Publications by authors named "Cécile Skrzynia"

12 Publications

  • Page 1 of 1

Genetic Complexity of Mitral Valve Prolapse Revealed by Clinical and Genetic Evaluation of a Large Family.

J Heart Valve Dis 2017 09;26(5):569-580

Department of Genetics, University of North Carolina at Chapel Hill, NC, USA.

Background: A genetic component to familial mitral valve prolapse (MVP) has been proposed for decades. Despite this, very few genes have been linked to MVP. Herein is described a four-generation pedigree with numerous individuals affected with severe MVP, some at strikingly young ages.

Methods: A detailed clinical evaluation performed on all affected family members demonstrated a spectrum of MVP morphologies and associated phenotypes.

Results: Linkage analysis failed to identify strong candidate loci, but revealed significant regions, which were investigated further using whole-exome sequencing of one of the severely affected family members. Whole-exome sequencing identified variants in this individual that fell within linkage analysis peak regions, but none was an obvious pathogenic candidate. Follow up segregation analysis of all exome-identified variants was performed to genotype other affected and unaffected individuals in the family, but no variants emerged as clear pathogenic candidates. Two notable variants of uncertain significance in candidate genes were identified: p.I1013S in PTPRJ at 11p11.2 and FLYWCH1 p.R540Q at 16p13.3. Neither gene has been previously linked to MVP in humans, although PTPRJ mutant mice display defects in endocardial cushions, which give rise to the cardiac valves. PTPRJ and FLYWCH1 expression was detected in adult human mitral valve cells, and in-silico analysis of these variants suggests they may be deleterious. However, neither variant segregated completely with all of the affected individuals in the family, particularly when 'affected' was broadly defined.

Conclusions: While a contributory role for PTPRJ and FLYWCH1 in this family cannot be excluded, the study results underscored the difficulties involved in uncovering the genomic contribution to MVP, even in apparently Mendelian families.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676909PMC
September 2017

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

Circ Cardiovasc Genet 2017 Jun;10(3)

From the Department of Pathology, Duke University, Durham, NC (G.T.H.); Division of Cardiology (B.C.J.), McAllister Heart Institute (B.C.J., L.A.S., W.H., J.L.), Department of Cell and Molecular Physiology (L.A.S., W.H., J.L.), Department of Genetics (D.M., C.S., C.T., B.A.S., E.A.R.-M., B.K., K.C.W., K.E.W., J.P.E., J.S.B.), Department of Pathology and Laboratory Medicine (J.L., K.E.W.), UNC School of Medicine, Chapel Hill; Renaissance Computing Institute, Chapel Hill, NC (K.C.W.); and ECU Heart Institute, Brody School of Medicine, Greenville, NC (H.A.).

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 , , and , which have not been implicated previously in cardiac disease. We also identified a heterozygous splice site variant in the nuclear envelope gene 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 and gene expression in zebrafish. Morphant embryos displayed cardiac abnormalities, including pericardial edema and heart failure. Furthermore, lymphoblasts from the patient carrying a 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 , , and 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.
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http://dx.doi.org/10.1161/CIRCGENETICS.116.001443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497793PMC
June 2017

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

Genet Med 2016 05 13;18(5):467-75. Epub 2015 Aug 13.

Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

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.
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http://dx.doi.org/10.1038/gim.2015.104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752935PMC
May 2016

Genetics and heart failure: a concise guide for the clinician.

Curr Cardiol Rev 2015 ;11(1):10-7

UNC Division of Cardiology, 160 Dental Circle, CB 7075, Chapel Hill, NC 27599-7075, USA.

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347203PMC
http://dx.doi.org/10.2174/1573403x09666131117170446DOI Listing
May 2015

Essential elements of genetic cancer risk assessment, counseling, and testing: updated recommendations of the National Society of Genetic Counselors.

J Genet Couns 2012 Apr 2;21(2):151-61. Epub 2011 Dec 2.

Southeast Nebraska Cancer Center, Lincoln, NE, USA.

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.
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http://dx.doi.org/10.1007/s10897-011-9462-xDOI Listing
April 2012

Comparison of the incidence of pancreatic abnormalities between high risk and control patients: prospective pilot study with 3 Tesla MR imaging.

J Magn Reson Imaging 2011 May;33(5):1080-5

Department of Radiology, University of North Carolina at Chapel Hill, North Carolina 27599-7510, USA.

Purpose: To compare the incidence of pancreatic abnormalities detected by MR imaging between high-risk patients and control patients.

Materials And Methods: Forty-one consecutive patients who had two or more first-degree relatives with pancreatic cancer and who were asymptomatic with no clinical evidence of pancreatic cancer were prospectively included in this study. A control group was obtained by reviewing consecutive patients undergoing 3 Tesla (T) MRI examinations for nonpancreatic indications. On MR imaging, the presence of pancreatic abnormalities were evaluated in consensus by two radiologists who were blinded to clinical history. Pancreatic abnormalities were categorized as developmental abnormalities, mass-type lesions, inflammatory disease, and others.

Results: Overall, the incidence of pancreatic abnormalities was greater in the high-risk group than in the control group, but not statistically significant (P = 0.244). In the high-risk group, a total of 16 patients (39%) were diagnosed with pancreatic abnormalities, whereas in the control group, 11 patients (25%) were diagnosed with pancreatic abnormalities. Regarding mass-type lesions, there was a significant difference in incidence between the high-risk group, with a total of seven patients (17%), and the control group, with one patient (2%) (P = 0.028). There were no cases of imaging diagnosis of pancreatic cancer or tissue evaluation by surgical pathology in either group.

Conclusion: Our prospective pilot study demonstrated a higher incidence of mass-type lesions in patients at increased risk for pancreatic cancer.
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http://dx.doi.org/10.1002/jmri.22551DOI Listing
May 2011

Genetic counseling and testing for hypertrophic cardiomyopathy: the pediatric perspective.

J Cardiovasc Transl Res 2009 Dec 24;2(4):500-7. Epub 2009 Sep 24.

Children's Healthcare of Atlanta-Sibley Heart Center Cardiology, Emory University, Atlanta, GA, USA.

Hypertrophic cardiomyopathy (HCM) is a common cardiac disease that is now being identified in the pediatric population. The etiology of this disease is largely genetic, and as a result, genetics professionals are becoming more involved in the management of these patients. We present multiple case scenarios that highlight the complex nature of this disease and how genetic counselors and cardiologists can interact to identify the genetic etiology of HCM and provide comprehensive care for these patients. Additionally, we describe knowledge gaps in this field and how research endeavors can assist in more effectively managing this patient cohort.
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http://dx.doi.org/10.1007/s12265-009-9126-5DOI Listing
December 2009

Genetic counseling and testing for hypertrophic cardiomyopathy: an adult perspective.

J Cardiovasc Transl Res 2009 Dec 26;2(4):493-9. Epub 2009 Sep 26.

Department of Medicine and Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Hypertrophic cardiomyopathy (HCM) is considered to be a genetic disease. As such, multidisciplinary approach is needed to evaluate and treat this condition. We present several patient vignettes to illustrate the complementary skills of cardiologists and genetic counselors in providing comprehensive care. Translational application of research will continue to expand as more genetic causes of HCM will be recognized and more genetic tests will become available. Now is the opportunity to build a strong collaboration between the two disciplines to be prepared for the era of personalized medicine.
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http://dx.doi.org/10.1007/s12265-009-9127-4DOI Listing
December 2009

Increased uptake of BRCA1/2 genetic testing among African American women with a recent diagnosis of breast cancer.

J Clin Oncol 2008 Jan;26(1):32-6

Department of Genetics, and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7264, USA.

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.
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http://dx.doi.org/10.1200/JCO.2007.10.6377DOI Listing
January 2008

Genetics and the young woman with breast cancer.

Breast Dis 2005-2006;23:17-29

Department of Genetics, University of North Carolina at Chapel Hill, 27599, USA.

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 patient's 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.
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http://dx.doi.org/10.3233/bd-2006-23104DOI Listing
August 2006

Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.

J Genet Couns 2004 Apr;13(2):83-114

Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan, USA.

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 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. 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 provider's professional judgment based on the clinical circumstances of a client.
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http://dx.doi.org/10.1023/B:JOGC.0000018821.48330.77DOI Listing
April 2004

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

Soc Sci Med 2003 Aug;57(3):403-12

Department of Anthropology, University of North Carolina, Chapel Hill, CB3115 Alumni Building, Chapel Hill, NC 27514, USA.

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 person's 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.
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http://dx.doi.org/10.1016/s0277-9536(02)00365-9DOI Listing
August 2003