisive about disclosure consistently across all risk levels, nearly one-quarter (24%) varied their responses based on penetrance, and this was associated with religiosity, education, parity and concern about fetal health (p-values <0.04). Among those who varied their choices, the risk threshold was lower among secular women (20%) than among ultraorthodox women (40%). In a multivariable analysis, ultraorthodox women were much less likely to vary their choices on ASD disclosure compared with secular women (aOR = 0.37, p < 0.001). CONCLUSION: Women's attitudes toward disclosure are influenced by the level of risk and their individual characteristics. We therefore encourage engaging women/couples in disclosure decisions regarding uncertain and probabilistic results from prenatal genomic tests.

Receiving uncertain results from prenatal chromosomal microarray analysis: Women's decisions on continuation or termination of pregnancy.

BACKGROUND: Chromosomal microarray analysis (CMA) may detect variants of uncertain clinical significance (VUS) and susceptibility loci (SL) with incomplete penetrance for neurodevelopmental disorders. This qualitative study provides empirical data on women's experiences with receiving such findings in pregnancy and their decisions regarding continuation or termination of the pregnancy. METHODS: Semi-structured interviews were conducted with women who received a VUS and/or SL from prenatal CMA in the last 2-4 years and were analyzed using Grounded Theory. RESULTS: The vast majority of women recalled being stressed by the findings. All women sought further advice and information to be able to decide whether to continue or terminate their pregnancy. The three pregnancies that were terminated have in common a de novo SL with a 10%-20% penetrance. Similar reasoning (coping with uncertainty, the quest for a perfect child, and a chance for recurrence in future pregnancies) led different women to contradicting conclusions regarding their pregnancies. All women felt satisfied with their decisions. CONCLUSION: Although uncertain/probabilistic information commonly involves a psychological burden, it may also be perceived as valuable and actionable. Pre-test parental choice regarding the disclosure of such information could allow personalized utilization of advanced genomic tests in pregnancy.

Postpartum women's attitudes to disclosure of adult-onset conditions in pregnancy.

BACKGROUND: Advanced prenatal genomic technologies can identify risks for adult-onset (AO) conditions in the fetus, challenging the traditional purpose of prenatal testing. Professional guidelines commonly support disclosure of high-penetrance AO actionable conditions, yet attitudes of women/parents to these findings and factors affecting their attitudes are understudied. METHODS: We explored 941 (77% response rate) postpartum women's attitudes towards receiving prenatal genetic information, and associations of sociodemographic, medical and psychological characteristics with their choices, focusing on AO conditions. RESULTS: Women largely support the disclosure of actionable AO findings (58.4%), in line with professional guidelines. A third of the women also supported the disclosure of non-actionable AO conditions. Stronger religious observance (p < 0.001) and higher psychological distress (p = 0.024) were associated with decreased interest in receiving actionable AO conditions, whereas higher concern for fetal health yielded increased interest (p = 0.032). Attitudes towards disclosure were strongly associated with women's perceived benefit of such information for their own, partner's, and future child's health. Termination of pregnancy based on such information received very little support. CONCLUSION: In-light of the demonstrated understanding of nuanced genetic information and the observed diversity in attitudes, a culturally competent opt-in/out policy could be considered. If full-disclosure is practiced, support should be provided to those expressing higher levels of distress.

Modified allelic replication in lymphocytes of patients with neurofibromatosis type 1.

Transcription activity of genes is related to their replication timing, accordingly gene activation is coupled with a shift from late replication to early replication and vice versa. The relationship between replication timing and gene expression is best manifested by monoallelically expressed genes which show an asynchronous pattern of allelic replication, with the active allele replicating earlier than the inactive counterpart. Biallelically expressed genes, which normally replicate highly synchronously, when present in lymphocytes derived from patients with various types of malignancies or premalignancies, replicate highly asynchronously, similar to monoallelically expressed genes. Since neurofibromatosis-type 1 (NF1) patients are at an increased risk to develop malignancies, we used the fluorescence in situ hybridization (FISH) replication assay and evaluated the level of replication synchrony of three cancer-implicated genes (RB1, AML1, and CMYC) in lymphocytes derived from patients with NF1 without malignancy. Each gene, which normally displayed synchrony in allelic replication, in the patients' cells displayed loss of synchrony. The loss of replication synchrony, of each gene, in the patients' cells was achieved by an advanced replication of a single allele, which replicated remarkably earlier than its normal scheduled timing. In addition, the second allele showed slightly earlier replication timing than that normal for the gene. Thus, it is assumed that the NF1 condition is associated with activation of cancer-implicated genes that may be the cause for increased risk of patients to develop malignancies. As loss of synchrony in allelic replication timing differentiates well between NF1 patients and control subjects, this marker may have a potential use for identification of presymptomatic carriers of NF1 disorders.

Sporadic aneuploidy in PHA-stimulated lymphocytes of Turner's syndrome patients.

In line with the view that aneuploidy destabilizes the karyotype, initiating an autocatalytic process that gives rise to further loss and/or gain of chromosomes, we examined whether a constitutional aneuploidy such as monosomy for one chromosome is associated with sporadic loss and/or gain of other chromosomes. We used PHA-stimulated lymphocytes from eight women with Turner's syndrome (six displayed X chromosome monosomy ranging from 60.2% to 97.9%, and two were below 10%), and eight healthy women who served as a control group. Fluorescence in-situ hybridization (FISH), applied at interphase, was used to evaluate the level of aneuploidy for three randomly selected chromosomes (autosomes 8, 15 and 18) in each sample. For each tested chromosome, our results showed a significantly higher level of aneuploid cells in the samples from patients than in those from controls (p < 0.01). The mean level of aneuploid cells for all three tested autosomes was almost twice as high in the patient samples as in the control samples (p < 0.002). It is noteworthy that, in the Turner's syndrome patients, X chromosome disomic cells also displayed increased levels of aneuploidy. It is possible that monosomy of X chromosome in female cells destabilizes their own genome and also affects X disomic cells in the region. One may also speculate that a common factor(s) is involved with both constitutional and sporadic aneuploidy.

A founder COL17A1 splice site mutation leading to generalized atrophic benign epidermolysis bullosa in an extended inbred Palestinian family from Israel.

PURPOSE: Generalized atrophic benign epidermolysis bullosa is a nonlethal form of junctional EB with an autosomal recessive inheritance. There is generalized cutaneous blister formation at sites of trauma, atrophic alopecia affecting scalp, eyelash and eyebrow, dystrophic nail changes, and tooth abnormalities. In this study, we have studied a five-generation Palestinian family affected with generalized atrophic benign epidermolysis bullosa. METHODS: We have performed linkage analysis to genes that are mutated in generalized atrophic benign epidermolysis bullosa, followed by direct sequencing of patient genomic DNA. RESULTS: We have shown that the disease is caused by a newly detected homozygous donor splice site mutation, IVS51+1G>A, in the type XVII collagen gene, COL17A1. CONCLUSION: The effect of a founder mutation introduced 3 to 4 generations before a disease appearance is demonstrated in this inbred family.