The genetic architecture of pediatric cardiomyopathy.

2022

2022 Jan 10

1537-6605

<p>To understand the genetic contribution to primary pediatric cardiomyopathy, we performed exome sequencing in a large cohort of 528 children with cardiomyopathy. Using clinical interpretation guidelines and targeting genes implicated in cardiomyopathy, we identified a genetic cause in 32% of affected individuals. Cardiomyopathy sub-phenotypes differed by ancestry, age at diagnosis, and family history. Infants &lt; 1 year were less likely to have a molecular diagnosis (p &lt; 0.001). Using a discovery set of 1,703 candidate genes and informatic tools, we identified rare and damaging variants in 56% of affected individuals. We see an excess burden of damaging variants in affected individuals as compared to two independent control sets, 1000 Genomes Project (p &lt; 0.001) and SPARK parental controls (p &lt; 1&nbsp;× 10). Cardiomyopathy variant burden remained enriched when stratified by ancestry, variant type, and sub-phenotype, emphasizing the importance of understanding the contribution of these factors to genetic architecture. Enrichment in this discovery candidate gene set suggests multigenic mechanisms underlie sub-phenotype-specific causes and presentations of cardiomyopathy. These results identify important information about the genetic architecture of pediatric cardiomyopathy and support recommendations for clinical genetic testing in children while illustrating differences in genetic architecture by age, ancestry, and sub-phenotype and providing rationale for larger studies to investigate multigenic contributions.</p>

10.1016/j.ajhg.2021.12.006

Am J Hum Genet

35026164

Genetic Causes of Cardiomyopathy in Children: First Results From the Pediatric Cardiomyopathy Genes Study.

2021

e017731

2021 Apr 28

2047-9980

<p>Background Pediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices. Methods and Results Children with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. Of the 152 enrolled probands, 41% had a family history of cardiomyopathy. Of 81 (53%) who had undergone clinical genetic testing for cardiomyopathy before enrollment, 39 (48%) had a positive result. Genetic testing rates varied from 0% to 97% between sites. A positive family history and hypertrophic cardiomyopathy subtype were associated with increased likelihood of genetic testing (=0.005 and =0.03, respectively). A molecular cause was identified in an additional 21% of the 63 children who did not undergo clinical testing, with positive results identified in both familial and idiopathic cases and across all phenotypic subtypes. Conclusions A definitive molecular genetic diagnosis can be made in a substantial proportion of children for whom the cause and heritable nature of their cardiomyopathy was previously unknown. Practice variations in genetic testing are great and should be reduced. Improvements can be made in comprehensive cardiac screening and predictive genetic testing in first-degree relatives. Overall, our results support use of routine genetic testing in cases of both familial and idiopathic cardiomyopathy. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01873963.</p>

10.1161/JAHA.120.017731

J Am Heart Assoc

33906374

No Obesity Paradox in Pediatric Patients With Dilated Cardiomyopathy.

2018

222-230

2018 Mar

2213-1787

<p><strong>OBJECTIVES: </strong>This study aimed to examine the role of nutrition in pediatric dilated cardiomyopathy (DCM).</p>

<p><strong>BACKGROUND: </strong>In adults with DCM, malnutrition is associated with mortality, whereas obesity is associated with survival.</p>

<p><strong>METHODS: </strong>The National Heart, Lung, and Blood Institute-funded Pediatric Cardiomyopathy Registry was used to identify patients with DCM and categorized by anthropometric measurements: malnourished (MN) (body mass index [BMI]&nbsp;&lt;5% for&nbsp;≥2 years or weight-for-length&nbsp;&lt;5% for&nbsp;&lt;2 years), obesity (BMI &gt;95% for age&nbsp;≥2 years or weight-for-length &gt;95% for&nbsp;&lt;2 years), or normal bodyweight (NB). Of 904 patients with DCM, 23.7% (214) were MN, 13.3% (120) were obese, and 63.1% (570) were NB.</p>

<p><strong>RESULTS: </strong>Obese patients were older (9.0 vs. 5.7 years for NB; p&nbsp;&lt; 0.001) and more likely to have a family history of DCM (36.1% vs. 23.5% for NB; p&nbsp;= 0.023). MN patients were younger (2.7 years vs. 5.7 years for NB; p&nbsp;&lt; 0.001) and more likely to have heart failure (79.9% vs. 69.7% for NB; p&nbsp;= 0.012), cardiac dimension z-scores &gt;2, and higher ventricular mass compared with NB. In multivariable analysis, MN was associated with increased risk of death (hazard&nbsp;ratio [HR]: 2.06; 95% confidence interval [CI]: 1.66 to 3.65; p&nbsp;&lt; 0.001); whereas obesity was not (HR: 1.49; 95% CI: 0.72 to 3.08). Competing outcomes analysis demonstrated increased risk of mortality for MN compared with NB (p&nbsp;=&nbsp;0.03), but no difference in transplant rate (p&nbsp;= 0.159).</p>

<p><strong>CONCLUSIONS: </strong>Malnutrition is associated with increased mortality and other unfavorable echocardiographic and clinical&nbsp;outcomes compared with those of NB. The same effect of obesity on survival was not observed. Further studies are needed investigating the long-term impact of abnormal anthropometric measurements on outcomes in pediatric DCM. (Pediatric&nbsp;Cardiomyopathy Registry; NCT00005391).</p>

10.1016/j.jchf.2017.11.015

JACC Heart Fail

29428438

Prevalence, predictors, and outcomes of cardiorenal syndrome in children with dilated cardiomyopathy: a report from the Pediatric Cardiomyopathy Registry.

2015

2177-88

2015 Dec

1432-198X

<p><strong>BACKGROUND: </strong>The association of cardiorenal syndrome (CRS) with mortality in children with dilated cardiomyopathy (DCM) is unknown.</p>

<p><strong>METHODS: </strong>With a modified Schwartz formula, we estimated glomerular filtration rates (eGFR) for children ≥1 year of age with DCM enrolled in the Pediatric Cardiomyopathy Registry at the time of DCM diagnosis and annually thereafter. CRS was defined as an eGFR of &lt;90 mL/min/1.73 m(2). Children with and without CRS were compared on survival and serum creatinine concentrations (SCr). The association between eGFR and echocardiographic measures was assessed with linear mixed-effects regression models.</p>

<p><strong>RESULTS: </strong>Of 285 eligible children with DCM diagnosed at ≥1 year of age, 93 were evaluable. CRS was identified in 57 of these 93 children (61.3%). Mean (standard deviation) eGFR was 62.0 (22.6) mL/min/1.73 m(2) for children with CRS and 108.0 (14.0) for those without (P &lt; 0.001); median SCr concentrations were 0.9 and 0.5 mg/dL, respectively (P &lt; 0.001). The mortality hazard ratio of children with CRS versus those with no CRS was 2.4 (95% confidence interval 0.8-7.4). eGFR was positively correlated with measures of left ventricular function and negatively correlated with age.</p>

<p><strong>CONCLUSIONS: </strong>CRS in children newly diagnosed with DCM may be associated with higher 5-year mortality. Children with DCM, especially those with impaired left ventricular function, should be monitored for renal disease.</p>

10.1007/s00467-015-3165-8

Pediatr. Nephrol.

26210985