An evaluation of needs of female BRCA1 and BRCA2 carriers undergoing genetic counselling

BACKGROUND—The discovery of the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 has improved our ability to counsel women at increased risk of developing breast and ovarian cancer. The objective of our study was to identify the needs of women who have undergone genetic counselling and testing for BRCA1/2 and to determine the impact of receiving a positive BRCA1/2 result. This is the first study to report on a large group of women who have received positive BRCA1/2 mutation results.
METHODS—Questionnaires were distributed to 105 women who had received pre- and post-test genetic counselling for a positive BRCA1/2 result at the University of Toronto or at McGill University in Montreal, Canada between the years of 1994 and 1998. The questionnaire items included patient motivation for seeking genetic services, information needs, screening and prophylactic surgery practices, satisfaction with access to services and support, the desire for a support group, and overall client satisfaction.
RESULTS—Seventy nine female carriers were surveyed. The majority of the respondents (77%) were satisfied with the information they received during the genetic counselling process. Women with a previous diagnosis of cancer indicated that they needed more information relating to cancer treatment compared to women without cancer (p=0.05). Nineteen percent of the women felt they needed more support than was received. Fifty eight percent of the women reported that their screening practices had changed since they received their result. Young women (below the age of 50) and women with no previous diagnosis of cancer were most likely to have changed their screening practices. Nearly two thirds of the respondents said they had considered prophylactic surgery of the breasts or ovaries. Twenty eight percent of the women had prophylactic mastectomy and 54% had undergone prophylactic oophorectomy. Women with an educational level of high school or more were more likely to have undergone prophylactic bilateral mastectomy than those with less education (p=0.07) but were less likely to undergo prophylactic oophorectomy (p=0.0007).
CONCLUSION—These findings have a direct impact on the counselling and risk management of female BRCA mutation carriers. Age, education, and a previous diagnosis of cancer are important determinants in a woman's decision making after receiving positive genetic test results.


Keywords: genetic counselling; BRCA1; BRCA2; cancer genetics     

Clinical studies on submicroscopic subtelomeric rearrangements: a checklist

BACKGROUND—Submicroscopic subtelomeric chromosome defects have been found in 7.4% of children with moderate to severe mental retardation and in 0.5% of children with mild retardation. Effective clinical preselection is essential because of the technical complexities and cost of screening for subtelomere deletions.
METHODS—We studied 29 patients with a known subtelomeric defect and assessed clinical variables concerning birth history, facial dysmorphism, congenital malformations, and family history. Controls were 110 children with mental retardation of unknown aetiology with normal G banded karyotype and no detectable submicroscopic subtelomeric abnormalities.
RESULTS—Prenatal onset of growth retardation was found in 37% compared to 9% of the controls (p<0.0005). A higher percentage of positive family history for mental retardation was reported in the study group than the controls (50% v 21%, p=0.002). Miscarriage(s) were observed in only 8% of the mothers of subtelomeric cases compared to 30% of controls (p=0.028) which was, however, not significant after a Bonferroni correction. Common features (>30%) among subtelomeric deletion cases were microcephaly, short stature, hypertelorism, nasal and ear anomalies, hand anomalies, and cryptorchidism. Two or more facial dysmorphic features were observed in 83% of the subtelomere patients. None of these features was significantly different from the controls. Using the results, a five item checklist was developed which allowed exclusion from further testing in 20% of the mentally retarded children (95% CI 13-28%) in our study without missing any subtelomere cases. As our control group was selected for the "chromosomal phenotype", the specificity of the checklist is likely to be higher in an unselected group of mentally retarded subjects.
CONCLUSIONS—Our results suggest that good indicators for subtelomeric defects are prenatal onset of growth retardation and a positive family history for mental retardation. These clinical criteria, in addition to features suggestive of a chromosomal phenotype, resulted in the development of a five item checklist which will improve the diagnostic pick up rate of subtelomeric defects among mentally retarded subjects.


Keywords: submicroscopic subtelomeric rearrangements; clinical preselection; checklist; chromosome deletion.     

Growth in North American white children with neurofibromatosis 1 (NF1)

OBJECTIVE—To analyse the distributions of and generate growth charts for stature and occipitofrontal circumference (OFC) in neurofibromatosis 1 (NF1) patients.
DESIGN—Cross sectional database survey.
SETTING—The National Neurofibromatosis Foundation International Database (NFDB) includes clinical information on NF1 patients from 14 participating centres in North America.
SUBJECTS—A total of 569 white, North American, NF1 patients, 55% female and 45% male.
MAIN OUTCOME MEASURES—Stature and OFC measurements of NF1 patients were compared to age and sex matched population norms using z score standardisation and centile curves.
RESULTS—The distributions of stature and OFC are shifted and unimodal among NF1 patients; 13% of patients have short stature (2 standard deviations below the population mean) and 24% have macrocephaly (OFC 2 standard deviations above the population mean).
CONCLUSIONS—Alterations of stature and OFC are not limited to NF1 patients with frank short stature or macrocephaly.


Keywords: neurofibromatosis 1; stature; occipitofrontal circumference; macrocephaly     

Frequency of mitochondrial transfer RNA mutations and deletions in 225 patients presenting with respiratory chain deficiencies

OBJECTIVE—To evaluate the frequency of pathogenic mtDNA transfer RNA mutations and deletions in biochemically demonstrable respiratory chain (RC) deficiencies in paediatric and adult patients.
METHODS—We screened for deletions and sequenced mitochondrial transfer RNA genes in skeletal muscle DNA from 225 index patients with clinical symptoms suggestive of a mitochondrial disorder and with biochemically demonstrable RC deficiency in skeletal muscle.
RESULTS—We found pathogenic mitochondrial DNA mutations in 29% of the patients. The detection rate was significantly higher in adults (48%) than in the paediatric group (18%). Only one pathogenic mutation was detected in the neonatal group. In addition, we describe seven novel transfer RNA sequence variations with unknown pathogenic relevance (six homoplasmic and one heteroplasmic) and 13 homoplasmic polymorphisms. One heteroplasmic transfer RNA^Leu(UUR) A>G mutation at position 3274 is associated with a distinct neurological syndrome.
CONCLUSIONS—We provide an estimation of the frequency of mitochondrial transfer RNA mutations and deletions in paediatric and adult patients with respiratory chain deficiencies.


Keywords: mtDNA; tRNA mutations; respiratory chain deficiency     

Mutation analysis of the spastin gene (SPG4) in patients with hereditary spastic paraparesis

BACKGROUND—Hereditary spastic paraparesis is a genetically heterogeneous condition. Recently, mutations in the spastin gene were reported in families linked to the common SPG4 locus on chromosome 2p21-22.
OBJECTIVES—To study a population of patients with hereditary spastic paraparesis for mutations in the spastin gene (SPG4) on chromosome 2p21-22.
METHODS—DNA from 32 patients (12 from families known to be linked to SPG4) was analysed for mutations in the spastin gene by single strand conformational polymorphism analysis and sequencing. All patients were also examined clinically.
RESULTS—Thirteen SPG4 mutations were identified, 11 of which are novel. These mutations include missense, nonsense, frameshift, and splice site mutations, the majority of which affect the AAA cassette. We also describe a nucleotide substitution outside this conserved region which appears to behave as a recessive mutation.
CONCLUSIONS—Recurrent mutations in the spastin gene are uncommon. This reduces the ease of mutation detection as a part of the diagnostic work up of patients with hereditary spastic paraparesis. Our findings have important implications for the presumed function of spastin and schemes for mutation detection in HSP patients.


Keywords: spastin; hereditary spastic paraparesis; mutation; recessive     

Optimism and Self-Esteem Are Related to Sleep. Results from a Large Community-Based Sample

Background

There is evidence that positive personality characteristics, such as optimism and self-esteem, are important for health. Less is known about possible determinants of positive personality characteristics.

Purpose

To test the relationship of optimism and self-esteem with insomnia symptoms and sleep duration.

Method

Sleep parameters, optimism, and self-esteem were assessed by self-report in a community-based sample of 1,805 adults aged between 30 and 84 years in the USA. Moderation of the relation between sleep and positive characteristics by gender and age as well as potential confounding of the association by depressive disorder was tested.

Results

Individuals with insomnia symptoms scored lower on optimism and self-esteem largely independent of age and sex, controlling for symptoms of depression and sleep duration. Short sleep duration (<6 h) was related to lower optimism and self-esteem when compared to individuals sleeping 7–8 h, controlling depressive symptoms. Long sleep duration (>9 h) was also related to low optimism and self-esteem independent of age and sex.

Conclusion

Good and sufficient sleep is associated with positive personality characteristics. This relationship is independent of the association between poor sleep and depression.     

Heterogeneous tissue distribution of a mitochondrial DNA polymorphism in heteroplasmic subjects without mitochondrial disorders

CONTEXT—Several maternally inherited point mutations of the mitochondrial genome cause mitochondrial disorders, but the correlation between genotype and phenotype remains obscure in many cases. The same mutation may cause various diseases, probably because of a different tissue distribution.
OBJECTIVE—To assess the role of random somatic segregation in generating interperson differences by analysis of an apparently neutral polymorphism.
DESIGN—Screening of 81 brain samples from subjects without mitochondrial disorders and selection of five necropsy cases showing a high level of heteroplasmy for the polymorphism.
MAIN OUTCOME MEASURES—A proportion of various distinct genotypes in the mtDNA pool of the tissues, identified by fluorescent PCR products, representing a short polycytosine tract of variable length in the mitochondrial displacement loop.
RESULTS—Differences were found between organs or groups of organs within subjects, pointing towards somatic segregation of mtDNA. In addition, marked differences of this organ distribution occurred between subjects, which cannot be explained by tissue specific selection.
CONCLUSIONS—The observed interperson differences can be explained by somatic segregation, which occurs randomly at various developmental stages. Besides tissue specific selection, this process might participate in the distribution of pathogenic mtDNA mutations.


Keywords: mtDNA; polymorphism; HVR2; heteroplasmy     

A clinical study of 57 children with fetal anticonvulsant syndromes

BACKGROUND—Anticonvulsants taken in pregnancy are associated with an increased risk of malformations and developmental delay in the children. To evaluate the pattern of abnormalities associated with prenatal anticonvulsant exposure further, we undertook a clinical study of 57 children with fetal anticonvulsant syndromes.
METHODS—Fifty two children were ascertained through the Fetal Anticonvulsant Syndrome Association and five were referred to the Aberdeen Medical Genetics Service. Pregnancy and medical history were obtained through a standardised questionnaire and interview and the children were examined.
RESULTS—Thirty four (60%) were exposed in utero to valproate alone, four (7%) to carbamazepine alone, four (7%) to phenytoin alone, and 15 (26%) to more than one anticonvulsant. Forty six (81%) reported behavioural problems, 22 (39%) with hyperactivity or poor concentration of whom four (7%) had a diagnosis of attention deficit and hyperactivity disorder. Thirty four (60%) reported two or more autistic features, of whom four had a diagnosis of autism and two of Asperger's syndrome. Forty four (77%) had learning difficulties, 46 (81%) had speech delay, 34 (60%) had gross motor delay, and 24 (42%) had fine motor delay. Nineteen (33%) had glue ear and 40 (70%) had joint laxity involving all sizes of joints. Of 46 who had formal ophthalmic evaluation, 16 (34%) had myopia.
CONCLUSIONS—Speech delay, joint laxity, glue ear, and myopia are common in the fetal anticonvulsant syndromes and autistic features and hyperactivity form part of the behavioural phenotype.


Keywords: fetal anticonvulsant syndrome; fetal valproate syndrome; teratogen; birth defects     

Evaluation of a counselling protocol for predictive genetic testing for hereditary non-polyposis colorectal cancer

OBJECTIVES—To evaluate the feasibility of a reduced counselling programme for predictive genetic testing for hereditary non-polyposis colorectal cancer (HNPCC) in terms of counsellees' opinions on the extent and significance of genetic counselling and need for psychological support at different phases of the testing procedure.
DESIGN—Prospective follow up study with pre-test questionnaire assessment of background sociodemographic variables. The protocol comprised a pre-test counselling session, a period for reflection, and a test disclosure session. The outcome variables were studied by post-test questionnaires at one month and one year follow up.
SUBJECTS—Two hundred and seventy one high risk members of 36 families with HNPCC who attended both counselling sessions and completed the questionnaires.
RESULTS—The pre-test counselling was considered fairly or very useful by 89% of respondents and one post-test session was considered sufficient by over 80% of respondents at follow up. Fifty three percent would have used extra psychological support had it been offered with the counselling. On enquiry one year after receiving the test result, only 2% stated that the need for support was at its greatest at that time, while the majority (46%) reported that the need for support had been greatest at the moment of test disclosure.
CONCLUSIONS—A protocol that includes one comprehensive pre-test counselling session and a test disclosure session, supplemented with the option of professional psychological support, seems to be sufficient for both the educational and supportive needs of counsellees. Only a minority expressed a need for post-test follow up sessions, which suggests that, in this disorder, resources can be directed to the beneficial surveillance programmes rather than to extensive psychological support.


Keywords: predictive genetic testing; genetic counselling; HNPCC; hereditary non-polyposis colorectal cancer     

Efficacy of a touchscreen computer based family cancer history questionnaire and subsequent cancer risk assessment

OBJECTIVE—A computer based touchscreen family cancer history questionnaire was developed and implemented to facilitate the provision of cancer risk assessments for the ambulatory and outpatient populations of a free standing cancer hospital.
METHODS—A questionnaire consisting of a series of branched point decision making screens was developed which enables the participant to enter demographic data, personal cancer history, and cancer histories for first and second degree relatives. A freestanding touchscreen computer kiosk system was used to place the questionnaire in public areas of the cancer hospital and clinic. Genetic professionals analysed the data received, using published criteria, and provided a basic cancer risk assessment and surveillance recommendations within 10 business days. A survey was completed by a small random group of users (n=59) three to six months after receipt of their risk assessment.
RESULTS—After 11 months, 1440 people had entered information and received a written communication. Only 2% of completed questionnaires contained insufficient information to provide a basic risk assessment. Of the small group of participants surveyed, almost all (95%) felt "very comfortable" using the system, 93% remembered receiving the risk assessment letter when queried three to six months later, 42% felt their perceptions about cancer risk had changed, and 20% had made changes in their or their family's cancer surveillance practices.
CONCLUSION—The touchscreen computer family history questionnaire allows easy collection of family history information, provision of risk assessments to a broad population, and promotes increased awareness of familial risk and appropriate surveillance.


Keywords: genetic counselling; risk assessment; computers; medical informatics