Skip to main content

Abstract

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.
1p36 deletion syndrome is the most common terminal deletion syndrome in humans, affecting approximately 1 in 5000 newborns.1 Children can present with a variety of deficits, including growth delay, intellectual disability, developmental delay, seizures, congenital heart defects, cardiomyopathy, and distinctive craniofacial abnormalities.1–3 Cardiomyopathy is an important clinical feature of 1p36 deletion syndrome as symptomatic pediatric cardiomyopathy carries a 40% risk of death or cardiac transplant within 2 years.4 Recently, 1 cohort of patients with 1p36 deletion syndrome found that 27% of patients had documented cardiomyopathy, particularly noncompaction cardiomyopathy (NCM) and dilated cardiomyopathy (DCM).2 NCM is characterized by prominent ventricular trabeculations with deep intertrabecular recesses.5,6 DCM is defined by a dilated left ventricle with systolic dysfunction, in the absence of an anatomic or hemodynamic cause.7 Of note, NCM can also lead to decreased systolic function and has considerable overlap with DCM.8 Within the 1p36 region, several candidate cardiomyopathic genes have been suggested, which has made the pathogenesis of 1p36 deletion syndrome-associated cardiomyopathy difficult to evaluate and prognosticate.1,3,9
PRDM16, which encodes a zinc-finger transcription factor and plays a role in negative TGF-β regulation, has been put forth as a candidate gene underlying the 1p36 deletion syndrome-associated cardiomyopathy.10,11 However, this remains controversial in humans as several cardiac genes are lost in 1p36 deletion syndrome and analysis of PRDM16 variants demonstrates there are documented nonpathogenic PRDM16 variants.12 Recent associational analyses indicated truncating variants in PRDM16 are associated with NCM,13 further suggesting PRDM16 loss is associated with or causes cardiomyopathy.
Multiple Prdm16 knockout mouse models have been generated to further investigate the role of PRDM16 deletion in cardiomyopathic pathogenesis. These models utilize cardiac-specific PRDM16 knockouts, because germline knockouts are embryonically lethal. There is variation between models, with some demonstrating age-related hypertrophic cardiomyopathy while others demonstrate effects consistent with NCM due to failure of cardiac compaction and maturation.14–18 All models demonstrate substantial cardiac morbidity and mortality caused by isolated Prdm16 loss. Still, there is minimal evidence regarding the role of PRDM16 in the human heart. Prdm16-knockout mice demonstrate cardiomyopathic effects similar to those observed clinically in patients with 1p36 deletion syndrome. Further, human data suggests loss of PRDM16 is associated with NCM.13 It remains to be determined if PRDM16 loss underlies cardiomyopathy observed in 1p36 deletion syndrome in humans and what the impact of this may be on outcomes.
To further elucidate the prognostic impact and clinical cardiovascular outcomes, such as cardiac diagnoses and medical management, of PRDM16 deletion, this multicenter cohort study investigates the outcomes and cardiac manifestations of PRDM16 loss in 1p36 deletion syndrome. We hypothesize that within the spectrum of 1p36 deletion syndrome, deletion of PRDM16 is associated with cardiomyopathy and confers an increased risk of mortality.

METHODS

Full methods are available in the Supplemental Material. The study was approved by the Duke University Hospital IRB. Informed consent was waived. Due to the sensitive nature of the human data collected for this study, requests to access the dataset from qualified researchers trained in human subject confidentiality protocols may be sent to the corresponding author. Murine data are available from the corresponding author upon request.

RESULTS

Cohort Characteristics

We identified a total of 71 patients with a deletion of 1p36 and at least 1 encounter, which comprised the retrospective cohort (Table 1; Figure 1). The median age at diagnosis was 1.4 years (interquartile range, 0.0–9.6). Thirty-seven subjects (52.1%) were female, and 34 subjects (47.9%) were male. Fifty-four individuals (76.1%) had a deletion of 1p36 and no other chromosomal deletions, while 17 subjects (23.9%) had 1p36 deletion as well as another chromosomal abnormality. Thirty subjects (42.3%) lost PRDM16 as part of their 1p36 deletion, henceforth referred to as the PRDM16 deleted group. Twenty-seven (38.0%) did not lose PRDM16 as part of their 1p36 deletion, referred to as the PRDM16 not deleted group. Fourteen patients (19.7%) did not have chromosomal microarrays that clearly identified PRDM16 status and were eliminated from PRDM16-specific analyses. Those with PRDM16 deleted were significantly more likely to have an isolated 1p36 deletion with no other chromosomal aberrations (P=0.003), to be diagnosed earlier (0.2 versus 3.4 years, P=0.02), and to receive an echocardiogram (96.7% versus 48.1%, P<0.0001). There was a female predominance in those with PRDM16 deleted (63.3% female, versus 37.0% female in those with PRDM16 not deleted, P=0.06) compared with males.
Table 1. Demographic and Clinical Features of a Retrospective Cohort of Subjects With 1p36 Deletion Syndrome
VariableTotal cohortPRDM16 Not deletedPRDM16 DeletedSignificance
NDUH1165 
 TCH291811 
 LBCH28311 
 PCH303 
 Total712730 
PRDM16 statusDeleted42.3% (30/71)   
 Not deleted38.0% (27/71)   
 Data unavailable19.7% (14/71)   
Deletion typeIsolated 1p36 deletion76.1% (54/71)55.6% (15/27)83.3% (25/30)P=0.003
 Multiple deletions23.9% (17/71)44.4% (12/27)16.7% (5/30)
Demographic informationMedian age at diagnosis (Y)1.4 (0.0–9.6, N=45)3.4 (1.6–13.0, N=23)0.2 (0.0–1.0, N=22)P=0.02
 Median age at last follow-up (Y)8.3 (4.3–14.2, N=64)9.9 (5.0–16.1, N=23)8.0 (4.0–11.4, N=28)P=0.32
SexFemale52.1% (37/71)37.0% (10/27)63.3% (19/30)P=0.06
 Male47.9% (34/71)63.0% (17/27)36.7% (11/30)
Severe adverse eventsN712730 
 Death5.6% (4/71)0% (0/27)13.3% (4/30)P=0.1
 Transplant1.4% (1/71)*0% (0/27)3.3% (1/30)*P>0.99
 Ventricular assist device1.4% (1/71)*0% (0/27)3.3% (1/30)*P>0.99
 Total7.0% (5/71)0% (0/27)16.7% (5/30)P=0.05
Cardiac phenotypes
EchocardiogramAt least 1 present78.9% (56/71)48.1% (13/27)96.7% (29/30)P<0.0001
CardiomyopathyN531128 
 Noncompaction28.3% (15/53)9.1% (1/11)25.0% (7/28)P=0.4
 Dilated7.5% (4/53)0% (0/11)14.3% (4/28)P=0.3
 Hypertrophic1.9% (1/53)0% (0/11)3.6% (1/28)P>0.99
 Total (any)34.0% (18/53)9.1% (1/11)35.7% (10/28)P=0.1
ArrhythmiaN39524 
 Baseline abnormalities15.4% (6/39)40.0% (2/5)16.7% (4/24)P=0.3
 Arrhythmia0% (0/39)0% (0/5)0% (0/24)P>0.99
 Total15.4% (6/39)40.0% (2/5)16.7% (4/24)P=0.3
Hemodynamically significant structural heart defectsN551329 
Total47.3% (26/55)69.2% (9/13)51.7% (15/29)P=0.3
There were 71 subjects included in this cohort, of which 57 had defined PRDM16 status with 30 subjects harboring a PRDM16 deletion. Demographic, genetic, and clinical features of subjects were obtained. Prevalence was assayed, displayed as percentage with parentheses denoting number of subjects with that feature over total N available for that analysis. P value for count data were derived using a Fisher exact test. Continuous variables, displayed as the mean with the interquartile range and N in brackets, were compared using a Wilcoxon Rank-sum test with continuity correction. DCM indicates dilated cardiomyopathy; DUH, Duke University Hospital; HCM, hypertrophic cardiomyopathy; LBCH, Le Bonheur Children’s Hospital; LVNC, left ventricular noncompaction; PCH, primary children’s hospital; and TCH, Texas Children’s Hospital.
*
Occurred in the same patient.
Three individuals were removed from cardiomyopathy analysis after blinded review deemed their echocardiograms insufficient for evaluation of cardiomyopathy. Of these individuals, two had PRDM16 not deleted and one had PRDM16 deleted.
Figure 1. Study overview for assembly and analysis of the retrospective cohort and the combined retrospective and systematic review cohort (combined cohort). A, Seventy-one subjects were identified from 4 institutions. All 71 subjects were analyzed for structural disease. Fifty-seven subjects had chromosomal microarrays that delineated PRDM16 deletion and a Kaplan-Meier for the primary outcome of death, cardiac transplantation, or ventricular assist device placement was performed stratifying by genotype. Of the 57 patients with defined PRDM16 status, 42 received echocardiograms and those subjects were analyzed using a Kaplan-Meier for the secondary outcome of systolic dysfunction defined as ejection fraction outside of 55% to 70% or reported qualitative read of abnormal. For cardiomyopathy analysis, 3 subjects were excluded due to nondiagnostic echocardiograms for a final N of 40 in genotype-cardiomyopathy analysis. B, A systematic review was performed to acquire additional subjects with defined PRDM16 status and cardiac workups. After filtering and excluding studies, a total of 27 studies remained providing 77 subjects. The combined cohort included a final N of 134. 2×2=2 by 2 contingency table. CMA indicates chromosomal microarray, using single nucleotide polymorphisms (SNP); DUH, Duke University Hospital; KM, Kaplan-Meier curve; LBCH, Le Bonheur Children’s Hospital; PCH, Primary Children’s Hospital; TCH, Texas Children’s Hospital; and VAD, ventricular assist device.
To expand the number of individuals analyzed within this rare disease, this cohort was combined with the systematic review-acquired cases from the literature. This formed a combined cohort (Table S1). The combined cohort included a total of 134 subjects with defined PRDM16 status; 81 subjects had a PRDM16 deletion. As in the retrospective cohort, there was a female predominance in those with PRDM16 deleted (69.1% female, P=0.002).

PRDM16 Deletion Is Associated With Cardiomyopathy

To determine whether there is an association of PRDM16 loss and cardiomyopathy, contingency tables were used to evaluate association between loss of PRMD16 and diagnoses of cardiomyopathy. In the retrospective cohort, there were 39 patients with at least one diagnostic echocardiogram available for review; this subset was used for analysis of cardiomyopathy development and assessment for structural defects (Figure 1). Interestingly, 93.3% (28/30) of patients with PRDM16 deleted received an echocardiogram versus 40.7% (11/27) of those with PRDM16 not deleted (P<0.0001, Table 1). Among those with PRDM16 deleted, 35.7% (10/28) of patients were diagnosed with any cardiomyopathy versus 9.1% (1/11) of patients with PRDM16 not deleted. For all cardiomyopathies, patients with PRDM16 deleted were overrepresented when compared with their PRDM16 not deleted peers (Figure 2A). In the retrospective cohort, the association between PRDM16 deletion and diagnosis of any cardiomyopathy appeared noteworthy but underpowered, prompting the analysis of the combined cohort.
Figure 2. Clinical outcomes in a retrospective cohort of patients with 1p36 deletion syndrome and in a combined cohort including patients with PRDM16 deletion acquired via systematic review. A, Prevalence of cardiomyopathy in the 1p36 deletion syndrome retrospective review cohort with and without PRDM16 deleted. Any cardiomyopathy diagnosis, noncompaction cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy were assessed. B, Prevalence of cardiomyopathy in the combined cohort of retrospective review and systematic review with and without PRDM16 deleted (combined cohort). PRDM16 deletion was associated with any cardiomyopathy diagnosis (P=0.03, Fisher exact test) and noncompaction cardiomyopathy (P=0.03, Fisher exact test). C, A Kaplan-Meier estimator was used to evaluate freedom from death, ventricular assist device placement, or cardiac transplantation among those with 1p36 deletion syndrome in the retrospective cohort (P=0.04, log-rank test). D, A Kaplan-Meier estimator was again used to evaluate freedom from systolic dysfunction defined as echocardiogram with ejection fraction outside 55% to 70% or recorded qualitative read as abnormal among those with 1p36 deletion syndrome in the retrospective cohort (P=0.4, log-rank test). DCM indicates dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; NCM, noncompaction cardiomyopathy; and VAD, ventricular assist device. *P<0.05.
The combined cohort was comprised of 134 individuals of which 116 had diagnostic echocardiograms. The trends were similar and statistically significant. Of those with PRDM16 deleted, 29.1% (23/79) carried a diagnosis of cardiomyopathy versus 10.8% of subjects with PRDM16 not deleted (P=0.03, Figure 2B; Table S2). NCM was specifically associated with PRDM16 deletion; 22.8% (18/79) of those with PRDM16 deleted developed NCM versus 5.4% (2/37) of their PRDM16 not deleted counterparts (P=0.03). Among the retrospective cohort, 15.4% (6/39) subjects had electrophysiological abnormalities and 46.4% (26/56) had hemodynamically significant congenital/structural heart defects; neither was associated with PRDM16 deletion (Table 1). Taken together, these data demonstrate PRDM16 deletion is associated with cardiomyopathy and, in particular, NCM.

PRDM16 Deletion Is Associated With Death, Heart Transplant, and Ventricular Assist Devices

To assess the impact of PRDM16 deletion on the cardiac mortality defined as death, heart transplant, or ventricular assist device (VAD) placement, a Kaplan-Meier survival estimate was generated. Among patients with 1p36 deletion syndrome in the retrospective cohort, loss of PRDM16 significantly increases probability of death, heart transplant, and VAD placement (Figure 2C, P=0.04, log-rank test). Four subjects met the survival outcome: 3 subjects died, and one subjects received a left VAD followed by cardiac transplant. All 4 patients had PRDM16 deleted, suggesting that PRDM16 is a risk locus and is necessary for cardiac mortality in patients with 1p36 deletion syndrome. Of note, each patient who met this outcome did so before the age of 15, supporting the echocardiographic data suggesting PRDM16 loss-mediated cardiac injury in 1p36 deletion syndrome is a primarily a pediatric disease. One additional subject was a fetus following intrauterine fetal demise and subsequent genetic testing discovered PRDM16 deletion in 1p36 deletion syndrome; this subject was removed from this analysis.
Schoenfeld residual testing demonstrated proportionality was not violated, thus permitting covariate analysis for sex-specific effects. In this cohort, there were no significant sex-specific effects on freedom from death, VAD placement, or transplant (Figure S1). While the retrospective cohort was not powered to examine the role of sex in PRDM16 deletion, of the 4 patients who met the composite survival outcome, 3 were female. In summary, we conclude that among those with 1p36 deletion, PRDM16 deletion confers an increased risk of cardiac mortality.

Subjects With PRDM16 Deleted Have High Risk of Systolic Dysfunction

Next, association between PRDM16 loss and systolic dysfunction was analyzed using a Kaplan-Meier estimator. This study analyzed freedom from systolic dysfunction in patients with 1p36 deletion, stratified by loss of PRDM16 (Figure 2D). Notably, systolic dysfunction was common among individuals with PRDM16 deleted, with a 64.4% probability of developing systolic dysfunction by age eighteen. These data suggest that patients who lose PRDM16 as part of their 1p36 deletion are at substantial risk for pediatric-onset systolic dysfunction. Schoenfeld residual testing demonstrated proportionality was not violated, thus permitting covariate analysis for sex-specific effects. In this cohort, there were no significant sex-specific effects on freedom from systolic dysfunction (Figure S1). Altogether, this cohort found that patients with 1p36 deletion syndrome have elevated but variable risk of systolic dysfunction, and that nearly two-thirds of patients with PRMD16 deleted develop pediatric-onset systolic dysfunction.

Medical Management of Cardiovascular Disease in 1p36 Deletion Syndrome

We next explored the medical management of these patients (Table 2). Of those with reported cardiac medications (41), 20 had PRDM16 deleted and 21 had PRDM16 not deleted. Patients with PRDM16 deleted were significantly more likely to be receiving cardiac medications, with 50.0% (10/20) of patients with PRDM16 deleted versus 9.5% (2/21) of patients with PRDM16 not deleted (P=0.006). Patients with PRDM16 deleted were significantly more likely to receive 2 classes of medications: beta blockers (P=0.04) and ACE (angiotensin-converting enzyme) inhibitors, angiotensin receptor blockers, and angiotensin receptor-neprilysin inhibitors (P=0.02). The most common beta blockers were second generation, cardioselective beta blockers (4 patients). The next most common class was third generation, vasodilatory beta blockers (3 patients). No patients received first generation, nonselective beta blockers. Nearly all patients with cardiomyopathy received cardioactive medications and few received cardiac medications without diagnosis of cardiomyopathy (Figure S2). Altogether, patients with PRDM16 deleted were significantly more likely to receive cardiac medications of any kind. Patients with PRDM16 deleted were specifically more likely to receive beta blockers and ACE inhibitors, angiotensin receptor blockers, and angiotensin receptor-neprilysin inhibitors.
Table 2. Medical Management in Patients With 1p36 Deletion Syndrome
VariableTotal cohortPRDM16 Not deletedPRDM16 DeletedSignificance
N412120 
Beta blocker*17.0% (7/41)4.8% (1/21)30.0% (6/20)P=0.04*
 First generation (nonselective)0% (0/41)0% (0/21)0% (0/20)P>0.99
 Second generation (cardioselective)9.8% (4/41)4.8% (1/21)15.0% (3/20)P=0.3
 Third generation (vasodilatory)7.3% (3/41)0% (0/21)15.0% (3/20)P=0.1
ACEI/ARB/ARNI19.5% (8/41)4.8% (1/21)35.0% (7/20)P=0.02*
Diuretics7.3% (3/41)0% (0/21)15.0% (3/20)P=0.1
CCB4.9% (2/41)0% (0/21)10.0% (2/20)P=0.5
Inotrope2.4% (1/41)0% (0/21)5.0% (1/20)P>0.99
Any cardiac medication29.3% (12/41)9.5% (2/21)50.0% (10/20)P=0.006*
Of those in the retrospective cohort, 20 subjects with PRDM16 deleted and 21 subjects with PRDM16 not deleted had medications eligible for review. Medications were queried and categorized into classes. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; and CCB, calcium channel blocker.
*
Beta blockers for noncardiovascular indications were excluded.

Females May Be at Increased Risk of PRDM16 Deletion-Associated Cardiomyopathy

We next explored the possibility that sex as a biological variable may influence phenotype in the setting of PRDM16 deletion. Of those with PRDM16 deletion, 63.3% are female versus 37.0% among those without a PRDM16 deletion (P=0.06). This stark difference prompted analysis of sex effects in PRDM16 deletion. As previously mentioned, among those with PRDM16 deletion, females seem to have excess cardiac mortality and increased risk of systolic dysfunction, although this study was not powered to detect such differences (Figure S1, P=0.8 and P=0.6, respectively). The combined cohort includes a total of 81 individuals with PRDM16 deletion and thus was targeted for analysis. Among those with PRDM16 deletion in the combined cohort, females comprised 69.1% of the cohort and were significantly overrepresented (Figure 3A, P=0.0008). Among those with PRDM16 deletion and cardiomyopathy, females comprised 82.6% of all subjects and were again overrepresented (P=0.003). Among those with PRDM16 deleted, females were twice as likely to carry a diagnosis of cardiomyopathy: 34.6% of females (19/55) were diagnosed with cardiomyopathy versus 16.7% of males (4/24), though this relationship was not significant (Figure 3B, P=0.18). Altogether, these data suggest that females may be especially affected by PRDM16 deletion given their overrepresentation in PRDM16 deletion and potentially increased burden of cardiomyopathy.
Figure 3. Analysis of sex effects on cardiomyopathy in the combined cohort. A, Sex distribution was analyzed in the combined cohort. Subjects with PRDM16 deletion were disproportionately female (P=0.0008, 2-tailed Binomial test). Of subjects with PRDM16 deleted who developed cardiomyopathy, females were again significantly overrepresented (P=0.003, 2-tailed Binomial test). B, Prevalence of cardiomyopathy was analyzed among those with PRDM16 deleted in the combined cohort and stratified by sex. Approximately 35% of females with PRDM16 deleted were diagnosed with cardiomyopathy vs 17% of their male peers (P=0.2, Fisher exact test). . DCM indicates dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; and NCM, noncompaction cardiomyopathy. *P<0.05, †P<0.005.

Cardiac-Specific Prdm16 Conditional Knockout Mice Develop DCM and Fibrosis in a Sex-Biased Way

To further evaluate the effects of sex in PRDM16 deletion, a Prdm16 conditional knockout (cKO) murine model was generated. We monitored cardiac function through blinded echocardiography in Prdm16 cKO mice at 4- and 6 to 7 months. At 4 months of age, female Prdm16 cKO mice had ≈38% reduction in ejection fraction and fractional shortening (FS) (P<0.05) when compared with age- and sex-matched WT controls (Figure 4A and 4B). Female cKO mice also exhibited signs of left ventricular (LV) dilation as evidenced by a significant (P<0.05) increase in LV internal diameter at systole (Figure 4C). Interestingly, none of these parameters were affected in male cKO mice when compared with male WT mice. By 6-7 months of age, both female and male Prdm16 cKO mice displayed a significant decrease in ejection fraction (P<0.005) and FS (P<0.005) indicating impairment of systolic function (Figure 4G and 4H). Furthermore, Prdm16 cKO mice demonstrate increased end-diastolic LV internal dimension (P<0.05) that were more severely affected in female cKO mice versus male cKO mice, when compared with their respective WT controls (Figure 4I and 4J). Finally, only female Prdm16 cKO mice had reduced LV posterior wall in systole, which indicates the development of DCM at 6-7 months (Figure 4K).
Figure 4. Loss of cardiac Prdm16 caused dilated cardiomyopathy in mice in a sex-specific manner. A and G, Percentage ejection fraction; (B and H) Percentage fractional shortening; (C and I) left ventricular internal diameter in systole; (D and J) left ventricular internal diameter in systole (LVIDs); (E and K) left ventricular posterior wall in diastole (LVIDd) and (F and L) left ventricular posterior wall in systole and diastole (LVPWs and LVPWd) in female and male wild-type and Prdm16 conditional knockout (cKO) mice at 4 and 6 to 7 months, respectively. Data are mean±SEM. Number of mice per group: 4 months: wild-type (WT) female (n=7); cKO female (n=6); WT male (n=5) and cKO male (n=9) and 6 to 7 months: WT female (n=10); cKO female (n=5); WT male (n=8) and cKO male (n=6). Data were analyzed by a 2-way ANOVA. *P<0.05, †P<0.005, ‡P<0.0005.
To examine if Prdm16 ablation in cardiac cells induced fibrosis, we performed histological examination using Trichrome and Picrosirius Red staining on predominantly male WT and cKO mice, WT female mice and only 1 female cKO mouse that survived to 7 months. The results demonstrate a 3- (P<0.05) and 8-fold (P<00005) increase in % fibrosis area as assessed by trichrome and picrosirius red, respectively, in the hearts of Prdm16 cKO mice at 7 months (Figure 5A through 5C). Consistent with the early cardiac dysfunction in female mice at 4 months of age, cardiac histology of the only female cKO mouse that survived to 7 months showed qualitatively more fibrosis when compared with age-matched make cKO mice.
Figure 5. Prdm16 conditional knockout (cKO) mice develop structural remodeling and fibrosis that is worse in female than male mice. A, Representative images of heart sections stained with trichrome or picrosirius red from wild-type (WT) and Prdm16 cKO female and male mice at 7 months. B and C, Quantification of fibrosis as expressed by % blue area over total area for trichrome or % red area over total area for picrosirius red in hearts from 7 months male and female WT and Predm16 cKO mice combined. D, Relative mRNA expression of Prdm16, Nppb (encoding natriuretic peptide b), Myh7 (myosin heavy chain 7), Tgfb (transforming growth factor beta), and Cola1 (collagen type I alpha 1 chain) in hearts from 7 months male and female WT and Prdm16 cKO mice combined. Data are mean±SEM. n=3 WT and 4 cKO for B and C and n=7 WT and 4 cKO mice for D. Data were analyzed using a Student t test to compare WT vs cKO mice (male and female combined). *P<0.05, †P<0.005, ‡P<0.0005.
As Prdm16 loss was linked to myocardial fibrosis development14,15 we next examined the expression of fibrotic genes by qPCR on male WT, male cKO mice, WT female mice, and one surviving female cKO mouse. In addition to observing the expected loss Prdm16 mRNA expression in the hearts of Prdm16 cKO mice (Figure 5D, P<0.005), we also observed elevated expression of the profibrotic genes Tgfb2, Tgfb3, and Cola1 (Figure 5D, P<0.05).19,20 In addition, we detected a nearly 10-fold increased expression of the natriuretic peptide gene Nppb though this was not significant (Figure 5D, P=0.06). Altogether the histological examination and qPCR analysis indicated a crucial role for Prdm16 in fibrosis in the murine heart.

Female Prdm16 cKO Mice Have Unique Risk of Mortality

Given the increased mortality among 1p36 deletion patients who lost PRDM16, we next determined whether loss of Prdm16 was associated with decreased survival. Indeed, Prdm16 cKO mice demonstrate decreased survival (Figure 6A, P=0.02), consistent with the human cohort and suggestive that loss of Prdm16 independently confers an increased risk of death. Because human cohort data suggested there was a potential sex-bias, we sought to evaluate the effects of sex; however, when introducing sex as a covariate, the proportional hazard assumption was violated (Figure S3, Schoenfeld residual P<0.05) thus a stratification approach was used. Interestingly, PRDM16 cKO demonstrated no effect on survival in male mice (Figure 6B, P=0.8). Female Prdm16 cKO mice, however, demonstrate remarkably poor survival with 100% of the female mice dying by week 29 (Figure 6C, P=0.0003). These data demonstrate that Prdm16 is critical for the maintenance of cardiac function and the prevention of fibrosis in the murine heart, with female mice demonstrating special vulnerability and especially deleterious outcomes.
Figure 6. Prdm16 deletion confers a significantly increased risk of death in female mice. A, A Kaplan-Meier estimator was used to evaluate freedom from death in mice with Prdm16 conditional knockout (cKO; n=16) vs wild-type (WT) mice (n=14) of all sexes. Prdm16 cKO have worse survival (P=0.02, log-rank test). B, A Kaplan-Meier estimator was used to evaluate freedom from death in male Prdm16 cKO mice (n=10) vs Prdm16 WT mice (n=7). Among male mice, Prdm16 cKO does not have an effect on survival (P=0.8, log-rank test). C, A Kaplan-Meier estimator was used to evaluate freedom from death in female Prdm16 cKO mice, demonstrating female Prdm16 cKO mice (n=6) have a uniquely poor survival (P=0.0003, long-rank test) compared with female Prdm16 WT mice (n=7).

DISCUSSION

1p36 deletion syndrome is genetically and phenotypically heterogeneous. Genetically, patients present with a range of deletion sizes and some individuals may have additional chromosomal deletions or translocations. Phenotypically, patients display a spectrum of neurological, craniofacial, and cardiovascular defects.1 To address the putative causative role of PRDM16 loss in development of cardiomyopathy and adverse outcomes in 1p36 deletion syndrome, we assembled a multicenter cohort to date of patients with 1p36 deletion syndrome and stratified the cohort by PRDM16 status. We then combined this cohort with reported cases of PRDM16 deletion in literature via a systematic review to validate PRDM16’s role in cardiomyopathy and investigate possible sex effects. In addition, we created a mouse model of Prdm16 deletion in cardiomyocytes to examine the role of sex in Prdm16 deletion-induced cardiomyopathy.
Our work builds on prior studies investigating the etiology of cardiac disease in 1p36 deletion syndrome. Arndt et al. performed multiallelic mapping in individuals with 1p36 deletion syndrome and cardiovascular disease and identified a common minimal region of loss containing PRDM16, which they supported with a zebrafish prdm16 knockdown demonstrating bradycardia and reduced cardiac output.10 They also identified 5 individuals with PRDM16 variants in a cohort of patients with cardiomyopathy, associating PRDM16 variants with NCM and DCM.10 As illustrated by De Leeuw et al, this region also contains other candidate cardioactive genes, such as SKI.12 SKI is more distal on the 1p arm; thus, to lose PRDM16, patients with terminal deletions may lose SKI. Consequently, it is difficult to demonstrate from studies of 1p36 deletion syndrome alone that PRDM16 underlies these cardiac effects.
Our cohort validates and builds upon these prior studies. 34.5% of patients with PRDM16 loss were diagnosed with cardiomyopathy, primarily NCM and DCM. Losing PRDM16 as part of 1p36 deletion was associated with significantly increased risk of death, heart transplant, and/or VAD placement; 20.0% of those with PRDM16 deleted met this end point versus 0.0% among patients with 2 intact copies of PRDM16. Interestingly, these patients did not die of isolated progressive heart failure but rather complications from surgical correction of congenital heart disease or systemic infection. This suggests that PRDM16 deletion generates a vulnerable myocardium susceptible to other stressors, which otherwise might be well-tolerated, that manifest this increased risk of death. This is consistent with literature that demonstrates there are genetic conditions that both predispose to cardiomyopathy and confer risk of heart failure and early mortality, such as truncating variants in TTN, encoding the sarcomeric protein titin, which both independently increase risk of DCM and have associated risk of heart failure/early mortality in the setting of peripartum cardiomyopathy or cardiomyopathy due to alcohol.21–23 Regarding the role of SKI, we identified 1 patient who lost SKI but did not lose PRDM16 as part of their deletion. This individual did not develop cardiomyopathy, consistent with the hypothesis that PRDM16 loss is the disease susceptibility locus. This supports previous work that identified 3 patients with isolated individual would be needed to rule out SKI as a contributing factor for cardiomyopathy development.24
In addition to our main findings, we found that individuals with PRDM16 loss were also significantly more likely to be managed on cardioactive medications (50.0% of patients), including beta blockers (30.0% of patients) and ACE inhibitor, angiotensin receptor blocker, and/or angiotensin receptor-neprilysin inhibitors (35.0% of patients). This is largely concordant with guidelines for pediatric heart failure, namely ACE inhibitor, angiotensin receptor blocker, or angiotensin receptor-neprilysin inhibitors with possible escalation to beta blockers.25,26 This work describes how patients with PRDM16 deletion in 1p36 deletion syndrome-associated heart disease are presently managed; further work might build a guideline-informed, unified approach to this genetic subset of cardiomyopathy.
There were no differences between the PRDM16 deleted and not deleted with regards to hemodynamically significant structural heart disease or arrhythmia, suggesting that PRDM16 loss specifically increases risk of cardiomyopathy. This cohort did note female predominance in human PRDM16 deletion (63% female in the retrospective cohort, 69% female in the combined cohort). Importantly, of those with PRDM16 deleted, females appear to have a doubled risk of cardiomyopathy. In the combined cohort, 35% of females with PRDM16 deletion were diagnosed with cardiomyopathy versus 17% of males, although this did not reach statistical significance. Such findings are especially relevant due to potential interface between PRDM16 and estrogen-receptor signaling27 and previously demonstrated Prdm16-deletion-associated hypotension in female mice.18 Our cohort conclusions are limited, however, due to sample size, and thus attention was turned to a murine model.
Given difficulties in studying PRDM16 loss in humans, several Prdm16-deficient animal models have been generated and have produced heterogeneous results. A zebrafish prdm16 knockout model was generated that demonstrated bradycardia and reduced cardiac output.10 Given embryonic lethality in germline murine Prdm16 knockouts, several cardiac-specific conditional knockouts have been generated. Interestingly, the phenotypes have been varied: α-MHC (Myh6)-Cre driven knockout demonstrates hypertrophy in 1 model and LV dilation in another.16,28 Mesp1-Cre-driven knockout demonstrates age-related hypertrophy and heart failure,15 and both Xmlc2-Cre and cTnT-Cre driven knockouts demonstrate noncompaction.16 Possible explanations for these variations include efficiency of the Cre driver, the cell type(s) in which Prdm16 is deleted, the timing of deletion, and background genetic effects.
Our murine model is similar to the one developed by Nam et al14 using the α-MHC (Myh6)-Cre-driven knockout. In contrast to the hypertrophic cardiomyopathy seen by Nam et al, our Prdm16 cKO mice develop a clear DCM phenotype characterized by increased LV dimensions, decreased ejection fraction, increased fibrosis, and increased mortality. The human cohort approached but did not reach statistical significance with regards to PRDM16 loss and cardiomyopathy; the Prdm16 cKO mice clearly demonstrate echocardiographic features consistent with dilated cardiomyopathy. Molecular characterization of these mice demonstrates increased expression of profibrotic and heart failure–associated transcripts. Furthermore, for the first time, we demonstrate sex-specific effects of Prdm16 loss on the incidence and the severity of contractile dysfunction as well as survival with female mice exhibiting unique poor outcomes with Prdm16 cKO. The mechanism underlying this sex difference in survival in Prdm16 cKO mice is not known and is currently being investigated in our laboratory. Altogether, because isolated Prdm16 knockout resembles the cardiac features of 1p36 deletion syndrome observed in this cohort and confirm statistically significant cardiomyopathy risk in a sex-biased way, these data support the hypothesis that PRDM16 loss underlies cardiomyopathy and adverse cardiac outcomes in patients with 1p36 deletion syndrome and females are more affected.
Overall, this study suggests that PRDM16 loss is a risk allele for cardiomyopathy and adverse cardiac outcomes in 1p36 deletion syndrome. This is clinically relevant insofar as it supports cardiac monitoring of these children and informs further research on the role of PRDM16 in cardiac development and maintenance in both sexes.
In summary, this cohort found patients with 1p36 deletion have a substantial burden of cardiac disease including cardiomyopathy and adverse cardiovascular outcomes; yet, cardiology evaluation and follow-up was heterogeneous. Children with PRDM16 loss demonstrate a significantly increased risk of death, transplant, or VAD placement, and nearly 75% were documented to have decreased systolic function. From these data, we propose that clinicians should screen children with 1p36 deletion syndrome, especially those with PRDM16 deleted, for cardiovascular disease.

Study Limitations

There are several limitations to this study. Most notably, there are many genes in the 1p36 region that may influence cardiac development and function, and loss of genes other than PRDM16 may underlie the variability. This is further complicated by varying deletion length in patients with 1p36 deletion syndrome. We address this by identifying a case of SKI loss without PRDM16 loss who did not develop cardiomyopathy and by generating a mouse model that recapitulated our clinical phenotypes with isolated Prdm16 loss. While this study represents one of the largest cohorts today, our sample size was nonetheless small and retrospective in nature, and thus subject to selection bias. Future research regarding clinical features of PRDM16 loss in 1p36 deletion syndrome, in particular, the role of sex as a moderator on risk of cardiac disease, would include development of a validation cohort or prospective cohort analysis. Additionally, comparison between inducible Cre models of cardiac-specific Prdm16 loss could allow for spatiotemporal characterization of Prdm16 expression throughout murine heart development and maintenance.

ARTICLE INFORMATION

Supplemental Material

Supplemental Methods
Tables S1 and S2
Figures S1–S3
References 29–31

Footnote

Nonstandard Abbreviations and Acronyms

ACE
angiotensin-converting enzyme
cKO
conditional knockout
DCM
dilated cardiomyopathy
NCM
noncompaction cardiomyopathy
VAD
ventricular assist device

Supplemental Material

File (circcvg2022003912_updatedsupplement.docx)
File (circgenetics_circcvg-2022-003912_supp1.pdf)

REFERENCES

1.
Jordan VK, Zaveri HP, Scott DA. 1p36 deletion syndrome: an update. Appl Clin Genet. 2015;8:189–200. doi: 10.2147/TACG.S65698
2.
Battaglia A, Hoyme HE, Dallapiccola B, Zackai E, Hudgins L, McDonald-McGinn D, Bahi-Buisson N, Romano C, Williams CA, Brailey LL, et al. Further delineation of deletion 1p36 syndrome in 60 patients: a recognizable phenotype and common cause of developmental delay and mental retardation. Pediatrics. 2008;121:404–410. doi: 10.1542/peds.2007-0929
3.
Zaveri HP, Beck TF, Hernández-García A, Shelly KE, Montgomery T, van Haeringen A, Anderlid BM, Patel C, Goel H, Houge G, et al. Identification of critical regions and candidate genes for cardiovascular malformations and cardiomyopathy associated with deletions of chromosome 1p36. PLoS One. 2014;9:e85600. doi: 10.1371/journal.pone.0085600
4.
Lipshultz SE, Cochran TR, Briston DA, Brown SR, Sambatakos PJ, Miller TL, Carrillo AA, Corcia L, Sanchez JE, Diamond MB, et al. Pediatric cardiomyopathies: causes, epidemiology, clinical course, preventive strategies and therapies. Future Cardiol. 2013;9:817–848. doi: 10.2217/fca.13.66
5.
Jenni R, Oechslin E, Schneider J, Attenhofer Jost C, Kaufmann PA. Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy. Heart. 2001;86:666–671. doi: 10.1136/heart.86.6.666
6.
Towbin JA, Lorts A, Jefferies JL. Left ventricular non-compaction cardiomyopathy. Lancet. 2015;386:813–825. doi: 10.1016/s0140-6736(14)61282-4
7.
Tayal U, Prasad S, Cook SA. Genetics and genomics of dilated cardiomyopathy and systolic heart failure. Genome Med. 2017;9:20. doi: 10.1186/s13073-017-0410-8
8.
Boban M, Pesa V, Persic V, Zulj M, Malcic I, Beck N, Vcev A. Overlapping phenotypes and degree of ventricular dilatation are associated with severity of systolic impairment and late gadolinium enhancement in non-ischemic cardiomyopathies. Med Sci Monit. 2018;24:5084–5092. doi: 10.12659/MSM.909172
9.
Shimada S, Shimojima K, Okamoto N, Sangu N, Hirasawa K, Matsuo M, Ikeuchi M, Shimakawa S, Shimizu K, Mizuno S, et al. Microarray analysis of 50 patients reveals the critical chromosomal regions responsible for 1p36 deletion syndrome-related complications. Brain Dev. 2015;37:515–526. doi: 10.1016/j.braindev.2014.08.002
10.
Arndt AK, Schafer S, Drenckhahn JD, Sabeh MK, Plovie ER, Caliebe A, Klopocki E, Musso G, Werdich AA, Kalwa H, et al. Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy. Am J HumGenet. 2013;93:67–77. doi: 10.1016/j.ajhg.2013.05.015
11.
Shim Y, Go YJ, Kim SY, Kim H, Hwang H, Choi J, Lim BC, Kim KJ, Chae JH. Deep phenotyping in 1p36 deletion syndrome. Ann Child Neurol. 2020;28:131–137. doi: 10.26815/acn.2020.00108
12.
de Leeuw N, Houge G. Loss of PRDM16 is unlikely to cause cardiomyopathy in 1p36 deletion syndrome. Am J Hum Genet. 2014;94:153–154. doi: 10.1016/j.ajhg.2013.11.016
13.
Mazzarotto F, Hawley MH, Beltrami M, Beekman L, de Marvao A, McGurk KA, Statton B, Boschi B, Girolami F, Roberts AM, et al. Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies. Genet Med. 2021;23:856–864. doi: 10.1038/s41436-020-01049-x
14.
Nam JM, Lim JE, Ha TW, Oh B, Kang JO. Cardiac-specific inactivation of Prdm16 effects cardiac conduction abnormalities and cardiomyopathy-associated phenotypes. Am J Physiol Heart Circ Physiol. 2020;318:H764–H777. doi: 10.1152/ajpheart.00647.2019
15.
Cibi DM, Bi-Lin KW, Shekeran SG, Sandireddy R, Tee N, Singh A, Wu Y, Srinivasan DK, Kovalik JP, Ghosh S, et al. Prdm16 deficiency leads to age-dependent cardiac hypertrophy, adverse remodeling, mitochondrial dysfunction, and heart failure. Cell Rep. 2020;33:108288. doi: 10.1016/j.celrep.2020.108288
16.
Wu T, Liang Z, Zhang Z, Liu C, Zhang L, Gu Y, Peterson KL, Evans SM, Fu XD, Chen J. PRDM16 is a compact myocardium-enriched transcription factor required to maintain compact myocardial cardiomyocyte identity in left ventricle. Circulation. 2022;145:586–602. doi: 10.1161/CIRCULATIONAHA.121.056666
17.
Pires KM, Boudina S. Abstract 100: PRDM16 is a novel regulator of cardiac hypertrophy, remodeling and mitochondrial dynamics. Circ Res. 2018;123:A100–A100. doi: 10.1161/res.123.suppl_1.100
18.
Kang JO, Ha TW, Jung HU, Lim JE, Oh B. A cardiac-null mutation of Prdm16 causes hypotension in mice with cardiac hypertrophy via increased nitric oxide synthase 1. PLoS One. 2022;17:e0267938. doi: 10.1371/journal.pone.0267938
19.
Felkin LE, Lara-Pezzi E, George R, Yacoub MH, Birks EJ, Barton PJR. Expression of extracellular matrix genes during myocardial recovery from heart failure after left ventricular assist device support. J Heart Lung Transplant. 2009;28:117–122. doi: 10.1016/j.healun.2008.11.910
20.
Lijnen PJ, Petrov VV, Fagard RH. Induction of cardiac fibrosis by transforming growth factor-β1. Mol Genet Metab. 2000;71:418–435. doi: 10.1006/mgme.2000.3032
21.
Garcia-Pavia P, Kim Y, Restrepo-Cordoba MA, Lunde IG, Wakimoto H, Smith AM, Toepfer CN, Getz K, Gorham J, Patel P, et al. Genetic variants associated with cancer therapy–induced cardiomyopathy. Circulation. 2019;140:31–41. doi: 10.1161/CIRCULATIONAHA.118.037934
22.
Ware JS, Amor-Salamanca A, Tayal U, Govind R, Serrano I, Salazar-Mendiguchía J, García-Pinilla JM, Pascual-Figal DA, Nuñez J, Guzzo-Merello G, et al. Genetic etiology for alcohol-induced cardiac toxicity. J Am Coll Cardiol. 2018;71:2293–2302. doi: 10.1016/j.jacc.2018.03.462
23.
Ware JS, Li J, Mazaika E, Yasso CM, DeSouza T, Cappola TP, Tsai EJ, Hilfiker-Kleiner D, Kamiya CA, Mazzarotto F, et al. Shared genetic predisposition in peripartum and dilated cardiomyopathies. N Engl J Med. 2016;374:233–241. doi: 10.1056/nejmoa1505517
24.
Rosenfeld JA, Crolla JA, Tomkins S, Bader P, Morrow B, Gorski J, Troxell R, Forster-Gibson C, Cilliers D, Hislop RG, et al. Refinement of causative genes in monosomy 1p36 through clinical and molecular cytogenetic characterization of small interstitial deletions. Am J Med Genet A. 2010;152A:1951–1959. doi: 10.1002/ajmg.a.33516
25.
Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Colvin MM, Drazner MH, Filippatos GS, Fonarow GC, Givertz MM, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136:e137–e161. doi: 10.1161/CIR.0000000000000509
26.
Kantor PF, Lougheed J, Dancea A, McGillion M, Barbosa N, Chan C, Dillenburg R, Atallah J, Buchholz H, Chant-Gambacort C, et al; Children’s Heart Failure Study Group. Presentation, diagnosis, and medical management of heart failure in children: Canadian Cardiovascular Society guidelines. Can J Cardiol. 2013;29:1535–1552. doi: 10.1016/j.cjca.2013.08.008
27.
Lapid K, Lim A, Clegg DJ, Zeve D, Graff JM. Oestrogen signalling in white adipose progenitor cells inhibits differentiation into brown adipose and smooth muscle cells. Nat Commun. 2014;5:5196. doi: 10.1038/ncomms6196
28.
Kodo K, Ong SG, Jahanbani F, Termglinchan V, Hirono K, InanlooRahatloo K, Ebert AD, Shukla P, Abilez OJ, Churko JM, et al. iPSC-derived cardiomyocytes reveal abnormal TGF-β signalling in left ventricular non-compaction cardiomyopathy. Nat Cell Biol. 2016;18:1031–1042. doi: 10.1038/ncb3411
29.
Lipshultz SE, Law YM, Asante-Korang A, Austin ED, Dipchand AI, Everitt MD, Hsu DT, Lin KY, Price JF, Wilkinson JD, et al. Cardiomyopathy in children: classification and diagnosis: a scientific statement from the American Heart Association. Circulation. 2019;140:e9–e68. doi: 10.1161/CIR.0000000000000682
30.
Corrigan DJ, Luchsinger LL, Justino de Almeida M, Williams LJ, Strikoudis A, Snoeck HW. PRDM16 isoforms differentially regulate normal and leukemic hematopoiesis and inflammatory gene signature. J Clin Invest. 2018;128:3250–3264. doi: 10.1172/JCI99862
31.
Cho JM, Park SK, Ghosh R, Ly K, Ramous C, Thompson L, Hansen M, Mattera MSLC, Pires KM, Ferhat M, et al. Late-in-life treadmill training rejuvenates autophagy, protein aggregate clearance, and function in mouse hearts. Aging Cell. 2021;20:e13467. doi: 10.1111/acel.13467

eLetters(0)

eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.

Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.

Information & Authors

Information

Published In

Go to Circulation: Genomic and Precision Medicine
Go to Circulation: Genomic and Precision Medicine
Circulation: Genomic and Precision Medicine
Pages: 390 - 400
PubMed: 37395136

Versions

You are viewing the most recent version of this article.

History

Received: 21 August 2022
Accepted: 10 May 2023
Published online: 3 July 2023
Published in print: August 2023

Permissions

Request permissions for this article.

Keywords

  1. cardiac disease
  2. cardiomyopathy
  3. gene knockout
  4. mortality
  5. sex differences

Subjects

Authors

Affiliations

Department of Pediatrics, Division of Pediatric Cardiology (R.J.K., A.C., B.S., L.E.P., M.B.R., K.B.P., K.M., S.L.A., A.P.L.), Duke University School of Medicine, Durham, NC.
Department of Nutrition and Integrative Physiology (A.N.F., O.M.T.R., M.A.H., S.B.), University of Utah, Salt Lake City.
Alice Chan, MD
Department of Pediatrics, Division of Pediatric Cardiology (R.J.K., A.C., B.S., L.E.P., M.B.R., K.B.P., K.M., S.L.A., A.P.L.), Duke University School of Medicine, Durham, NC.
Jeffery Mortenson, MD
Department of Pediatrics, Division of Pediatric Cardiology, University of Tennessee Health Science Center, Memphis (J.M., J.O., H.R.M.).
Jennifer Osher, BA
Department of Pediatrics, Division of Pediatric Cardiology, University of Tennessee Health Science Center, Memphis (J.M., J.O., H.R.M.).
Department of Pediatrics, Division of Pediatric Cardiology (R.J.K., A.C., B.S., L.E.P., M.B.R., K.B.P., K.M., S.L.A., A.P.L.), Duke University School of Medicine, Durham, NC.
Lauren E. Parker, BS
Department of Pediatrics, Division of Pediatric Cardiology (R.J.K., A.C., B.S., L.E.P., M.B.R., K.B.P., K.M., S.L.A., A.P.L.), Duke University School of Medicine, Durham, NC.
Michael B. Rosamilia, MD, MHS https://orcid.org/0000-0003-1927-7176
Department of Pediatrics, Division of Pediatric Cardiology (R.J.K., A.C., B.S., L.E.P., M.B.R., K.B.P., K.M., S.L.A., A.P.L.), Duke University School of Medicine, Durham, NC.
Kyra B. Potter, BS
Department of Pediatrics, Division of Pediatric Cardiology (R.J.K., A.C., B.S., L.E.P., M.B.R., K.B.P., K.M., S.L.A., A.P.L.), Duke University School of Medicine, Durham, NC.
Kaila Moore, BS
Department of Pediatrics, Division of Pediatric Cardiology (R.J.K., A.C., B.S., L.E.P., M.B.R., K.B.P., K.M., S.L.A., A.P.L.), Duke University School of Medicine, Durham, NC.
Sage L. Atkins, BS
Department of Pediatrics, Division of Pediatric Cardiology (R.J.K., A.C., B.S., L.E.P., M.B.R., K.B.P., K.M., S.L.A., A.P.L.), Duke University School of Medicine, Durham, NC.
Baylor Genetic Laboratories (J.A.R.), Baylor College of Medicine, Houston, TX.
Department of Molecular and Human Genetics (J.A.R., D.A.S., S.L.), Baylor College of Medicine, Houston, TX.
Alona Birjiniuk, MD, PhD
Department of Pediatrics, Division of Pediatric Cardiology, Northwestern Feinberg School of Medicine, Chicago, IL (A.B.).
Department of Pediatrics, Section of Pediatric Cardiology (E.J., T.S.H., J.J.K.), Baylor College of Medicine, Houston, TX.
Taylor S. Howard, MD
Department of Pediatrics, Section of Pediatric Cardiology (E.J., T.S.H., J.J.K.), Baylor College of Medicine, Houston, TX.
Department of Pediatrics, Section of Pediatric Cardiology (E.J., T.S.H., J.J.K.), Baylor College of Medicine, Houston, TX.
Department of Molecular and Human Genetics (J.A.R., D.A.S., S.L.), Baylor College of Medicine, Houston, TX.
Seema Lalani, MD
Department of Molecular and Human Genetics (J.A.R., D.A.S., S.L.), Baylor College of Medicine, Houston, TX.
Omid M.T. Rouzbehani, MSC
Department of Nutrition and Integrative Physiology (A.N.F., O.M.T.R., M.A.H., S.B.), University of Utah, Salt Lake City.
Samantha Kaplan, PhD
Medical Center Library & Archives (S.K.), Duke University School of Medicine, Durham, NC.
Marissa A. Hathaway, BS
Department of Nutrition and Integrative Physiology (A.N.F., O.M.T.R., M.A.H., S.B.), University of Utah, Salt Lake City.
Jennifer L. Cohen, MD
Department of Pediatrics, Division of Medical Genetics (J.L.C.), Duke University School of Medicine, Durham, NC.
Department of Pediatrics, Division of Pediatric Cardiology (S.Y.A.), University of Utah, Salt Lake City.
Department of Pediatrics, Division of Pediatric Cardiology, University of Tennessee Health Science Center, Memphis (J.M., J.O., H.R.M.).
Department of Nutrition and Integrative Physiology (A.N.F., O.M.T.R., M.A.H., S.B.), University of Utah, Salt Lake City.
Department of Pediatrics, Division of Pediatric Cardiology (R.J.K., A.C., B.S., L.E.P., M.B.R., K.B.P., K.M., S.L.A., A.P.L.), Duke University School of Medicine, Durham, NC.
Department of Cell Biology (A.P.L.), Duke University School of Medicine, Durham, NC.

Notes

This article was sent to Ruth McPherson, MD, PhD, Guest Editor, for review by expert referees, editorial decision, and final disposition.
*
R.J. Kramer and A.N. Fatahian contributed equally as co-equal first authors.
For Sources of Funding and Disclosures, see page 399–400.
Supplemental Material is available at Supplemental Material.
Correspondence to: Sihem Boudina, PhD, University of Utah Molecular Medicine Program, 15 N 2030 E Bldg No. 533, Rm. 3410B, Salt Lake City, Utah 84112, Email [email protected]
Andrew Landstrom, MD, PhD, Duke University School of Medicine, Box No. 2652, Durham, NC 27278, Email [email protected]

Disclosures

Disclosures The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing performed at Baylor Genetics Laboratories.

Sources of Funding

This work was supported by the National Heart, Lung and Blood Institute (NHLBI) grant R01HL149870-01A1 (Dr Boudina) and the National Center for Advancing Translational Sciences (NCATS) grant UL1TR002538 (Dr Boudina). Dr Landstrom is supported by National Institutes of Health (K08-HL136839, R01-HL149870, R01-EB032726), Doris Duke Charitable Foundation (CSDA-2020098), American Sudden Infant Death Syndrome Institute, John Taylor Babbitt Foundation, The Hartwell Foundation, Additional Ventures, Y.T. and Alice Chen Pediatric Genetics and Genomics Research Center. R.J. Kramer is supported by the Sarnoff Cardiovascular Research Foundation. Dr Martinez is supported by the St. Jude Pediatric Research Recruitment Support Fund.

Metrics & Citations

Metrics

Citations

Download Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.

  1. The Genetic Basis of Sudden Cardiac Death: From Diagnosis to Emerging Genetic Therapies, Annual Review of Medicine, 76, 1, (283-299), (2025).https://doi.org/10.1146/annurev-med-042423-042903
    Crossref
  2. PRDM16 determines specification of ventricular cardiomyocytes by suppressing alternative cell fates, Life Science Alliance, 7, 12, (e202402719), (2024).https://doi.org/10.26508/lsa.202402719
    Crossref
  3. A case report of adolescent myofibrillar myopathy due to a de novo R406W pathogenic variant in desmin with symptoms of “hypertrophic cardiomyopathy”, Heliyon, 10, 3, (e25009), (2024).https://doi.org/10.1016/j.heliyon.2024.e25009
    Crossref
  4. Unravelling the function of prdm16 in human tumours: A comparative analysis of haematologic and solid tumours, Biomedicine & Pharmacotherapy, 178, (117281), (2024).https://doi.org/10.1016/j.biopha.2024.117281
    Crossref
  5. Nonsense Variant PRDM16-Q187X Causes Impaired Myocardial Development and TGF-β Signaling Resulting in Noncompaction Cardiomyopathy in Humans and Mice, Circulation: Heart Failure, 16, 12, (e010351), (2023)./doi/10.1161/CIRCHEARTFAILURE.122.010351
    Abstract
Loading...

View Options

View options

PDF and All Supplements

Download PDF and All Supplements

PDF/EPUB

View PDF/EPUB
Login options

Check if you have access through your login credentials or your institution to get full access on this article.

Personal login Institutional Login
Purchase Options

Purchase this article to access the full text.

Purchase access to this article for 24 hours

PRDM16 Deletion Is Associated With Sex-dependent Cardiomyopathy and Cardiac Mortality: A Translational, Multi-Institutional Cohort Study
Circulation: Genomic and Precision Medicine
  • Vol. 16
  • No. 4

Purchase access to this journal for 24 hours

Circulation: Genomic and Precision Medicine
  • Vol. 16
  • No. 4
Restore your content access

Enter your email address to restore your content access:

Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

Figures

Tables

Media

Share

Share

Share article link

Share

Comment Response