Tan-Arroyo, Jennifer

Abstract Pathogenic variants in cardiomyopathy genes confer substantial disease risk, yet clinical penetrance varies widely. The population-level prevalence, age-specific penetrance, and the extent to which polygenic susceptibility modifies disease risk across diverse ancestries remain poorly defined. This population-based cohort study leveraged genome sequencing and linked electronic health record data from the All of Us Research Program (n=414,830). This study found that P/LP variants in cardiomyopathy-associated genes were present in 0.91% of participants (95% CI, 0.88%–0.94%), with similar prevalence across ancestry groups. Compared with non-carriers, variant carriers had significantly higher odds of all-cause heart failure (ACHF, OR, 2.58; 95% CI, 2.31–2.89), non-ischemic heart failure (NIHF, OR, 2.74; 95% CI, 2.42–3.10), and non-ischemic cardiomyopathy (NICM, OR, 4.99; 95% CI, 4.44–5.63). Among carriers, by age 50 years, 24.5% (95% CI, 14.5%–33.4%) developed ACHF, 17.2% (95% CI, 8.8%–24.8%) developed NIHF, and 30.1% (95% CI, 19.5%–40.2%) developed NICM. Higher polygenic risk for heart failure was independently associated with increased risk of ACHF (OR, 1.81; 95% CI, 1.74–1.89), NIHF (OR, 1.66; 95% CI, 1.58–1.75), and NICM (OR, 1.69; 95% CI, 1.59–1.80). Among carriers with elevated polygenic risk, odds of disease were substantially higher than among non-carriers at average polygenic risk (ACHF: OR, 4.71; 95% CI, 4.17–5.32; NIHF: OR, 4.56; 95% CI, 3.99–5.22; NICM: OR, 8.51; 95% CI, 7.44–9.73). Results showed that P/LP variants in cardiomyopathy genes were relatively common in this large, ancestrally diverse cohort, and conferred increased risk of cardiomyopathy and HF, with incomplete but clinically meaningful penetrance. Polygenic risk for HF independently and additively increased disease risk across ancestries. Integrating both may improve risk stratification and enable more precise, equitable care.

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder that increases risk for premature coronary artery disease and has accessible and effective interventions. The Dutch lipid clinic network is currently the most used diagnostic criterion; however, genetic sequencing provides a definitive diagnosis of FH. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify individuals who were genotype positive for FH. METHODS: Participants were recruited from 3 geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; and Jacksonville, FL). Participants underwent Exome+ sequencing (dba Helix, San Mateo, CA) and return of results for specific genetic findings in APOB , LDLR , or PCSK9 . A chart review was performed to collect demographics, personal, and family cardiovascular history. RESULTS: At the time of the study, 84 413 participants were enrolled in the Tapestry study. Annotation and interpretation of all variants in genes for FH resulted in the identification of 419 likely pathogenic and pathogenic variants (prevalence, 0.50%), which included 116 APOB , 298 LDLR , and 5 PCSK9 . Sixty-six percent were female, the mean body mass index was 27.3, with 12.3% reporting a history of diabetes. Hypertriglyceridemia (≥150 mg/dL) was present in 39.5% and reduced HDL (<50 mg/dL) was present in 56.7% of patients. 27.5% of patients were not on cholesterol-lowering medications, and only 10% of FH carriers were at goal low-density lipoprotein cholesterol levels. A history of coronary artery disease was reported in 22.4% of the cohort. Nearly 90% of these participants were newly diagnosed carriers of FH. Only 30.8% of confirmed genetic diagnoses of FH satisfied clinical (Dutch lipid clinic network) criteria for a diagnosis. CONCLUSIONS: Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have familial hypercholesterolemia. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05212428.

Key Points Genetic testing of individuals suspected of monogenic urinary stone disease resolved 34% of families with 22 different genes detected. Resolved individuals had a lower baseline and last visit eGFR and earlier age of stone presentation than the unresolved group. Specific phenotypes and younger diagnostic age were associated with a monogenic cause, allowing refinement of future screenings. Background Urinary stone disease with a clear genetic cause, monogenic stone disease (MSD), is increasingly recognized as a significant proportion of the total population. When MSD is suspected, genetic testing provides a firm diagnosis that can alter management and treatment. Here, we present testing results from a large cohort with suspected MSD. Methods Patients with features suggestive of MSD (early onset, family history, frequent stones, nephrocalcinosis [NC], and/or CKD) were recruited by the Rare Kidney Stone Consortium and genotyped for up to 160 known or candidate MSD genes via a targeted massively parallel sequencing panel. We compared clinical and biochemical features between genetically resolved MSD and unresolved individuals. Results Of 426 families (657 patients) enrolled, 145 (34%) were resolved with identified disease associated variants in 22 known MSD genes. Ninety-nine families were biallelic, 37 monoallelic, and two digenic. An additional 21 of the 231 screened family members were resolved. Genes identified in ten or more families include the following: AGXT , HOGA1 , SLC34A3 , CYP24A1 , SLC3A1 , and CLCN5 . Compared with the unresolved group, MSD probands had a lower baseline and last visit eGFR, earlier age of stone presentation, and more stone events and procedures/year of life. The resolve rate was higher in those <16 years, and NC was seen earlier in the MSD group. Overall, NC was a risk factor for lower eGFR. Among the specific disorders, patients with primary hyperoxaluria had the earliest age of stone and NC diagnosis, and as expected, the highest urinary oxalate level. Conclusions Our study emphasizes the value of selecting patients enriched for factors associated with MSD, and comprehensive genetic testing to achieve a high yield of genetic diagnoses. Significant clinical and biochemical characteristics of patients with MSD were defined. A definitive MSD diagnosis facilitates individualized management and strategies to delay disease progression in probands and affected family members.

Background: Cardiomyopathies (CM) are a leading cause of heart failure. Identification of genetic risk preemptively may allow detection of the earliest phenotypic manifestations through implementation of interval-based cardiac screening. Previous population-based genetic screening studies have limited follow-up and inadequate phenotyping. Hypothesis: Disease penetrance of CM variants is significantly higher than previously reported. Aims: To determine the prevalence, penetrance, and disease expression of incidental CM-related genetic variants in an unselected, richly phenotyped, adult population. Methods: We analyzed a random sample of 10,000 patients from a quaternary medical center-based biobank cohort for reportable variants in 22-cardiomyopathy genes. Prioritization of genetic variants was performed using Semi-Automated Variant Interpretation, a novel software that has been previously developed and validated at our center. Prioritized variants were then manually curated by 2 independent variant interpretation specialists. Clinical phenotypes and outcomes of participants with likely pathogenic/pathogenic (LP/P) variants were determined. Results: LP/P cardiomyopathy variants were present in 1% of our cohort (n=104) within the following genes: TNNT2 (n=1), DES (n=2), LMNA (n=2), MYL2 (n=2), TNNI3 (n=2), DSG (n=4), FLNC (n=4), DSC2 (n=6), SCN5A (n=7), PKP2 (n=10), DSP (n=12), MYH7 (n=14), TTN (n=17), MYBPC3 (n=21). Only 1 participant carried two different LP/P variants. A definitive disease penetrance defined as heart failure or cardiomyopathy was found in 34% of genotype positive (G+) individuals. Possible disease penetrance defined as presence of structural heart disease identified by echocardiography was found in an additional 16% of participants (concentric left ventricular hypertrophy, diastolic dysfunction, biatrial and left atrial enlargement). Combined definitive and possible disease penetrance was found in 50% of G+ individuals. Arrhythmias and/or cardiac conduction disease (atrial fibrillation, atrioventricular block, ventricular arrhythmia) were present in 31% of G+ individuals. Conclusion: Cardiomyopathy associated LP/P variants are present in a small subset of a large quaternary medical center population as previously reported but unlike prior studies, disease penetrance manifesting as cardiac structural abnormalities and heart failure is high in G+ individuals.

Vascular abnormalities are the most important non-cystic complications in Polycystic Kidney Disease (PKD) and contribute to renal disease progression. Endothelial dysfunction and oxidative stress are evident in patients with ADPKD, preserved renal function, and controlled hypertension. The underlying biological mechanisms remain unknown. We hypothesized that in early ADPKD, the reactive oxygen species (ROS)-producing nicotinamide adenine dinucleotide phosphate hydrogen (NAD(P)H)-oxidase complex-4 (NOX4), a major source of ROS in renal tubular epithelial cells (TECs) and endothelial cells (ECs), induces EC mitochondrial abnormalities, contributing to endothelial dysfunction, vascular abnormalities, and renal disease progression. Renal oxidative stress, mitochondrial morphology (electron microscopy), and NOX4 expression were assessed in 4- and 12-week-old PCK and Sprague-Dawley (wild-type, WT) control rats (n = 8 males and 8 females each). Endothelial function was assessed by renal expression of endothelial nitric oxide synthase (eNOS). Peritubular capillaries were counted in hematoxylin–eosin (H&E)-stained slides and correlated with the cystic index. The enlarged cystic kidneys of PCK rats exhibited significant accumulation of 8-hydroxyguanosine (8-OHdG) as early as 4 weeks of age, which became more pronounced at 12 weeks. Mitochondria of TECs lining cysts and ECs exhibited loss of cristae but remained preserved in non-cystic TECs. Renal expression of NOX4 was upregulated in TECs and ECs of PCK rats at 4 weeks of age and further increased at 12 weeks. Contrarily, eNOS immunoreactivity was lower in PCK vs. WT rats at 4 weeks and further decreased at 12 weeks. The peritubular capillary index was lower in PCK vs. WT rats at 12 weeks and correlated inversely with the cystic index. Early PKD is associated with NOX4-induced oxidative stress and mitochondrial abnormalities predominantly in ECs and TECs lining cysts. Endothelial dysfunction precedes capillary loss, and the latter correlates with worsening of renal disease. These observations position NOX4 and EC mitochondria as potential therapeutic targets in PKD.