2024 Australia-New Zealand Expert Consensus Statement on Cardiac Amyloidosis.

Over the past 5 years, early diagnosis of and new treatments for cardiac amyloidosis (CA) have emerged that hold promise for early intervention. These include non-invasive diagnostic tests and disease modifying therapies. Recently, CA has been one of the first types of cardiomyopathy to be treated with gene editing techniques. Although these therapies are not yet widely available to patients in Australia and New Zealand, this may change in the near future. Given the rapid pace with which this field is evolving, it is important to view these advances within the Australian and New Zealand context. This Consensus Statement aims to update the Australian and New Zealand general physician and cardiologist with regards to the diagnosis, investigations, and management of CA.

Genetic testing in cardiovascular disease.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally and is responsible for an estimated one-third of deaths as well as significant morbidity and health care utilisation. Technological and bioinformatic advances have facilitated the discovery of pathogenic germline variants for some specific CVDs, including familial hypercholesterolaemia, cardiomyopathies and arrhythmic syndromes. Use of these genetic tests for earlier disease identification is increasing due, in part, to decreasing costs, Medicare rebates, and consumer comfort with genetic testing. However, CVDs that occur more commonly, including coronary artery disease and atrial fibrillation, do not display monogenic inheritance patterns. Genetically, these diseases have generally been associated with many genetic variants each with a small effect size. This complexity can be expressed mathematically as a polygenic risk score. Genetic testing kits that provide polygenic risk scoring are becoming increasingly available directly to private-paying consumers outside the traditional clinical setting. An improved understanding of the evidence of genetics in CVD will offer clinicians new opportunities for individualised risk prediction and preventive therapy.

Polygenic Risk in Families With Spontaneous Coronary Artery Dissection.

Importance: Spontaneous coronary artery dissection (SCAD) is a poorly understood cause of acute coronary syndrome that predominantly affects women. Evidence to date suggests a complex genetic architecture, while a family history is reported for a minority of cases. Objective: To determine the contribution of rare and common genetic variants to SCAD risk in familial cases, the latter via the comparison of a polygenic risk score (PRS) with those with sporadic SCAD and healthy controls. Design, Setting, and Participants: This genetic association study analyzed families with SCAD, individuals with sporadic SCAD, and healthy controls. Genotyping was undertaken for all participants. Participants were recruited between 2017 and 2021. A PRS for SCAD was calculated for all participants. The presence of rare variants in genes associated with connective tissue disorders (CTD) was also assessed. Individuals with SCAD were recruited via social media or from a single medical center. A previously published control database of older healthy individuals was used. Data were analyzed from January 2022 to October 2023. Exposures: PRS for SCAD comprised of 7 single-nucleotide variants. Main Outcomes and Measures: Disease status (familial SCAD, sporadic SCAD, or healthy control) associated with PRS. Results: A total of 13 families with SCAD (27 affected and 12 unaffected individuals), 173 individuals with sporadic SCAD, and 1127 healthy controls were included. A total of 188 individuals with SCAD (94.0%) were female, including 25 of 27 with familial SCAD and 163 of 173 with sporadic SCAD; of 12 unaffected individuals from families with SCAD, 6 (50%) were female; and of 1127 healthy controls, 672 (59.6%) were female. Compared with healthy controls, the odds of being an affected family member or having sporadic SCAD was significantly associated with a SCAD PRS (where the odds ratio [OR] represents an increase in odds per 1-SD increase in PRS) (affected family member: OR, 2.14; 95% CI, 1.78-2.50; adjusted P = 1.96 × 10-4; sporadic SCAD: OR, 1.63; 95% CI, 1.37-1.89; adjusted P = 5.69 × 10-4). This association was not seen for unaffected family members (OR, 1.03; 95% CI, 0.46-1.61; adjusted P = .91) compared with controls. Further, those with familial SCAD were overrepresented in the top quintile of the control PRS distribution (OR, 3.70; 95% CI, 2.93-4.47; adjusted P = .001); those with sporadic SCAD showed a similar pattern (OR, 2.51; 95% CI, 1.98-3.04; adjusted P = .001). Affected individuals within a family did not share any rare deleterious variants in CTD-associated genes. Conclusions and Relevance: Extreme aggregation of common genetic risk appears to play a significant role in familial clustering of SCAD as well as in sporadic case predisposition, although further study is required.

Reduced Ejection Fraction in Elite Endurance Athletes: Clinical and Genetic Overlap With Dilated Cardiomyopathy.

BACKGROUND: Exercise-induced cardiac remodeling can be profound, resulting in clinical overlap with dilated cardiomyopathy, yet the significance of reduced ejection fraction (EF) in athletes is unclear. The aim is to assess the prevalence, clinical consequences, and genetic predisposition of reduced EF in athletes. METHODS: Young endurance athletes were recruited from elite training programs and underwent comprehensive cardiac phenotyping and genetic testing. Those with reduced EF using cardiac magnetic resonance imaging (defined as left ventricular EF <50%, or right ventricular EF <45%, or both) were compared with athletes with normal EF. A validated polygenic risk score for indexed left ventricular end-systolic volume (LVESVi-PRS), previously associated with dilated cardiomyopathy, was assessed. Clinical events were recorded over a mean of 4.4 years. RESULTS: Of the 281 elite endurance athletes (22±8 years, 79.7% male) undergoing comprehensive assessment, 44 of 281 (15.7%) had reduced left ventricular EF (N=12; 4.3%), right ventricular EF (N=14; 5.0%), or both (N=18; 6.4%). Reduced EF was associated with a higher burden of ventricular premature beats (13.6% versus 3.8% with >100 ventricular premature beats/24 h; P=0.008) and lower left ventricular global longitudinal strain (-17%±2% versus -19%±2%; P<0.001). Athletes with reduced EF had a higher mean LVESVi-PRS (0.57±0.13 versus 0.51±0.14; P=0.009) with athletes in the top decile of LVESVi-PRS having an 11-fold increase in the likelihood of reduced EF compared with those in the bottom decile (P=0.034). Male sex and higher LVESVi-PRS were the only significant predictors of reduced EF in a multivariate analysis that included age and fitness. During follow-up, no athletes developed symptomatic heart failure or arrhythmias. Two athletes died, 1 from trauma and 1 from sudden cardiac death, the latter having a reduced right ventricular EF and a LVESVi-PRS >95%. CONCLUSIONS: Reduced EF occurs in approximately 1 in 6 elite endurance athletes and is related to genetic predisposition in addition to exercise training. Genetic and imaging markers may help identify endurance athletes in whom scrutiny about long-term clinical outcomes may be appropriate. REGISTRATION: URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374976&isReview=true; Unique identifier: ACTRN12618000716268.

Genetic Atrial Cardiomyopathies: Common Features, Specific Differences, and Broader Relevance to Understanding Atrial Cardiomyopathy.

Atrial cardiomyopathy is a condition that causes electrical and contractile dysfunction of the atria, often along with structural and functional changes. Atrial cardiomyopathy most commonly occurs in conjunction with ventricular dysfunction, in which case it is difficult to discern the atrial features that are secondary to ventricular dysfunction from those that arise as a result of primary atrial abnormalities. Isolated atrial cardiomyopathy (atrial-selective cardiomyopathy [ASCM], with minimal or no ventricular function disturbance) is relatively uncommon and has most frequently been reported in association with deleterious rare genetic variants. The genes involved can affect proteins responsible for various biological functions, not necessarily limited to the heart but also involving extracardiac tissues. Atrial enlargement and atrial fibrillation are common complications of ASCM and are often the predominant clinical features. Despite progress in identifying disease-causing rare variants, an overarching understanding and approach to the molecular pathogenesis, phenotypic spectrum, and treatment of genetic ASCM is still lacking. In this review, we aim to analyze the literature relevant to genetic ASCM to understand the key features of this rather rare condition, as well as to identify distinct characteristics of ASCM and its arrhythmic complications that are related to specific genotypes. We outline the insights that have been gained using basic research models of genetic ASCM in vitro and in vivo and correlate these with patient outcomes. Finally, we provide suggestions for the future investigation of patients with genetic ASCM and improvements to basic scientific models and systems. Overall, a better understanding of the genetic underpinnings of ASCM will not only provide a better understanding of this condition but also promises to clarify our appreciation of the more commonly occurring forms of atrial cardiomyopathy associated with ventricular dysfunction.

Loss of Sec-1 Family Domain-Containing 1 (scfd1) Causes Severe Cardiac Defects and Endoplasmic Reticulum Stress in Zebrafish.

Dilated cardiomyopathy (DCM) is a common heart muscle disorder that frequently leads to heart failure, arrhythmias, and death. While DCM is often heritable, disease-causing mutations are identified in only ~30% of cases. In a forward genetic mutagenesis screen, we identified a novel zebrafish mutant, heart and head (hahvcc43), characterized by early-onset cardiomyopathy and craniofacial defects. Linkage analysis and next-generation sequencing identified a nonsense variant in the highly conserved scfd1 gene, also known as sly1, that encodes sec1 family domain-containing 1. Sec1/Munc18 proteins, such as Scfd1, are involved in membrane fusion regulating endoplasmic reticulum (ER)/Golgi transport. CRISPR/Cas9-engineered scfd1vcc44 null mutants showed severe cardiac and craniofacial defects and embryonic lethality that recapitulated the phenotype of hahvcc43 mutants. Electron micrographs of scfd1-depleted cardiomyocytes showed reduced myofibril width and sarcomere density, as well as reticular network disorganization and fragmentation of Golgi stacks. Furthermore, quantitative PCR analysis showed upregulation of ER stress response and apoptosis markers. Both heterozygous hahvcc43 mutants and scfd1vcc44 mutants survived to adulthood, showing chamber dilation and reduced ventricular contraction. Collectively, our data implicate scfd1 loss-of-function as the genetic defect at the hahvcc43 locus and provide new insights into the role of scfd1 in cardiac development and function.

DMD-Associated Dilated Cardiomyopathy: Genotypes, Phenotypes, and Phenocopies.

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.

Risks of Ventricular Arrhythmia and Heart Failure in Carriers of RBM20 Variants.

BACKGROUND: Variants in RBM20 are reported in 2% to 6% of familial cases of dilated cardiomyopathy and may be associated with fatal ventricular arrhythmia and rapid heart failure progression. We sought to determine the risk of adverse events in RBM20 variant carriers and the impact of sex on outcomes. METHODS: Consecutive probands and relatives carrying RBM20 variants were retrospectively recruited from 12 cardiomyopathy units. The primary end point was a composite of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF). MVA and ESHF end points were also analyzed separately and men and women compared. Left ventricular ejection fraction (LVEF) contemporary to MVA was examined. RBM20 variant carriers with left ventricular systolic dysfunction (RBM20LVSD) were compared with variant-elusive patients with idiopathic left ventricular systolic dysfunction. RESULTS: Longitudinal follow-up data were available for 143 RBM20 variant carriers (71 men; median age, 35.5 years); 7 of 143 had an MVA event at baseline. Thirty of 136 without baseline MVA (22.0%) reached the primary end point, and 16 of 136 (11.8%) had new MVA with no significant difference between men and women (log-rank P=0.07 and P=0.98, respectively). Twenty of 143 (14.0%) developed ESHF (17 men and 3 women; log-rank P<0.001). Four of 10 variant carriers with available LVEF contemporary to MVA had an LVEF >35%. At 5 years, 15 of 67 (22.4%) RBM20LVSD versus 7 of 197 (3.6%) patients with idiopathic left ventricular systolic dysfunction had reached the primary end point (log-rank P<0.001). RBM20 variant carriage conferred a 6.0-fold increase in risk of the primary end point. CONCLUSIONS: RBM20 variants are associated with a high risk of MVA and ESHF compared with idiopathic left ventricular systolic dysfunction. The risk of MVA in male and female RBM20 variant carriers is similar, but male sex is strongly associated with ESHF.

Multicenter clinical and functional evidence reclassifies a recurrent noncanonical filamin C splice-altering variant.

BACKGROUND: Truncating variants in filamin C (FLNC) can cause arrhythmogenic cardiomyopathy (ACM) through haploinsufficiency. Noncanonical splice-altering variants may contribute to this phenotype. OBJECTIVE: The purpose of this study was to investigate the clinical and functional consequences of a recurrent FLNC intronic variant of uncertain significance (VUS), c.970-4A>G. METHODS: Clinical data in 9 variant heterozygotes from 4 kindreds were obtained from 5 tertiary health care centers. We used in silico predictors and functional studies with peripheral blood and patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Isolated RNA was studied by reverse transcription polymerase chain reaction. iPSC-CMs were further characterized at baseline and after nonsense-mediated decay (NMD) inhibition, using quantitative polymerase chain reaction (qPCR), RNA-sequencing, and cellular electrophysiology. American College of Medical Genetics and Genomics (ACMG) criteria were used to adjudicate variant pathogenicity. RESULTS: Variant heterozygotes displayed a spectrum of disease phenotypes, spanning from mild ventricular dysfunction with palpitations to severe ventricular arrhythmias requiring device shocks or progressive cardiomyopathy requiring heart transplantation. Consistent with in silico predictors, the c.970-4A>G FLNC variant activated a cryptic splice acceptor site, introducing a 3-bp insertion containing a premature termination codon. NMD inhibition upregulated aberrantly spliced transcripts by qPCR and RNA-sequencing. Patch clamp studies revealed irregular spontaneous action potentials, increased action potential duration, and increased sodium late current in proband-derived iPSC-CMs. These findings fulfilled multiple ACMG criteria for pathogenicity. CONCLUSION: Clinical, in silico, and functional evidence support the prediction that the intronic c.970-4A>G VUS disrupts splicing and drives ACM, enabling reclassification from VUS to pathogenic.

Genome-wide association meta-analysis of spontaneous coronary artery dissection identifies risk variants and genes related to artery integrity and tissue-mediated coagulation.

Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions.

Atrial cardiomyopathy: Current and future imaging methods for assessment of atrial structure and function.

Changes in atrial size and function have historically been considered a surrogate marker of ventricular dysfunction. However, it is now recognized that atrial cardiomyopathy (ACM) may also occur as a primary myocardial disorder. Emerging evidence that ACM is a major risk factor for atrial fibrillation, heart failure, and thromboembolic stroke, has highlighted the significance of this disorder and the need for better assessment of atrial metrics in clinical practice. Key barriers in this regard include a lack of standardized criteria or hierarchy for the diagnosis of ACM and lack of consensus for the most accurate phenotyping methods. In this article we review existing literature on ACM, with a focus on current and future non-invasive imaging methods for detecting abnormalities of atrial structure and function. We discuss the relative advantages and disadvantages of transthoracic echocardiography and cardiac magnetic resonance imaging for assessing a range of parameters, including atrial size and contractile function, strain, tissue characteristics, and epicardial adipose tissue. We will also present the potential application of novel imaging methods such as sphericity index and four- or five-dimensional flow.

Heritable defects in telomere and mitotic function selectively predispose to sarcomas.

Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specific pathways underlying cancer susceptibility. Sarcomas are rare malignancies predominantly derived from embryonic mesoderm. To identify pathways specific to mesenchymal cancers, we performed whole-genome germline sequencing on 1644 sporadic cases and 3205 matched healthy elderly controls. Using an extreme phenotype design, a combined rare-variant burden and ontologic analysis identified two sarcoma-specific pathways involved in mitotic and telomere functions. Variants in centrosome genes are linked to malignant peripheral nerve sheath and gastrointestinal stromal tumors, whereas heritable defects in the shelterin complex link susceptibility to sarcoma, melanoma, and thyroid cancers. These studies indicate a specific role for heritable defects in mitotic and telomere biology in risk of sarcomas.

Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant.

BACKGROUND: Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy. METHODS: Individuals with DSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSPtv performed. RESULTS: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSPtv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P<0.0001). CONCLUSIONS: In the largest series of individuals with DSPtv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.

Non-ischaemic dilated cardiomyopathy: recognising the genetic links.

The landscape of genetically related cardiac disease continues to evolve. Heritable genetic variants can be a primary cause of familial or sporadic dilated cardiomyopathy (DCM). There is also increasing recognition that genetic variation is an important determinant of susceptibility to acquired causes of DCM. Genetic forms of DCM can show a wide variety of phenotypic manifestations. Identifying patients who are most likely to benefit from genetic testing is paramount. The objective of this review is to highlight the importance of recognising genetic DCM, key genotype-phenotype correlations and the value of genetic testing in clinical management for both the individual and their family. This is likely to become more relevant as management strategies continue to be refined with genotype-specific recommendations and disease-modifying therapies.

The Athlete's Heart-Challenges and Controversies: JACC Focus Seminar 4/4.

Regular exercise promotes structural, functional, and electrical remodeling of the heart, often referred to as the "athlete's heart," with intense endurance sports being associated with the greatest degree of cardiac remodeling. However, the extremes of exercise-induced cardiac remodeling are potentially associated with uncommon side effects. Atrial fibrillation is more common among endurance athletes and there is speculation that other arrhythmias may also be more prevalent. It is yet to be determined whether this arrhythmic susceptibility is a result of extreme exercise remodeling, genetic predisposition, or other factors. Gender may have the greatest influence on the cardiac response to exercise, but there has been far too little research directed at understanding differences in the sportsman's vs sportswoman's heart. Here in part 4 of a 4-part seminar series, the controversies and ambiguities regarding the athlete's heart, and in particular, its arrhythmic predisposition, genetic, and gender influences are reviewed in depth.

Natural History of MYH7-Related Dilated Cardiomyopathy.

BACKGROUND: Variants in myosin heavy chain 7 (MYH7) are responsible for disease in 1% to 5% of patients with dilated cardiomyopathy (DCM); however, the clinical characteristics and natural history of MYH7-related DCM are poorly described. OBJECTIVES: We sought to determine the phenotype and prognosis of MYH7-related DCM. We also evaluated the influence of variant location on phenotypic expression. METHODS: We studied clinical data from 147 individuals with DCM-causing MYH7 variants (47.6% female; 35.6 ± 19.2 years) recruited from 29 international centers. RESULTS: At initial evaluation, 106 (72.1%) patients had DCM (left ventricular ejection fraction: 34.5% ± 11.7%). Median follow-up was 4.5 years (IQR: 1.7-8.0 years), and 23.7% of carriers who were initially phenotype-negative developed DCM. Phenotypic expression by 40 and 60 years was 46% and 88%, respectively, with 18 patients (16%) first diagnosed at <18 years of age. Thirty-six percent of patients with DCM met imaging criteria for LV noncompaction. During follow-up, 28% showed left ventricular reverse remodeling. Incidence of adverse cardiac events among patients with DCM at 5 years was 11.6%, with 5 (4.6%) deaths caused by end-stage heart failure (ESHF) and 5 patients (4.6%) requiring heart transplantation. The major ventricular arrhythmia rate was low (1.0% and 2.1% at 5 years in patients with DCM and in those with LVEF of ≤35%, respectively). ESHF and major ventricular arrhythmia were significantly lower compared with LMNA-related DCM and similar to DCM caused by TTN truncating variants. CONCLUSIONS: MYH7-related DCM is characterized by early age of onset, high phenotypic expression, low left ventricular reverse remodeling, and frequent progression to ESHF. Heart failure complications predominate over ventricular arrhythmias, which are rare.

Titin-related Cardiomyopathy: Is it a Distinct Disease?

PURPOSE OF REVIEW: Truncating TTN variants (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM), but the underlying mechanisms are incompletely understood and effective therapeutic strategies are lacking. Here we review recent data that shed new light on the functional consequences of TTNtv and how these effects may vary with mutation location. RECENT FINDINGS: Whether TTNtv act by haploinsufficiency or dominant negative effects has been hotly debated. New evidence now implicates both mechanisms in TTNtv-related DCM, showing reduced titin content and persistent truncated titin that may be incorporated into protein aggregates. The extent to which aggregate formation and protein quality control defects differ with TTNtv location and contribute to contractile dysfunction is unresolved. TTNtv-associated DCM has a complex etiology that involves varying combinations of wild-type titin deficiency and dominant negative effects of truncated mutant titin. Therapeutic strategies to improve protein handling may be beneficial in some cases.

Exploring the Genetic Architecture of Spontaneous Coronary Artery Dissection Using Whole-Genome Sequencing.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is a cause of acute coronary syndrome that predominantly affects women. Its pathophysiology remains unclear but connective tissue disorders (CTD) and other vasculopathies have been observed in many SCAD patients. A genetic component for SCAD is increasingly appreciated, although few genes have been robustly implicated. We sought to clarify the genetic cause of SCAD using targeted and genome-wide methods in a cohort of sporadic cases to identify both common and rare disease-associated variants. METHODS: A cohort of 91 unrelated sporadic SCAD cases was investigated for rare, deleterious variants in genes associated with either SCAD or CTD, while new candidate genes were sought using rare variant collapsing analysis and identification of novel loss-of-function variants in genes intolerant to such variation. Finally, 2 SCAD polygenic risk scores were applied to assess the contribution of common variants. RESULTS: We identified 10 cases with at least one rare, likely disease-causing variant in CTD-associated genes, although only one had a CTD phenotype. No genes were significantly associated with SCAD from genome-wide collapsing analysis, however, enrichment for TGF (transforming growth factor)-ß signaling pathway genes was found with analysis of 24 genes harboring novel loss-of-function variants. Both polygenic risk scores demonstrated that sporadic SCAD cases have a significantly elevated genetic SCAD risk compared with controls. CONCLUSIONS: SCAD shares some genetic overlap with CTD, even in the absence of any major CTD phenotype. Consistent with a complex genetic architecture, SCAD patients also have a higher burden of common variants than controls.