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PubMed2026

Genetic Testing Unveils a Novel Thrombospondin-1 Domain Containing Protein 1 Gene Variant as the Cause of Chronic Edema in a 79-Year-Old Woman.

Edema requires management tailored to its underlying etiology; however, in some cases the cause remains elusive. We describe a 79-year-old woman with lifelong unexplained peripheral edema. Comprehensive evaluation excluded common etiologies such as heart failure, renal dysfunction, and venous thrombosis. Whole-genome sequencing identified a novel homozygous splice-site variant (NM_018676.4:c.58+2T>G) in the thrombospondin-1 domain-containing protein 1 (THSD1) gene, which has previously been associated with non-immune hydrops fetalis (NIHF). This report describes, to our knowledge, the first elderly patient with chronic peripheral edema harboring a likely pathogenic THSD1 variant, suggesting that THSD1-related disease may, in rare instances, persist beyond the perinatal period and present into late adulthood. Although causality cannot be established definitively from a single case, the findings highlight the potential utility of genetic testing in adults with chronic unexplained edema.

chronic edema↗
PubMed2025

Ten years of exome sequencing and reanalysis among racial, ethnic, and ancestral groups: The importance of equitable reanalysis access.

PURPOSE: Race, ethnicity, and ancestry (REA) affect the diagnostic utility of genetic testing. In addition to barriers to accessing genetics services, some non-European REA groups experience decreased diagnostic results and increased uncertain results. Exome sequencing (ES) is a unique genetic test because data can be reanalyzed with new information and variants may be reclassified after the original result. METHODS: We performed a retrospective review of 10,416 clinical ES cases originally analyzed by Ambry Genetics between 2011 and 2021 with reanalysis events through 2023. The relationship between assigned REA group, ES result, reanalysis and reclassification rates, and reanalysis initiators were analyzed with logistic regression. RESULTS: Reanalyses increased the total diagnostic yield from 21.4% to 25.5%. There were no significant differences in reclassification rate among REA groups. However, the African American and Black group (P = 2.8E-07), the Hispanic and Latino group (P = .0022), and the Asian group (P = .033) were significantly less likely to receive provider-initiated reanalysis compared with the White group. CONCLUSION: Although reclassification rates were not found to be associated with REA group, not all REA groups had the same access to ES reanalysis. Laboratory-initiated proactive reanalysis can help reduce disparities in ES diagnostic utility by reducing barriers to accessing reanalysis.

Female↗
PubMed2005

Genetic testing for risk stratification in hypertrophic cardiomyopathy and long QT syndrome: fact or fiction?

PURPOSE OF REVIEW: Hypertrophic cardiomyopathy, affecting 1 in 500 persons, is the most common identifiable cause of sudden cardiac death in the young, whereas congenital long QT syndrome, affecting 1 in 5000 persons, is perhaps one of the most common causes of autopsy negative sudden unexplained death. Since May 2004, genetic testing has been available as a clinical diagnostic test for both hypertrophic cardiomyopathy and long QT syndrome. It is now critical to carefully scrutinize the relationships between genotype and phenotype as they pertain to clinical practice. RECENT FINDINGS: In 1990, the molecular underpinnings of hypertrophic cardiomyopathy were exposed with the identification of a mutation in the MYH7-encoded beta myosin heavy chain. Since then, hundreds of mutations scattered among at least 14 genes confer the pathogenetic substrate for this 'disease of the sarcomere'. In 1995, the discipline of cardiac channelopathies was born with the revelation that mutations in critical cardiac channel genes cause long QT syndrome. Today, hundreds of mutations involving several cardiac channel genes account for approximately 75% of long QT syndrome. Over the past decade, scores of genotype-phenotype correlation studies in both hypertrophic cardiomyopathy and long QT syndrome have been conducted. SUMMARY: Genomic medicine has now entered the clinical practice as it pertains to the evaluation and management of both hypertrophic cardiomyopathy and long QT syndrome. The diagnostic utility of genetic testing for both diseases is clearly evident, as well as current limitations. While treatment decisions are certainly influenced by knowing the underlying genotype in long QT syndrome, there seems to be negligible prognostic value associated with particular hypertrophic cardiomyopathy-causing mutations at this time.

Cardiomyopathy, Hypertrophic↗
PubMed1994

Hereditary nonpolyposis colorectal carcinoma (HNPCC): clinical application of molecular diagnostic testing.

An increased risk of colorectal cancer amongst close relatives of afflicted patients has been recognized for some time. Hereditary nonpolyposis colorectal cancer (HNPCC) represents an extreme example of this risk, in which single-gene inheritance predisposes relatives of affected family members. Approaches to surveillance and management of subjects at greater or lesser heritable risk have been evolving in the past two decades, but these efforts have suffered due to our inability to better characterize and quantify that risk. Recent discovery of susceptibility loci that are linked to disease in HNPCC has already begun to refine our understanding of the pathogenesis of the disease. At a clinical level, these advances now offer an improved ability to recognize carriers of the condition. Speculation is provided as to the probable utility of genetic testing in groups with varying strengths of colorectal cancer familiality. Notions of how positive and negative tests might be applied to surveillance and treatment are explored.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed2001

Extreme warfarin sensitivity in siblings associated with multiple cytochrome P450 polymorphisms.

Warfarin use is complicated by an erratic dose response. Warfarin is metabolized by two distinct subfamilies of the cytochrome P450 (CYP) complex. We describe two siblings with extreme sensitivity to warfarin who share an unusual CYP genotype. These individuals illustrate both the importance of genetics in influencing the metabolism of warfarin as well as the potential utility of genetic testing as a guide to prescribing this medication.

Aged↗
PubMed2026

Potential contributors to variable penetrance of NOTCH3 p.Arg1231Cys Variant.

Missense mutations in NOTCH3, especially cysteine-altering pathogenic variants, are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. The NOTCH3 p.Arg1231Cys variant, located in EGFr domain 31, is classified as low-risk under the three-tiered EGFr domain risk stratification system. We report two cases of p.Arg1231Cys heterozygosity presenting with early-onset dementia, strokes, and extensive leukoencephalopathy. These cases highlight the potential contributing factors to increasing penetrance of p.Arg1231Cys variant, and the need for functional evaluation to improve the clinical utility of genetic testing in hereditary small vessel disease.

Humans↗
PubMed2004

Anterior basement membrane corneal dystrophy and pseudo-unilateral lattice corneal dystrophy in a patient with recurrent corneal erosions.

PURPOSE: To report the utility of genetic testing in the diagnosis and management of patients with suspected corneal dystrophies. DESIGN: Case report. METHODS: A 58-year-old man with a history of recurrent corneal erosions was diagnosed with bilateral anterior basement membrane dystrophy and unilateral lattice corneal dystrophy. All 17 exons of the TGFBI gene were screened for mutations previously associated with lattice corneal dystrophy as well as novel coding region changes. RESULTS: No mutations were found in the 17 exons of the TGFBI gene. A nucleotide change in exon 6 (651C>G) did not result in a change in the encoded amino acid (Leu217Leu). CONCLUSIONS: In cases of suspected TGFBI corneal dystrophies, genetic testing is a useful tool to confirm the clinical diagnosis. In this case of suspected unilateral lattice corneal dystrophy, screening of the TGFBI gene ruled out the diagnosis, raising the possibility that the corneal changes were related to the coexistent anterior basement membrane dystrophy.

Basement Membrane↗
PubMed2001

Apparent Mendelian inheritance of breast and colorectal cancer: chance, genetic heterogeneity or a new gene?

It is not uncommon for cancer geneticists to be referred families with apparently Mendelian co-inheritance of breast and bowel cancer. Such families present a particular problem as regards the intensity of their screening for these diseases and the utility of genetic testing. Many 'breast-colon' cancer families probably result from chance clustering of two common cancers. Other 'breast-colon' cancer families may result from known cancer syndromes, such as hereditary breast-ovarian cancer or hereditary non-polyposis colon cancer, either by conferring a high risk of one cancer type and a slightly increased risk of the other, or through a predisposition to one of the two cancers and chance occurrence of the other. Anecdotally, however, many geneticists wonder about the existence of a distinct 'breast-colon cancer syndrome', since some families present good a priori evidence of genetic disease and yet cannot readily be accounted for by known genes or chance. The identification of unknown 'breast-colon cancer' genes is likely to be difficult, relying primarily on candidate gene analysis, including loci separately implicated in breast or colorectal cancer, or in other multiple cancer syndromes. Studies such as those on APC I1307K and CHEK2 1100delC may suggest the way forward for the identification of 'breast-colon cancer' genes.

Adult↗
PubMed2026

A novel truncating FBN1 variant in a family with Marfan syndrome.

Marfan syndrome is caused by pathogenic variants in FBN1. We identified a novel heterozygous frameshift variant in FBN1 (NM_000138.5: c.6784_6787del, NP_000129.3:p.(Gln2262TrpfsTer28)) in an adult male with severe cardiovascular manifestations. The variant was absent from population databases and fulfilled PVS1 and PM2 criteria. This finding expands the mutational and phenotypic spectrum of FBN1 and highlights the clinical utility of genetic testing in family-based clinical management of Marfan syndrome.

Journal Article↗
PubMed1998

Screening for breast and ovarian cancer: the relevance of family history.

The recent identification of two breast and ovarian cancer susceptibility genes--BRCA1 and BRCA2--has received a lot of publicity. Public and professional expectations of the availability and utility of genetic testing have been raised and the importance of a family history of breast cancer overemphasized. In this chapter, we examine the significance of a family history of breast or ovarian cancer in determining individual risk. A strategy for management is proposed, based on stratifying women with such a history into three different categories of risk for breast cancer: high, moderate and low. Some of the more controversial aspects of screening for breast and ovarian cancer are reviewed, including the issue of management of women who are at increased risk of these cancers by virtue of a family history, genetic predisposition, or both. There is a need for further research to clarify the most appropriate management of those at moderate risk of developing these cancers. A management strategy for women at high risk is proposed. We believe that adoption of this strategy will strengthen consistent information giving from primary to tertiary care.

Breast Neoplasms↗
PubMed2004

Uptake of offer to receive genetic information about BRCA1 and BRCA2 mutations in an Australian population-based study.

Research on the utilization of genetic testing services for mutations in BRCA1 and BRCA2 has focused on women with a strong family history of breast and ovarian cancer. We conducted a population-based case-control-family study of Australian women diagnosed with invasive breast cancer before age 40 years, unselected for family history, and tested for germ line mutations in BRCA1 and BRCA2. Case subjects found to carry a deleterious mutation and their relatives who had given a research blood sample were informed by mail that the study had identified "genetic information" and were offered the opportunity to learn more. Those interested were referred to a government-funded family cancer clinic. Of 94 subjects who received the letter, 3 (3%) did not respond and 38 (40%) declined to learn their result (16 declined the referral, 10 accepted but did not attend a clinic, and 12 attended a clinic but declined testing), and 12 (13%) remain "on hold." The remaining 41 (44%) chose to learn their result (3 of whom already knew their mutation status). There was no evidence that the decision to learn of mutation status depended on age, gender, family history, or having been diagnosed with breast cancer. Of 19 families with more than one participant, in 11 (58%) there was discordance between relatives in receiving genetic results. Although in Australia genetic testing is offered free of charge and insurance issues are not a major consideration, we found considerable reluctance, indecision, and unexplained variability both between and within case families in the desire to know their mutation status.

Adult↗
PubMed1989

Impact of medical genetics on research and practices in the area of cardiovascular disease.

The evidence that genetic factors are of importance in the etiology of coronary heart disease (CHD) originates from several areas. Cases of premature CHD cluster in families in a way which indicates the importance of genetic factors, and having a first-degree relative who contracted CHD before the age of 50-55 is by itself a significant risk factor. Genes are of importance in determining the level of several established risk or "anti-risk" factors, and association between risk factor level and random genetic markers has been known for several years. The "candidate gene" approach was first applied in the 1970s, when a strong association between genetically determined Lp(a) lipoprotein and premature CHD was found, and associations between Ag allotypes and lipid levels were uncovered. The new DNA technology has greatly increased the potential of the "candidate gene" approach. Genes are of importance not only for the absolute risk factor level but also with respect to the amount of variation in risk factor level that any one person can have. Thus, in addition to traditional "level genes", new "variability genes" are being identified. Knowledge of genetic factors in the etiology of coronary heart disease has not so far been adequately utilized in attempts to combat premature CHD. The time has now come to utilize genetic information in a setting of family-oriented preventive medicine. This approach would greatly improve the efficiency of preventive efforts, utilizing predictive genetic testing and targeting counseling on those who need it most.

Cholesterol↗
PubMed2025

Characterizing trends in clinical genetic testing: A single-center analysis of EHR data from 1.8 million patients over two decades.

A lack of structural data in electronic health records (EHRs) makes assessing the impact of genetic testing on clinical practice challenging. We extracted clinical genetic tests from the EHRs of more than 1.8 million patients seen at Vanderbilt University Medical Center from 2002 to 2022. With these data, we quantified the use of clinical genetic testing in healthcare and described how testing patterns and results changed over time. We assessed trends in types of genetic tests, tracked usage across medical specialties, and introduced a new measure, the genetically attributable fraction (GAF), to quantify the proportion of observed phenotypes attributable to a genetic diagnosis over time. We identified 104,392 tests and 19,032 molecularly confirmed diagnoses. The proportion of patients with genetic testing in their EHRs increased from 1.0% in 2002 to 6.1% in 2022, and testing became more comprehensive with the growing use of multi-gene panels. The number of unique diseases diagnosed with genetic testing increased from 51 in 2002 to 509 in 2022, and there was a rise in the number of variants of uncertain significance. The phenome-wide GAF for 6,505,620 diagnoses made in 2022 was 0.46%, and the GAF was greater than 5% for 74 phenotypes, including pancreatic insufficiency (67%), chorea (64%), atrial septal defect (24%), microcephaly (17%), paraganglioma (17%), and ovarian cancer (6.8%). Our study provides a comprehensive quantification of the increasing role of genetic testing at a major academic medical institution and demonstrates its growing utility in explaining the observed medical phenome.

Humans↗
PubMed2006

Disparities in genetic testing: thinking outside the BRCA box.

The impact of predictive genetic testing on cancer care can be measured by the increased demand for and utilization of genetic services as well as in the progress made in reducing cancer risks in known mutation carriers. Nonetheless, differential access to and utilization of genetic counseling and cancer predisposition testing among underserved racial and ethnic minorities compared with the white population has led to growing health care disparities in clinical cancer genetics that are only beginning to be addressed. Furthermore, deficiencies in the utility of genetic testing in underserved populations as a result of limited testing experience and in the effectiveness of risk-reducing interventions compound access and knowledge-base disparities. The recent literature on racial/ethnic health care disparities is briefly reviewed, and is followed by a discussion of the current limitations of risk assessment and genetic testing outside of white populations. The importance of expanded testing in underserved populations is emphasized.

Genetic Predisposition to Disease↗
PubMed2000

Separating predictive genetic testing from snake oil: regulation, liabilities, and lost opportunities.

This article explores the extent to which completion of maps of the human genome, coupled with the introduction of technology that will accelerate the identification of gene and protein function, have introduced immeasurable potential to advance life science and health care through genetic profiling. In light of definitional uncertainty, the regulatory and legal environment surrounding predictive genetic testing threatens to impede clinical utilization of genetic profiling technologies that could significantly improve human health. Especially given that genetic testing technologies have been stigmatized in the public and medical community, they must enter the marketplace with a regulatory framework that assures safety, efficacy, and market responsibility.

Biotechnology↗
PubMed2001

Empirical evaluation of genetic clustering methods using multilocus genotypes from 20 chicken breeds.

We tested the utility of genetic cluster analysis in ascertaining population structure of a large data set for which population structure was previously known. Each of 600 individuals representing 20 distinct chicken breeds was genotyped for 27 microsatellite loci, and individual multilocus genotypes were used to infer genetic clusters. Individuals from each breed were inferred to belong mostly to the same cluster. The clustering success rate, measuring the fraction of individuals that were properly inferred to belong to their correct breeds, was consistently approximately 98%. When markers of highest expected heterozygosity were used, genotypes that included at least 8-10 highly variable markers from among the 27 markers genotyped also achieved >95% clustering success. When 12-15 highly variable markers and only 15-20 of the 30 individuals per breed were used, clustering success was at least 90%. We suggest that in species for which population structure is of interest, databases of multilocus genotypes at highly variable markers should be compiled. These genotypes could then be used as training samples for genetic cluster analysis and to facilitate assignments of individuals of unknown origin to populations. The clustering algorithm has potential applications in defining the within-species genetic units that are useful in problems of conservation.

Algorithms↗
PubMed1989

Utility of short-term tests for genetic toxicity.

By definition, short-term tests (STTs) for genetic toxicity detect genotoxic agents, not carcinogens specifically. However, there is sufficient evidence, based on mechanistic considerations alone, to say that genotoxic agents are potential carcinogens. STTs have high statistical power, are almost always replicated, can be performed rather easily under various sets of experimental conditions, are relatively inexpensive, and detect a variety of endpoints relevant to carcinogenesis. In addition, several STTs have shown considerable utility in evaluating the genotoxic effects of real-world, environmental complex mixtures as well as the antimutagenic effects of various pure compounds and complex mixtures. STTs are likely to continue to be refined, resulting in STTs that are increasingly more relevant to human mutation and disease. Their utility should not be judged solely against the questionable standard of a rodent carcinogenicity assay.

Animals↗