Burden Of Genetic Variants Research Articles

Profiling genetic variants in cardiovascular disease genes among a Heterogeneous cohort of Mendelian conditions patients and electronic health records.

This study addresses the rising cardiovascular disease (CVD) rates in the United Arab Emirates (UAE) by investigating the occurrence and impact of genetic variants in CVD-related genes. We collected all genes linked to heritable CVD from public and diagnostic databases and mapped them to their corresponding biological processes and molecular pathways. We then evaluated the types and burden of genetic variants within these genes in 343 individuals from the Emirati Mendelian Study Cohort and 3,007 national electronic health records. We identified a total of 735 genes associated with heritable CVD, covering a range of cardiovascular conditions. Enrichment analysis revealed key biological processes and pathways, including Apelin, FoxO, and Ras signaling, that are implicated across all forms of heritable CVD. Analysis of a UAE cohort of 3,350 individuals showed a predominance of rare and unique CVD variants specific to the population. The study found a significant burden of pathogenic variants in families with CVD within the Emirati Mendelian cohort and re-assessed the pathogenicity of 693 variants from national health records, leading to the discovery of new CVD-causing variants. This study underscores the importance of continuously updating our understanding of genes and pathways related to CVD. It also highlights the significant underrepresentation of the UAE population in public databases and clinical literature on CVD genetics, offering valuable insights that can inform future research and intervention strategies.

Abstract PO2-12-08: Increased burden of genetic variants in idiopathic cardiomyopathy genes is associated with cancer therapy-related cardiomyopathy

Abstract Background: Breast cancer (BC) patients are at significant risk of therapy-related cardiotoxicity, but prediction of which patients will experience cardiotoxicity and the severity of the outcome are lacking. We hypothesized that germline genetic variants are potential risk factors for cancer treatment-related cardiomyopathy (CTRC) and in this study, we focused on rare non-synonymous variants within 57 genes deemed causative of familial and sporadic forms of idiopathic cardiomyopathies. Methods: We developed a clinical database and biorepository for patients receiving any potentially cardiotoxic cancer therapy at Mayo Clinic Florida. Enrollment is ongoing and includes consent to access external records. Patient data is extracted from records at baseline, completion of treatment and then once per year. The clinical database includes the following datasets: demographics, pathology, chemotherapy, radiation, echocardiography, cardiac MRI, PET/CT scan, blood pressure, BMI, labs, treatment complications. Treatment complications includes pre-existing conditions (smoking, alcohol and drug use history, hypertension, diabetes, coronary artery disease, hyperlipidemia, prior stroke or myocardial infarction, peripheral vascular disease, renal failure); cardiac medications at baseline; cardiac side-effects; time to cardiotoxicity; cardiotoxicity interventions and outcomes. Exome sequencing was performed by the Mayo Clinic NGS core on the first 86 patients in the registry, average of ~120x read depth following Illumina’s standard protocol for the NovaSeq 6000 and S4 flow cell. Genomic variants were extracted for 57 genes known to be causative of dilated, hypertrophic and arrhythmogenic right ventricular cardiomyopathies and channelopathies. Putative risk variants in known cardiomyopathy genes were defined as non-synonymous variants with a frequency of < 0.0004 in the GnomAD database. We compared the number of patients with putative risk variants in those groups with and without CTRC. Results: 84/86 patients had BC diagnosis. Key characteristics are described in the table below. 60/86 (70%) patients had at least one putative risk variant in one of 31 genes (there were no risk variants identified in 27/57 genes). The average number of putative risk variants per patient within the CTRC group was higher than that observed in patients without CTRC (2.06 vs 1.62). Post-hoc analysis suggested this difference is largely from patients with >2 risk variants in the group who experienced CTRC (N=7/17, 41%) compared to those who did not (N=14/69, 20%), p=0.023. Conclusions: Rare missense variants in the causative genes of idiopathic cardiomyopathies are potential risk factors for CTRC and risk may be increased in patients with a higher burden of variants. Analysis of the genetic data from patients that continue to be accrued in this study, including effects of additional clinical risk factors will be undertaken to improve prediction of cardiotoxicity. Table 1 Distribution of putative cardiomyopathy genetic variants in 86 cancer patients with and without treatment-related cardiomyopathy, separated by treatment regimen Citation Format: Nadine Norton, Thien Nguyen, Joseph Reddy, Jinky Harvey, Morgan Weidner, Amanda Arnold, Lily Evans, Laura Vallow, Pooja Advani. Increased burden of genetic variants in idiopathic cardiomyopathy genes is associated with cancer therapy-related cardiomyopathy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-12-08.

Variants in structural cardiac genes in patients with cancer therapy-related cardiac dysfunction after anthracycline chemotherapy: a case control study

BackgroundVariants in cardiomyopathy genes have been identified in patients with cancer therapy-related cardiac dysfunction (CTRCD), suggesting a genetic predisposition for the development of CTRCD. The diagnostic yield of genetic testing in a CTRCD population compared to a cardiomyopathy patient cohort is not yet known and information on which genes should be assessed in this population is lacking.MethodsWe retrospectively included 46 cancer patients with a history of anthracycline induced CTRCD (defined as a decrease in left ventricular ejection fraction (LVEF) to < 50% and a ≥ 10% reduction from baseline by echocardiography). Genetic testing was performed for 59 established cardiomyopathy genes. Only variants of uncertain significance and (likely) pathogenic variants were included. Diagnostic yield of genetic testing was compared with a matched cohort of patients with dilated cardiomyopathy (DCM, n = 46) and a matched cohort of patients without cardiac disease (n = 111).ResultsAverage LVEF at time of CTRCD diagnosis was 30.1 ± 11.0%. Patients were 52.9 ± 14.6 years old at time of diagnosis and 30 (65.2%) were female. Most patients were treated for breast cancer or lymphoma, with a median doxorubicin equivalent dose of 300 mg/m2 [112.5-540.0]. A genetic variant, either pathogenic, likely pathogenic or of uncertain significance, was identified in 29/46 (63.0%) of patients with CTRCD, which is similar to the DCM cohort (34/46, 73.9%, p = 0.262), but significantly higher than in the negative control cohort (47/111, 39.6%, p = 0.018). Variants in TTN were the most prevalent in the CTRCD cohort (43% of all variants). All (likely) pathogenic variants identified in the CTRCD cohort were truncating variants in TTN.There were no significant differences in severity of CTRCD and in recovery rate in variant-harbouring individuals versus non-variant harbouring individuals.ConclusionsIn this case-control study, cancer patients with anthracycline-induced CTRCD have an increased burden of genetic variants in cardiomyopathy genes, similar to a DCM cohort. If validated in larger prospective studies, integration of genetic data in risk prediction models for CTRCD may guide cancer treatment. Moreover, genetic results have important clinical impact, both for the patient in the setting of precision medicine, as for the family members that will receive genetic counselling.

The burden of rare variants in DPYS gene is a novel predictor of the risk of developing severe fluoropyrimidine-related toxicity

BackgroundDespite a growing number of publications highlighting the potential impact on the therapy outcome, rare genetic variants (minor allele frequency < 1%) in genes associated to drug adsorption, distribution, metabolism, and elimination are poorly studied. Previously, rare germline DPYD missense variants were shown to identify a subset of fluoropyrimidine-treated patients at high risk for severe toxicity. Here, we investigate the impact of rare genetic variants in a panel of 54 other fluoropyrimidine-related genes on the risk of severe toxicity.MethodsThe coding sequence and untranslated regions of 54 genes related to fluoropyrimidine pharmacokinetics/pharmacodynamics were analyzed by next-generation sequencing in 120 patients developing grade 3–5 toxicity (NCI-CTC vs3.0) and 104 matched controls. Sequence Kernel Association Test (SKAT) analysis was used to select genes with a burden of genetic variants significantly associated with risk of severe toxicity. The statistical association of common and rare genetic variants in selected genes was further investigated. The functional impact of genetic variants was assessed using two different in silico prediction tools (Predict2SNP; ADME Prediction Framework).ResultsSKAT analysis highlighted DPYS and PPARD as genes with a genetic mutational burden significantly associated with risk of severe fluoropyrimidine-related toxicity (Bonferroni adjusted P = 0.024 and P = 0.039, respectively). Looking more closely at allele frequency, the burden of rare DPYS variants was significantly higher in patients with toxicity compared with controls (P = 0.047, Mann–Whitney test). Carrying at least one rare DPYS variant was associated with an approximately fourfold higher risk of severe cumulative (OR = 4.08, P = 0.030) and acute (OR = 4.21, P = 0.082) toxicity. The burden of PPARD rare genetic variants was not significantly related to toxicity. Some common variants with predictive value in DPYS and PPARD were also identified: DPYS rs143004875-T and PPARD rs2016520-T variants predicted an increased risk of severe cumulative (P = 0.002 and P = 0.001, respectively) and acute (P = 0.005 and P = 0.0001, respectively) toxicity.ConclusionThis work demonstrated that the rare mutational burden of DPYS, a gene strictly cooperating with DPYD in the catabolic pathway of fluoropyrimidines, is a promising pharmacogenetic marker for precision dosing of fluoropyrimidines. Additionally, some common genetic polymorphisms in DPYS and PPARD were identified as promising predictive markers that warrant further investigation.

1467-P: Type 2 Diabetes Polygenic Score Predicts the Risk of Glucocorticoid-Induced Hyperglycemia in Patients without Diabetes

Introduction: Glucocorticoids are commonly prescribed medications with a known side effect of hyperglycemia due to their effect on glucose metabolism. However, only 10-50% of patients receiving glucocorticoids develop overt hyperglycemia. It is unknown whether patients with increased genetic risk for type 2 diabetes (T2D) are predisposed to develop hyperglycemia after glucocorticoid treatment. Methods: We accessed electronic health records and genetic data in the Mass General Brigham Biobank. We examined patients with no diagnosis of diabetes or prediabetes who received a glucocorticoid dose equivalent to 10 mg of prednisone or more, and who had glucose levels checked within 7 days of glucocorticoid administration. Hyperglycemia was defined as fasting blood glucose ≥126 mg/dL or random blood glucose ≥200 mg/dL. A T2D global extended polygenic score was constructed through a meta-analysis of T2D genome-wide association studies in the Million Veteran Program, DIAMANTE, and FinnGen. We performed logistic regression to analyze the association between the polygenic score and hyperglycemia, controlling for age, gender, BMI, baseline creatinine, glucocorticoid dose and duration, and the first 10 principal components of genetic ancestry. Results: Out of 552 patients who received glucocorticoids, 216 developed hyperglycemia and 336 did not. The T2D polygenic score was significantly associated with glucocorticoid-induced hyperglycemia (p = 0.032, OR = 1.5 per standard deviation of the polygenic score). Other significant covariates included baseline creatinine (p = 8.0 × 10−4, OR = 2.2 per mg/dL of creatinine) and glucocorticoid dose (p = 9.5 × 10−5, OR = 1.01 per 10 mg of prednisone). Conclusions: Patients carrying a higher burden of genetic variants that confer risk for T2D have an increased risk of hyperglycemia after receiving glucocorticoids. This finding offers a mechanism for risk stratification as part of a precision approach to medical treatment. Disclosure A.J.Deutsch: None. P.H.Schroeder: None. R.Mandla: None. F.Erenler: None. J.M.Mercader: None. M.Udler: None. J.C.Florez: Consultant; AstraZeneca, Novo Nordisk, Other Relationship; AstraZeneca, Merck &amp; Co., Inc. L.Brenner: None. Funding National Institutes of Health (T32DK007028)

Congenital hydrocephalus: new Mendelian mutations and evidence for oligogenic inheritance

BackgroundCongenital hydrocephalus is characterized by ventriculomegaly, defined as a dilatation of cerebral ventricles, and thought to be due to impaired cerebrospinal fluid (CSF) homeostasis. Primary congenital hydrocephalus is a subset of cases with prenatal onset and absence of another primary cause, e.g., brain hemorrhage. Published series report a Mendelian cause in only a minority of cases. In this study, we analyzed exome data of PCH patients in search of novel causal genes and addressed the possibility of an underlying oligogenic mode of inheritance for PCH.Materials and methodsWe sequenced the exome in 28 unrelated probands with PCH, 12 of whom from families with at least two affected siblings and 9 of whom consanguineous, thereby increasing the contribution of genetic causes. Patient exome data were first analyzed for rare (MAF < 0.005) transmitted or de novo variants. Population stratification of unrelated PCH patients and controls was determined by principle component analysis, and outliers identified using Mahalanobis distance 5% as cutoff. Patient and control exome data for genes biologically related to cilia (SYScilia database) were analyzed by mutation burden test.ResultsIn 18% of probands, we identify a causal (pathogenic or likely pathogenic) variant of a known hydrocephalus gene, including genes for postnatal, syndromic hydrocephalus, not previously reported in isolated PCH. In a further 11%, we identify mutations in novel candidate genes. Through mutation burden tests, we demonstrate a significant burden of genetic variants in genes coding for proteins of the primary cilium in PCH patients compared to controls.ConclusionOur study confirms the low contribution of Mendelian mutations in PCH and reports PCH as a phenotypic presentation of some known genes known for syndromic, postnatal hydrocephalus. Furthermore, this study identifies novel Mendelian candidate genes, and provides evidence for oligogenic inheritance implicating primary cilia in PCH.

Association of Early-Onset Alzheimer Disease With Elevated Low-Density Lipoprotein Cholesterol Levels and Rare Genetic Coding Variants of APOB

Early-onset Alzheimer disease (EOAD) is a rare form of Alzheimer disease (AD) with a large genetic basis that is only partially understood. In late-onset AD, elevated circulating cholesterol levels increase AD risk even after adjusting for the apolipoprotein E ε4 (APOE E4) allele, a major genetic factor for AD and elevated cholesterol levels; however, the role of circulating cholesterol levels in EOAD is unclear. To investigate the association between circulating cholesterol levels and EOAD and to identify genetic variants underlying this possible association. In this case series, plasma cholesterol levels were directly measured in 267 samples from the AD research centers (ADRCs) of Emory University and University of California, San Francisco, collected from January 21, 2009, through August 21, 2014. The association between cholesterol and EOAD was examined using multiple linear regression. To determine the underlying genetic variants, APOB, APP, PSEN1, and PSEN2 were sequenced in samples from 2125 EOAD cases and controls recruited from 29 ADRCs from January 1, 1984, through December 31, 2015. Data were analyzed from November 23, 2016, through April 10, 2018. Clinical diagnosis, age at clinical diagnosis, plasma cholesterol measures (total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol, triglycerides, and apolipoprotein B), and genetic variants in APOE, APP, PSEN1, PSEN2, and APOB. The primary outcome was the association between EOAD and plasma cholesterol measures. The secondary outcome was the association between EOAD and the burden of genetic variants in APOB. Of the 2125 samples that underwent genetic sequencing, 1276 were from women (60.0%) and 654 (30.8%) were from patients with EOAD (mean [SD] ages, 55.6 [4.3] years for cases and 72.0 [9.6] years for controls). APOE E4 explained 10.1% of the variance of EOAD. After controlling for APOE E4, EOAD cases had higher levels of total cholesterol (mean difference [SE], 21.9 [5.2] mg/dL; P = 2.9 × 10-5), LDL-C (mean difference [SE], 22.0 [4.5] mg/dL; P = 1.8 × 10-6), and ApoB (mean difference [SE], 12.0 [2.4] mg/dL; P = 2.0 × 10-6) than controls in 267 frozen samples. Approximately 3% of EOAD cases carried known AD-causing mutations. Gene-based rare variant burden testing in 2066 samples showed that rare APOB coding variants were significantly more abundant in EOAD cases after adjusting for sex, APOE E4, genetic principal components, ADRC center, and batch (effect size, 0.20; P = 4.20 × 10-4). Elevated LDL-C levels were associated with higher probability of having EOAD, and EOAD cases were enriched for rare coding variants in APOB, which codes for the major protein of LDL-C. Collectively, these novel findings highlight the important role of LDL-C in EOAD pathogenesis and suggest a direct link of APOB variants to AD risk.

High burden of birthweight-lowering genetic variants in Africans and Asians

BackgroundBirthweight is an important predictor of infant morbidity and mortality, and is associated with cardiovascular diseases, obesity, and diabetes in childhood and adulthood. Birthweight and fetal growth show regional and population variations even under similar maternal conditions, and a large proportion of these differences are not explained by environmental factors. Whether and to what extent population genetic variations at key birthweight-associated loci account for the residual birthweight disparities not explained by environmental determinants is unknown. We hypothesized that the cumulative burden of genetic variants with a birthweight-lowering effect (GRB) is different among ancestrally diverse populations.MethodsGenotype data were extracted from phase 3 of the 1000 Genomes Project for 2504 participants from 26 global populations grouped into five super-populations. GRB was calculated in offspring as the weighted sum of the number of birthweight-lowering genetic variants of 59 autosomal single-nucleotide polymorphisms associated with birthweight, and comparisons were made between Europeans and non-Europeans.ResultsGRB was significantly higher in Africans (mean difference 3.15; 95% confidence interval 2.64, 3.66), admixed Americans (3.02; 2.34, 3.70), East Asians (2.85; 2.29, 3.41), and South Asians (1.07; 0.49, 1.65) compared to Europeans. Birthweight-lowering genetic variants in Africans and East Asians were enriched for rare and frequency-fixed alleles (P < 0.001). African and Asian populations had the greatest deviation from the expectation of the common disease-common variant hyothesis. Compared to Europeans, the GRB of ancestral alleles was significantly higher and that of derived alleles was significantly lower in non-Europeans (P < 0.001).ConclusionsThe burden of birthweight-lowering genetic variants is higher in Africans and East Asians. This finding is consistent with the high incidence of low birthweight in the two populations. The genetic variants we studied may not be causal and the extent to which they tag the causal variants in non-Europeans is unknown; however, our findings highlight that genetic variations contribute to population differences in birthweight.

Ethnic Differences in Cardiac Potassium Channel Variants: Implications for Genetic Susceptibility to Sudden Cardiac Death and Genetic Testing for Congenital Long QT Syndrome

To determine the spectrum, frequency, and ethnic-specificity of channel variants in the potassium channel genes implicated in congenital long QT syndrome (LQTS) among healthy subjects. Genomic DNA from 744 apparently healthy individuals-305 black, 187 white, 134 Asian, and 118 Hispanic--was subject to a comprehensive mutational analysis of the 4 LQTS-causing potassium channel genes: KCNQ1 (LQT1), KCNH2 (LQT2), KCNE1 (LQT5), and KCNE2 (LQT6). Overall, 49 distinct amino acid-altering variants (36 novel) were identified: KCNQ1 (n = 16), KCNH2 (n = 25),KCNE1 (n = 5), and KCNE2 (n = 3). More than half of these variants (26/49) were found exclusively in black subjects. The known K897T-HERG and the G38S-min K common polymorphisms were identified in all 4 ethnic groups. Excluding these 2 common polymorphisms, 25% of black subjects had at least 1 nonsynonymous potassium channel variant compared with 14% of white subjects (P < .01). To our knowledge, this study represents the first comprehensive determination of the frequency and spectrum of cardiac channel variants found among healthy subjects from 4 major ethnic groups. Defining the population burden of genetic variants in these critical cardiac ion channels is crucial for proper interpretation of genetic test results of individuals at risk for LQTS. This compendium provides a resource for epidemiological and functional investigation of variant effects on the repolarization properties of cardiac tissues, including susceptibility to lethal cardiac arrhythmias.