Cécile Skrzynia

Genetic Cancer Risk Assessment and Counseling: Recommendations of the National Society of Genetic Counselors

These cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Cancer Genetic Counseling Special Interest Group. The information contained in this document is derived from extensivereview of the current literature on cancer genetic risk assessment and counseling as well as the personal expertise of genetic counselors specializing in cancer genetics. The recommendations are intended to provid information about the process of genetic counseling and risk assessment for hereditary cancer disorders rather than specific information about individual syndromes. Key components include the intake (medical and family histories), psychosocial assessment (assessment of risk perception), cancer risk assessment (determination and communication of risk), molecular testing for hereditary cancer syndromes (regulations, informed consent, and counseling process), and follow-up considerations. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. These recommendations do not displace a health care providers professional judgment based on the clinical circumstances of a client.

Essential Elements of Genetic Cancer Risk Assessment, Counseling, and Testing: Updated Recommendations of the National Society of Genetic Counselors

Updated from their original publication in 2004, these cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of counseling at-risk individuals through genetic cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Familial Cancer Risk Counseling Special Interest Group. The information contained in this document is derived from extensive review of the current literature on cancer genetic risk assessment and counseling as well as the personal expertise of genetic counselors specializing in cancer genetics. The recommendations are intended to provide information about the process of genetic counseling and risk assessment for hereditary cancer disorders rather than specific information about individual syndromes. Essential components include the intake, cancer risk assessment, genetic testing for an inherited cancer syndrome, informed consent, disclosure of genetic test results, and psychosocial assessment. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. These recommendations do not displace a health care provider’s professional judgment based on the clinical circumstances of a client.

The new genetics and its consequences for family, kinship, medicine and medical genetics.

In the past several decades there has been an explosion in our understanding of genetics. The new genetics is an integral part of contemporary biomedicine and promises great advances in alleviating disease, prolonging human life and leading us unto the medicine of the future. The aim of this paper is to explore the ways in which people make sense of the uncertainties that are associated with the new genetics, which by definition involve family and kinship relations. We explore the degree to which medical genetics places the patient in a double bind between the qualitative certainty and quantitative uncertainty of genetic inheritance that reinforce notions both of fear, and control of a persons future health. Second, we propose that the new genetics has medicalized family and kinship creating profound ethical and practical dilemmas for both the individual and for medicine as a whole.

An Alu-mediated 7.1 kb deletion of BRCA1 exons 8 and 9 in breast and ovarian cancer families that results in alternative splicing of exon 10.

Constitutive large deletions and duplications of BRCA1 resulting from Alu‐mediated recombination account for a significant proportion of disease‐causing mutations in breast and/or ovarian cancer families. Using Southern blot analysis and a protein truncation test (PTT), we have identified a 7.1 kb germline deletion in two families with breast and ovarian cancer. This deletion, which includes exons 8 and 9 and leads to a frameshift at the mRNA level, appears to result from homologous recombination between closely related Alu repeats, one in intron 7 and one in intron 9. In addition to the transcript without exons 8 and 9, analysis of RNA by protein truncation test from individuals with the deletion also identified the presence of alternative splicing of exon 10 from the mutant allele, which results in a transcript that lacks exons 8, 9, and 10. Of interest is that the two American families who carry this deletion are of northern European ancestry and share a common haplotype, suggesting that this deletion may represent a founder mutation. Genes Chromosomes Cancer 28:300–307, 2000.

Targeted transformation in Coprinus cinereus.

SummaryWe examined the influence of DNA form and size on the arrangement and genomic location of transforming DNA sequences in the basidiomycete Coprinus cinereus. Protoplasts with either single or double mutations in the tryptophan synthetase (TRPI) gene were transformed with cloned copies of this gene which contained only a single DNA strand, contained a specific single nick within the C. cinereus sequences (4.8 kb), contained a specific double-strand break, or contained an additional 35 kb of flanking genomic sequences. Gene replacement events were recovered when each DNA type was used. However, none of these substrates offers a substantial improvement in transformation or targeting frequency when compared to supercoiled circular DNA, which has allowed recovery of both gene replacements as well as homologous insertions in 5 % of the transformants analyzed. The frequency of transformants carrying tandem insertions with multiple copies of the transforming DNA was reduced when single-stranded DNA was used, and increased when DNA containing double-strand breaks was used. These results have important implications for the efficient design of targeted transformation and co-transformation experiments.

Increased Uptake of BRCA1/2 Genetic Testing Among African American Women With a Recent Diagnosis of Breast Cancer

PURPOSE Studies suggest that African American women are less likely to pursue BRCA1/2 genetic testing than white women. However, such studies are often confounded by unequal access to care. METHODS Data from 132 African American and 636 white women, obtained from a clinical database at the University of North Carolina (Chapel Hill, NC) between 1998 and 2005, were analyzed to assess BRCA1/2 genetic testing uptake. Importantly, the clinical setting minimized barriers of both cost and access. Race and time of new breast cancer diagnosis (recent v > 1 year before genetic evaluation) were assessed for association with BRCA1/2 testing uptake using multivariable logistic regression models. RESULTS Both race (P = .0082) and a recent diagnosis of breast cancer (P = .014) were independently associated with testing uptake. African American women had a lower estimated odds of pursuing testing than white women (odds ratio [OR], 0.54; 95%CI, 0.34 to 0.85), and women with a recent diagnosis had a higher OR than those with a remote diagnosis (OR, 1.58; 95% CI, 1.10 to 2.29). In a race-stratified analysis, there was no statistical evidence for association between recent status and testing uptake in the larger white stratum (OR, 1.38, P = .13) while there was for the smaller African American sample (OR, 2.77, P = .018). The test of interaction between race and remote status was not significant (P = .15). CONCLUSION African American race was associated with an overall decreased uptake of BRCA1/2 genetic testing, even when barriers of ascertainment and cost were minimized. However, among African American women, a recent diagnosis of breast cancer was associated with substantially increased uptake of testing.

Genetics and the young woman with breast cancer

While many individual risk factors have been defined for breast cancer, a family history was recognized long ago as one of the most potent. Mutations within BRCA1 or BRCA2, both identified about 10 years ago, are responsible for the majority of inherited breast cancer. By virtue of her age alone, a young woman diagnosed with breast cancer has a greatly elevated probability to carry a BRCA mutation. Other risk factors, including a personal or family history of ovarian cancer, bilateral breast cancer or Jewish ancestry, only serve to increase that chance. It is critical that clinicians caring for a young woman understand their patients elevated risk to carry such a mutation and thoughtfully investigate this risk. Upon identification of a mutation in a young woman there are many consequences which necessitate careful consideration of various treatment and preventative options including prophylactic mastectomy and oophorectomy. Finally, the diagnosis of breast cancer in a young woman and the attendant genetic implications have immediate and serious consequences for her family members. Genetic professionals can help navigate the complex technical and psychosocial issues. This chapter explores the molecular, clinical and ethical intricacies of BRCA genetic testing.

A semiquantitative metric for evaluating clinical actionability of incidental or secondary findings from genome-scale sequencing.

Purpose:As genome-scale sequencing is increasingly applied in clinical scenarios, a wide variety of genomic findings will be discovered as secondary or incidental findings, and there is debate about how they should be handled. The clinical actionability of such findings varies, necessitating standardized frameworks for a priori decision making about their analysis.Methods:We established a semiquantitative metric to assess five elements of actionability: severity and likelihood of the disease outcome, efficacy and burden of intervention, and knowledge base, with a total score from 0 to 15.Results:The semiquantitative metric was applied to a list of putative actionable conditions, the list of genes recommended by the American College of Medical Genetics and Genomics (ACMG) for return when deleterious variants are discovered as secondary/incidental findings, and a random sample of 1,000 genes. Scores from the list of putative actionable conditions (median = 12) and the ACMG list (median = 11) were both statistically different than the randomly selected genes (median = 7) (P < 0.0001, two-tailed Mann-Whitney test).Conclusion:Gene–disease pairs having a score of 11 or higher represent the top quintile of actionability. The semiquantitative metric effectively assesses clinical actionability, promotes transparency, and may facilitate assessments of clinical actionability by various groups and in diverse contexts.Genet Med 18 5, 467–475.

Whole Exome Sequencing Identifies Truncating Variants in Nuclear Envelope Genes in Patients with Cardiovascular Disease

Background— The genetic variation underlying many heritable forms of cardiovascular disease is incompletely understood, even in patients with strong family history or early age at onset. Methods and Results— We used whole exome sequencing to detect pathogenic variants in 55 patients with suspected monogenic forms of cardiovascular disease. Diagnostic analysis of established disease genes identified pathogenic variants in 21.8% of cases and variants of uncertain significance in 34.5% of cases. Three patients harbored heterozygous nonsense or splice-site variants in the nucleoporin genes NUP37, NUP43, and NUP188, which have not been implicated previously in cardiac disease. We also identified a heterozygous splice site variant in the nuclear envelope gene SYNE1 in a child with severe dilated cardiomyopathy that underwent transplant, as well as in his affected father. To confirm a cardiovascular role for these candidate genes in vivo, we used morpholinos to reduce SYNE1, NUP37, and NUP43 gene expression in zebrafish. Morphant embryos displayed cardiac abnormalities, including pericardial edema and heart failure. Furthermore, lymphoblasts from the patient carrying a SYNE1 splice-site variant displayed changes in nuclear morphology and protein localization that are consistent with disruption of the nuclear envelope. Conclusions— These data expand the repertoire of pathogenic variants associated with cardiovascular disease and validate the diagnostic and research use of whole exome sequencing. We identify NUP37, NUP43, and NUP188 as novel candidate genes for cardiovascular disease, and suggest that dysfunction of the nuclear envelope may be an under-recognized component of inherited cardiac disease in some cases.

Genetics and Heart Failure: A Concise Guide for the Clinician

The pathogenesis of heart failure involves a complex interaction between genetic and environmental factors. Genetic factors may influence the susceptibility to the underlying etiology of heart failure, the rapidity of disease progression, or the response to pharmacologic therapy. The genetic contribution to heart failure is relatively minor in most multifactorial cases, but more direct and profound in the case of familial dilated cardiomyopathy. Early studies of genetic risk for heart failure focused on polymorphisms in genes integral to the adrenergic and renin-angiotensin-aldosterone system. Some of these variants were found to increase the risk of developing heart failure, and others appeared to affect the therapeutic response to neurohormonal antagonists. Regardless, each variant individually confers a relatively modest increase in risk and likely requires complex interaction with other variants and the environment for heart failure to develop. Dilated cardiomyopathy frequently leads to heart failure, and a genetic etiology increasingly has been recognized in cases previously considered to be “idiopathic”. Up to 50% of dilated cardiomyopathy cases without other cause likely are due to a heritable genetic mutation. Such mutations typically are found in genes encoding sarcomeric proteins and are inherited in an autosomal dominant fashion. In recent years, rapid advances in sequencing technology have improved our ability to diagnose familial dilated cardiomyopathy and those diagnostic tests are available widely. Optimal care for the expanding population of patients with heritable heart failure involves counselors and physicians with specialized training in genetics, but numerous online genetics resources are available to practicing clinicians.