Predictive testing for Huntington's disease has potential benefits for the psychological health of persons who receive results that indicate either an increase or a decrease in the risk of inheriting the gene for the disease.

By January 1, 1991, a total of 388 persons had enrolled in the Canadian collaborative study of predictive testing for Huntington disease (HD). Of these participants, 105 persons have been given a decreased risk result. Contrary to expectations, approximately 10% of persons with a decreased risk result have had psychological difficulties coping with their new status. Here, we describe the individual responses of 6 such persons and experimental themes emerging after following these persons for up to 2 years. Individuals who are more likely to suffer an adverse reaction to a decreased risk result include those persons who have made irreversible decisions based on the belief they would develop HD or those who had unrealistic overoptimistic expectations of the positive effects of a decreased risk result. In contrast to those receiving an increased risk result, the most vulnerable time for persons receiving a decreased risk result is between 2 and 12 months after learning the outcome. The need for assessment and counselling of participants in predictive testing programs, even when there is a decreased risk result, is emphasized.

Chromosome 17p13.3 is a gene rich region that when deleted is associated with the well-known Miller-Dieker syndrome. A recently described duplication syndrome involving this region has been associated with intellectual impairment, autism and occasional brain MRI abnormalities. We report 34 additional patients from 21 families to further delineate the clinical, neurological, behavioral, and brain imaging findings. We found a highly diverse phenotype with inter- and intrafamilial variability, especially in cognitive development. The most specific phenotype occurred in individuals with large duplications that include both the YWHAE and LIS1 genes. These patients had a relatively distinct facial phenotype and frequent structural brain abnormalities involving the corpus callosum, cerebellar vermis and cranial base. Autism spectrum disorders were seen in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes such as CRK. The typical neurobehavioral phenotype was usually seen in those with the larger duplications. We did not confirm the association of early overgrowth with involvement of YWHAE and CRK, or growth failure with duplications of LIS1. Older patients were often overweight. Three variant phenotypes included cleft lip/palate (CLP), split hand/foot with long bone deficiency (SHFLD), and a connective tissue phenotype resembling Marfan syndrome. The duplications in patients with clefts appear to disrupt ABR, while the SHFLD phenotype was associated with duplication of BHLHA9 as noted in two recent reports. The connective tissue phenotype did not have a convincing critical region. Our experience with this large cohort expands knowledge of this diverse duplication syndrome.

Predictive testing for Huntington disease (HD) has been offered in some parts of Canada for nearly 5 years. Candidates who were expected to have a significant likelihood for psychological problems were those who received an increased risk for developing HD. Sixty-six persons have now received such an increased risk result. In this manuscript we describe in detail the experience of 4 such persons who were chosen to illustrate recurrent and common themes which have emerged during counselling, and to highlight the strategies of coping with this information. Themes include difficulties communicating about HD, defensive postures adopted in preparing for testing, ramifications of testing for the whole family, and the impact of being at high risk on the candidates' perception of the future. One candidate has had testing postponed due to active suicidal risk. Only a few candidates have expressed regret at taking the test and no person receiving an increased risk result has made a suicide attempt or required hospitalization. After receiving results, symptoms of depression and anxiety are most common in the first 2 months, but over 1 year, candidates, in general, have less depression but live with a heightened perception of the present. The potential risk of premature diagnosis of HD in an individual with an increased risk results is highlighted. The significant ramifications of testing for the relative are shown. The importance of communication as a means of establishing a social support network, as well as the hazards of open communication, are discussed. Longitudinal evaluation will provide much needed data on the long-term effects of living at increased risk for HD.

The term "duty to recontact" refers to the possible ethical and/or legal obligation of genetics service providers (GSPs) to recontact former patients about advances in research that might be relevant to them. Although currently this practice is not part of standard care, some argue that such an obligation may be established in the future. Little information is available, however, on the implications of this requirement, from the point of view of GSPs. To explore the opinions of genetics professionals on this issue, we sent a self-administered questionnaire to 1,000 randomly selected U.S. and Canadian members of the American Society of Human Genetics. We received 252 completed questionnaires. The major categories of respondents were physician geneticist (41%), Ph.D. geneticist (30%), and genetic counselor (18%); 72% of the total stated that they see patients. Respondents indicated that responsibility for staying in contact should be shared between health professionals and patients. Respondents were divided about whether recontacting patients should be the standard of care: 46% answered yes, 43% answered no, and 11% did not know. Those answering yes included 44% of physician geneticists, 53% of Ph.D. geneticists, and 31% of genetic counselors; answers were statistically independent of position or country of practice but were dependent on whether the respondent sees patients (43% answered yes) or not (54% answered yes). There also was a lack of consensus about the possible benefits and burdens of recontacting patients and about various alternative methods of informing patients about research advances. Analysis of qualitative data suggested that most respondents consider recontacting patients an ethically desirable, but not feasible, goal. Points to consider in the future development of guidelines for practice are presented.

Deletions of the long arm of chromosome 6 are relatively uncommon and to date minimal genotype-phenotype correlations have been observed. We report on three unrelated patients with de novo paternal interstitial deletions of 6q24.3. FISH mapping was used to delineate the minimal region of overlap between these three patients. Although all three patients had different size deletions and different breakpoints, two of the patients shared a 2.5 Mb region of overlap and strikingly similar facial features including a triangular face, frontal bossing with metopic prominence, short and upward-slanting palpebral fissures, asymmetry of upper eyelids, hooded eyelids, shallow orbits, prominent inferior orbital crease, wide mouth, and long and flat philtrum. They also had redundant skin, joint laxity, a small thorax, and early developmental delay. The smallest region of overlap between all three patients was a region of deletion less than 1 Mb; all had a history of IUGR and postnatal short stature without overt radiologic skeletal anomalies. The dysmorphic features, early developmental and growth delay may be due to the hemizygous state for one of the genes in the deleted region of two of the patients or to a long range effect of the deletion on expression of other genes. In addition, since imprinted genes have been reported in this region, paternal deletion of an imprinted gene in all three patients may contribute to the growth phenotype. We propose that this is a new congenital malformation syndrome associated with a paternal deletion of 6q24.3.

The objective of our article is to illustrate the earliest prenatal sonographic diagnosis of femoral-facial syndrome (FFS) and to illustrate the spectrum of clinical manifestations of this condition. We present serial sonographic evaluation with 3D evaluation in two fetuses diagnosed prenatally with FFS and the postnatal findings in three patients (one fetus following pregnancy interruption and two newborns one of whom was diagnosed prenatally) with FFS. The two patients with prenatally diagnosed FFS were found to have femoral shortening and characteristic facial features, one 12 weeks of gestation, and one at 15 weeks of gestation. The sonographic findings in the two prenatally diagnosed patients were confirmed after delivery. We also present a third patient who was diagnosed at delivery in whom the diagnosis was missed at a routine prenatal sonogram at 19 weeks of gestation. The patients reported herein expand the clinical spectrum of FFS. The utility of sonographic evaluation in diagnosis of the facial appearance and of the bony abnormalities in this condition is emphasized.

There is increasing evidence that genetic factors play a role in the etiology of mood disorders. As a result, relatives of affected individuals are more often asking about their own risks to develop a mood disorder. From 1988 to 1990, all consecutive, unrelated inpatients and outpatients (index cases) presenting to the Mood Disorders Service, Department of Psychiatry, University of British Columbia, had detailed family histories taken, thus creating the Mood Disorders Service Genetic Database. Diagnoses for index cases and their first-degree relatives were made according to Research Diagnostic Criteria and Family History Research Diagnostic Criteria respectively. Morbidity risks for mood disorders were calculated for first-degree relatives (parents, siblings, children--aged 10 and above) of all index cases with a diagnosis of single depression, recurrent depression, bipolar I, or bipolar II disorder. Morbidity risks were calculated using the maximum likelihood approach. Morbidity risk data are presented according to the sex and diagnosis for the index case in an easy reference format for risk counselling. The risks are presented twice, including and excluding data for "high-risk" families whose genetic pedigree is suggestive of "autosomal dominant" inheritance.