Preimplantation genetic haplotyping a new application for diagnosis of translocation carrier's embryos- preliminary observations of two robertsonian translocation carrier families.

PURPOSE: Preimplantation genetic diagnosis using fluorescence in-situ hybridization (PGD-FISH) is currently the most common reproductive solution for translocation carriers. However, this technique usually does not differentiate between embryos carrying the balanced form of the translocation and those carrying the homologous normal chromosomes. We developed a new application of preimplantation genetic haplotyping (PGH) that can identify and distinguish between all forms of the translocation status in cleavage stage embryos prior to implantation. METHODS: Polymorphic markers were used to identify and differentiate between the alleles that carry the translocation and those that are the normal homologous chromosomes. RESULTS: Embryos from two families of robertsonian translocation carriers were successfully analyzed using polymorphic markers haplotyping. CONCLUSIONS: Our preliminary results indicate that the PGH is capable of distinguishing between normal, balanced and unbalanced translocation carrier embryos. This method will improve PGD and will enable translocation carriers to avoid transmission of the translocation and the associated medical complications to offspring.

Patients' information needs and decision-making processes: what can be learned from genetic counselees?

This field study investigated the information needs and decision-making strategies of 161 genetic counselees interviewed just prior to counseling. Patients were interested mostly in information about the outcomes and consequences of the alternative options at their disposal and about measures to defuse the risks. They wanted mainly information stated with certainty and were less interested in probability information. There was no difference in the search for information between the alternative eventually chosen and the one not chosen. There was a difference, however, among types of decisions and the interest in the various categories of information. These findings were interpreted within the theoretical model of decision making in natural risky situations (O. Huber, 1997). Practical implications for shared medical decision making are presented.

Combined genetic profiles of components and regulators of the vitamin K-dependent gamma-carboxylation system affect individual sensitivity to warfarin.

We examined the influence of combined genotypes on interindividual variability in warfarin dose-response. In 100 anticoagulated patients we quantified the effects of polymorphisms in: CYP2C9, VKORC1, calumenin (CALU), gamma-glutamyl carboxylase (GGCX) and microsomal epoxide hydrolase (EPHX1) on warfarin dose requirements. The G(1542)C VKORC1 polymorphism was associated with decreased warfarin doses in the hetero- and homozygous mutant patients (21% and 50% lower, respectively; p < 0.0001). Warfarin daily dose was predominantly determined by VKORC1 and CYP2C9 genotypes (partial r(2) = 0.21; 0.20, respectively). Together with age and body weight, these two genotypes explained 63% of the dose variance. A single patient, homozygous for G(11)A CALU mutant allele, required an exceptionally high warfarin dose (20 mg/day) and the prevalence of heterozygous (11)A allele carriers in the upper 10(th) dose percentile was significantly higher (0.27 vs. 0.18, p < 0.02). Combined genotype analysis revealed that CYP2C9 andVKORC1 wild type and CALU mutant patients required the highest warfarin doses (7.8 +/- 1.5mg/day; n = 9) as compared to the CYP2C9 and VKORC1 mutant and CALU wild type genotypes (2.8 +/- 0.3 mg/day; n = 18; p < 0.01). The odds ratio for doses <3mg/day was 5.9 (1.9-18.4) for this genotype. Compound genetic profiles comprising VKORC1, CALU and CYP2C9 improve categorization of individual warfarin dose requirements in more than 25% of patients at steady-state anticoagulation.

The facilitating role of information provided in genetic counseling for counselees' decisions.

PURPOSE: To investigate genetic counselees' evaluations of the helpfulness of the information they receive in genetic counseling and of their difficulty in making decisions, and to determine correlates of these two outcomes. METHODS: A field study on 108 counselees seeking genetic counseling aimed at arriving at a reproduction-related decision. Prior to counseling, questionnaires measuring individual differences in factors expected to correlate with outcomes were administered. The objective controllability of the information conveyed in counseling was evaluated by counselors. The outcomes--decision difficulty and information helpfulness--were evaluated one month after counseling in a telephone interview. RESULTS: Information about consequences of options and about possible controlling actions were evaluated as most helpful; whether other information was helpful depended on the type of decision to be made. Decision difficulty was unrelated to counselees' evaluations of the helpfulness of the information. Decision difficulty was also unrelated to individual difference variables, but was related to the objective controllability of the information. CONCLUSION: These findings may help develop guidelines for identifying clients prior to counseling for whom making reproduction-related decisions will be difficult, and for tailoring information that will help such clients reach a decision.

CAG repeat polymorphism within the KCNN3 gene is a significant contributor to susceptibility to anorexia nervosa: a case-control study of female patients and several ethnic groups in the Israeli Jewish population.

The human small-conductance Ca(2+)-activated potassium channel gene KCNN3 has been involved in mechanisms underlying neuronal function and plasticity. A multiallelic CAG repeat polymorphism within the KCNN3 has been associated with schizophrenia and bipolar disorder. We have previously reported in a family-based study that longer CAG repeats are preferentially transmitted to patients with anorexia nervosa (AN). The present study extends the analysis of KCNN3 allele distribution to a larger series of AN female patients and control groups, incorporating information on ethnicity and co-morbidities associated with AN. The data analysis is presented while considering separately the two alleles of each individual, namely a minor (shorter) and a major (longer) allele. This study has found that the KCNN3 allele distribution in the general Israeli population does not differ significantly in at least four Jewish ethnic groups of Ashkenazi, North African, Iraqi, and Yemenite origin. These have been used as control groups in a matched case-control analysis that has demonstrated a significant over-representation of KCNN3 alleles with longer CAG repeats among AN patients (P < 0.001 for the major allele and P = 0.035 for allele sum). Under dichotomization, a significantly higher prevalence of the L allele (>19 repeats) has been observed among AN patients (P < 0.001). While considering AN and co-morbid phenotypes, a tendency towards longer (L) alleles has been observed in the subset of patients with obsessive-compulsive disorder (OCD) co-morbidity. These findings further implicate KCNN3 as a significant contributor to predisposition to AN.