Circulation: Genomic and Precision Medicine最新文献

Background: Familial hypercholesterolemia (FH) is a common but underdiagnosed genetic disorder characterized by high low-density lipoprotein cholesterol levels and premature cardiovascular disease. Current sequencing methods to diagnose FH are expensive and time-consuming. In this study, we evaluated the accuracy of a low-cost, high-throughput genotyping array for diagnosing FH.

Methods: An Illumina Global Screening Array was customized to include probes for 636 variants, previously classified as FH-causing variants. First, its theoretical coverage was assessed in all FH variant carriers diagnosed through next-generation sequencing between 2016 and 2022 in the Netherlands (n=1772). Next, the performance of the array was validated in another sample of FH variant carriers previously identified in the Dutch FH cascade screening program (n=1268).

Results: The theoretical coverage of the array for FH-causing variants was 91.3%. Validation of the array was assessed in a sample of 1268 carriers of whom 1015 carried a variant in LDLR, 250 in APOB, and 3 in PCSK9. The overall sensitivity was 94.7% and increased to 98.2% after excluding participants with variants not included in the array design. Copy number variation analysis yielded a 89.4% sensitivity. In 18 carriers, the array identified a total of 19 additional FH-causing variants. Subsequent DNA analysis confirmed 5 of the additionally identified variants, yielding a false-positive result in 16 subjects (1.3%).

Conclusions: The FH genotyping array is a promising tool for genetically diagnosing FH at low costs and has the potential to greatly increase accessibility to genetic testing for FH. Continuous customization of the array will further improve its performance.

Background: Many cardiovascular disorders propel the development of advanced heart failure that necessitates cardiac transplantation. When treatable causes are excluded, studies to define causes are often abandoned, resulting in a diagnosis of end-stage idiopathic cardiomyopathy. We studied whether DNA sequence analyses could identify unrecognized causes of end-stage nonischemic cardiomyopathy requiring heart transplantation and whether the prevalence of genetic causes differed from ambulatory cardiomyopathy cases.

Methods: We performed whole exome and genome sequencing of 122 explanted hearts from 101 adult and 21 pediatric patients with idiopathic cardiomyopathy from a single center. Data were analyzed for pathogenic/likely pathogenic variants in nuclear and mitochondrial genomes and assessed for nonhuman microbial sequences. The frequency of damaging genetic variants was compared among cardiomyopathy cohorts with different clinical severity.

Results: Fifty-four samples (44.3%) had pathogenic/likely pathogenic cardiomyopathy gene variants. The frequency of pathogenic variants was similar in pediatric (42.9%) and adult (43.6%) samples, but the distribution of mutated genes differed (P=8.30×10^-4). The prevalence of causal genetic variants was significantly higher in end-stage than in previously reported ambulatory adult dilated cardiomyopathy cases (P<0.001). Among remaining samples with unexplained causes, no damaging mitochondrial variants were identified, but 28 samples contained parvovirus genome sequences, including 2 samples with 6- to 9-fold higher levels than the overall mean levels in other samples.

Conclusions: Pathogenic variants and viral myocarditis were identified in 45.9% of patients with unexplained end-stage cardiomyopathy. Damaging gene variants are significantly more frequent among transplant compared with patients with ambulatory cardiomyopathy. Genetic analyses can help define cause of end-stage cardiomyopathy to guide management and risk stratification of patients and family members.

Previous studies on cardiomyopathies have been particularly valuable for clarifying pathological mechanisms in heart failure, an etiologically heterogeneous disease. In this review, we specifically focus on cardiomyopathies in Asia, where heart failure is particularly pertinent. There has been an increase in prevalence of cardiomyopathies in Asia, in sharp contrast with the decline observed in Western countries. Indeed, important disparities in cardiomyopathy incidence, clinical characteristics, and prognosis have been reported in Asian versus White cohorts. These have been accompanied by emerging descriptions of a distinct rare and common genetic basis for disease among Asian cardiomyopathy patients marked by an increased burden of variants with uncertain significance, reclassification of variants deemed pathogenic based on evidence from predominantly White cohorts, and the discovery of Asian-specific cardiomyopathy-associated loci with underappreciated pathogenicity under conventional classification criteria. Findings from epigenetic studies of heart failure, particularly DNA methylation studies, have complemented genetic findings in accounting for the phenotypic variability in cardiomyopathy. Though extremely limited, findings from Asian ancestry-focused DNA methylation studies of cardiomyopathy have shown potential to contribute to general understanding of cardiomyopathy pathophysiology by proposing disease and cause-relevant pathophysiological mechanisms. We discuss the value of multiomics study designs incorporating genetic, methylation, and transcriptomic information for future DNA methylation studies in Asian cardiomyopathy cohorts to yield Asian ancestry-specific insights that will improve risk stratification in the Asian population.

Background: Variants in the DMD gene, that encodes the cytoskeletal protein, dystrophin, cause a severe form of dilated cardiomyopathy (DCM) associated with high rates of heart failure, heart transplantation, and ventricular arrhythmias. Improved early detection of individuals at risk is needed.

Methods: Genetic testing of 40 male probands with a potential X-linked genetic cause of primary DCM was undertaken using multi-gene panel sequencing, multiplex polymerase chain reaction, and array comparative genomic hybridization. Variant location was assessed with respect to dystrophin isoform patterns and exon usage. Telomere length was evaluated as a marker of myocardial dysfunction in left ventricular tissue and blood.

Results: Four pathogenic/likely pathogenic DMD variants were found in 5 probands (5/40: 12.5%). Only one rare variant was identified by gene panel testing with 3 additional multi-exon deletion/duplications found following targeted assays for structural variants. All of the pathogenic/likely pathogenic DMD variants involved dystrophin exons that had percent spliced-in scores >90, indicating high levels of constitutive expression in the human adult heart. Fifteen DMD variant-negative probands (15/40: 37.5%) had variants in autosomal genes including TTN, BAG3, LMNA, and RBM20. Myocardial telomere length was reduced in patients with DCM irrespective of genotype. No differences in blood telomere length were observed between genotype-positive family members with/without DCM and controls.

Conclusions: Primary genetic testing using multi-gene panels has a low yield and specific assays for structural variants are required if DMD-associated cardiomyopathy is suspected. Distinguishing X-linked causes of DCM from autosomal genes that show sex differences in clinical presentation is crucial for informed family management.

Background: Lp(a) (lipoprotein[a]) is a highly atherogenic lipoprotein subfraction that may contribute to polygenic risk of coronary artery disease (CAD), but the extent of this contribution is unknown. Our objective was to estimate the contribution of Lp(a) to polygenic risk of CAD and to evaluate the respective contributions of Lp(a) and a CAD polygenic risk score (PRS) to CAD.

Methods: A total of 372 385 UK Biobank participants of European ancestry free of CAD at baseline were included. Plasma Lp(a) levels were measured and a CAD-PRS was calculated using the LDpred2 algorithm. Over the median follow-up of 12.6 years, 13 538 participants had incident CAD (myocardial infarction, coronary artery bypass grafting, or coronary angioplasty).

Results: The LPA region contribution to the CAD-PRS-mediated CAD risk was modest (7.2% [95% CI, 6.1-8.3]). Lp(a) levels significantly increased the predictive performance of a CAD-PRS including age and sex in Cox regression (C statistic 0.751 versus 0.746, difference, 0.005 [95% CI, 0.004-0.006]). Compared with participants in the bottom CAD-PRS quintile with Lp(a) levels <25 nmol/L (CAD event rate, 1.4%), the hazard ratio for incident CAD in participants in the top CAD-PRS quintile with Lp(a) levels ≥125 nmol/L was 5.45 (95% CI, 4.93-6.03; P=9.35×10^-242, CAD event rate 6.6%).

Conclusions: Compared with individuals with a low genetic risk of CAD (low CAD-PRS and low Lp[a] levels), those with a high genetic risk (high CAD-PRS and high Lp[a] levels) had a 5-fold higher CAD risk. These results highlight a substantial contribution of genetic risk factors to CAD and that accurate estimation of genetic risk of CAD may need to consider blood levels of Lp(a).

Background: Genetic variants in TNNI3K (troponin-I interacting kinase) have previously been associated with dilated cardiomyopathy (DCM), cardiac conduction disease, and supraventricular tachycardias. However, the link between TNNI3K variants and these cardiac phenotypes shows a lack of consensus concerning phenotype and protein function.

Methods: We describe a systematic retrospective study of a cohort of patients undergoing genetic testing for cardiac arrhythmias and cardiomyopathy including TNNI3K. We further performed burden testing of TNNI3K in the UK Biobank. For 2 novel TNNI3K variants, we tested cosegregation. TNNI3K kinase function was estimated by TNNI3K autophosphorylation assays.

Results: We demonstrate enrichment of rare coding TNNI3K variants in DCM patients in the Amsterdam cohort. In the UK Biobank, we observed an association between TNNI3K missense (but not loss-of-function) variants and DCM and atrial fibrillation. Furthermore, we demonstrate genetic segregation for 2 rare variants, TNNI3K-p.Ile512Thr and TNNI3K-p.His592Tyr, with phenotypes consisting of DCM, cardiac conduction disease, and supraventricular tachycardia, together with increased autophosphorylation. In contrast, TNNI3K-p.Arg556_Asn590del, a likely benign variant, demonstrated depleted autophosphorylation.

Conclusions: Our findings demonstrate an increased burden of rare coding TNNI3K variants in cardiac patients with DCM. Furthermore, we present 2 novel likely pathogenic TNNI3K variants with increased autophosphorylation, suggesting that enhanced autophosphorylation is likely to drive pathogenicity.

Background: 1p36 deletion syndrome can predispose to pediatric-onset cardiomyopathy. Deletion breakpoints are variable and may delete the transcription factor PRDM16. Early studies suggest that deletion of PRDM16 may underlie cardiomyopathy in patients with 1p36 deletion; however, the prognostic impact of PRDM16 loss is unknown.

Methods: This retrospective cohort included subjects with 1p36 deletion syndrome from 4 hospitals. Prevalence of cardiomyopathy and freedom from death, cardiac transplantation, or ventricular assist device were analyzed. A systematic review cohort was derived for further analysis. A cardiac-specific Prdm16 knockout mouse (Prdm16 conditional knockout) was generated. Echocardiography was performed at 4 and 6 to 7 months. Histology staining and qPCR were performed at 7 months to assess fibrosis.

Results: The retrospective cohort included 71 patients. Among individuals with PRDM16 deleted, 34.5% developed cardiomyopathy versus 7.7% of individuals with PRDM16 not deleted (P=0.1). In the combined retrospective and systematic review cohort (n=134), PRDM16 deletion-associated cardiomyopathy risk was recapitulated and significant (29.1% versus 10.8%, P=0.03). PRDM16 deletion was associated with increased risk of death, cardiac transplant, or ventricular assist device (P=0.04). Among those PRDM16 deleted, 34.5% of females developed cardiomyopathy versus 16.7% of their male counterparts (P=0.2). We find sex-specific differences in the incidence and the severity of contractile dysfunction and fibrosis in female Prdm16 conditional knockout mice. Further, female Prdm16 conditional knockout mice demonstrate significantly elevated risk of mortality (P=0.0003).

Conclusions: PRDM16 deletion is associated with a significantly increased risk of cardiomyopathy and cardiac mortality. Prdm16 conditional knockout mice develop cardiomyopathy in a sex-biased way. Patients with PRDM16 deletion should be assessed for cardiac disease.