Yield of Clinical Screening for Hypertrophic Cardiomyopathy in Child First-Degree Relatives

Norrish, Gabrielle; Jager, Joanna; Field, Ella; Quinn, Ellie; Fell, Hannah; Lord, E; Cicerchia, Marcos; Ochoa, Juan Pablo; Cervi, Elena; Elliott, Perry; Kaski, Juan Pablo

doi:10.1161/circulationaha.118.038846

Cited by 70 publications

(45 citation statements)

References 23 publications

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“…However, the guidelines for when to offer screening differ by age likely based on previous studies with an underrepresentation of children and pre-adolescents that reported that most HCM does not manifest until adolescence or adulthood 6–10 . Our findings and the recent report by Norrish et al 11 which include large patient cohorts suggest that disease prevalence in children and pre-adolescents is not lower than in adolescents. They found that in 1198 consecutive children aged ≤18 years from 594 families who underwent serial evaluation, 72% of diagnoses were made in pre-adolescents with over a third of patients requiring medical, surgical or device therapy before 18 years of age.…”

Section: Discussionmentioning

confidence: 39%

Family screening for hypertrophic cardiomyopathy: Is it time to change practice guidelines?

Lafrenière-Roula

Bolkier

Zahavich

et al. 2019

European Heart Journal

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Aims Current guidelines recommend initiating family screening for hypertrophic cardiomyopathy (HCM) after age 10 or 12 years unless early screening criteria are met. The aim was to evaluate if current screening guidelines miss early onset disease. Methods and results Children who underwent family screening for HCM before age 18 years were analysed. Major cardiac events (MaCEs) were defined as death, sudden cardiac death (SCD), or need for major cardiac interventions (myectomy, implantable cardioverter-defibrillator insertion, transplantation). Of 524 children screened, 331 were under 10 years of age, 9.9% had echocardiographic evidence of HCM, and 1.1% were symptomatic at first screening. The median (interquartile range) age at HCM onset was 8.9 (4.7–13.4) years, and at MaCE was 10.9 (8.5–14.3) years with a median time to MaCE from HCM onset of 1.5 (0.5–4.1) years. About 52.5% phenotype-positive children and 41% with MaCEs were <10 years old. Only 69% children with early HCM met early screening criteria. Cox regression identified male gender, family history of SCD, and pathogenic variants in MYH7/MYBPC3 as a predictor of early onset HCM and MaCEs. Conclusion A third of children not eligible for early screening by current guidelines had phenotype-positive HCM. MYH7 and MYBC3 mutation-positive patients were at highest risk for developing early HCM and experiencing an event or requiring a major intervention. Our findings suggest that younger family members should be considered for early clinical and genetic screening to identify the subset in need of closer monitoring and interventions.

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Section: Discussionmentioning

confidence: 39%

Family screening for hypertrophic cardiomyopathy: Is it time to change practice guidelines?

Lafrenière-Roula

Bolkier

Zahavich

et al. 2019

European Heart Journal

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“…A further 31 subjects underwent a single screening visit and were also excluded. The final study cohort therefore consisted of 285 individuals from 156 families who did not fulfill diagnostic criteria for HCM at first evaluation; 141 (49.5%) were male and median age at first evaluation was 14.2 years (IQR: 6.8 to 31.6 years); 167 subjects (58.6%) were aged <18 years (including some who have been previously reported [ 9 ]).…”

Section: Resultsmentioning

confidence: 99%

“…All were evaluated between 1988 and October 2018 at the Inherited Cardiovascular Diseases units at The Heart Hospital, St Bartholomew’s Hospital, and Great Ormond Street Hospital in London. All underwent standard electrocardiography (ECG) and 2-dimensional echocardiography at 1 to 3 yearly intervals and cardiac magnetic resonance (CMR) imaging at physician’s discretion as previously described ( 9 ). The study conforms to the declaration of Helsinki ( 10 ) and the retrospective data collection was approved by the local ethics committee (reference 19/WS/0100).…”

Section: Methodsmentioning

confidence: 99%

Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers

Lorenzini

Norrish

Field

et al. 2020

Journal of the American College of Cardiology

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127

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Background Predictive genetic screening of relatives of patients with hypertrophic cardiomyopathy (HCM) caused by sarcomere protein (SP) gene mutations is current standard of care, but there are few data on long-term outcomes in mutation carriers without HCM. Objectives The aim of this study was to determine the incidence of new HCM diagnosis in SP mutation carriers. Methods This was a retrospective analysis of adult and pediatric SP mutation carriers identified during family screening who did not fulfill diagnostic criteria for HCM at first evaluation. Results The authors evaluated 285 individuals from 156 families (median age 14.2 years [interquartile range: 6.8 to 31.6 years], 141 [49.5%] male individuals); 145 (50.9%) underwent cardiac magnetic resonance (CMR). Frequency of causal genes was as follows: MYBPC3 n = 123 (43.2%), MYH7 n = 69 (24.2%), TNNI3 n = 39 (13.7%), TNNT2 n = 34 (11.9%), TPM1 n = 9 (3.2%), MYL2 n = 6 (2.1%), ACTC1 n = 1 (0.4%), multiple mutations n = 4 (1.4%). Median follow-up was 8.0 years (interquartile range: 4.0 to 13.3 years) and 86 (30.2%) patients developed HCM; 16 of 50 (32.0%) fulfilled diagnostic criteria on CMR but not echocardiography. Estimated HCM penetrance at 15 years of follow-up was 46% (95% confidence interval [CI]: 38% to 54%). In a multivariable model adjusted for age and stratified for CMR, independent predictors of HCM development were male sex (hazard ratio [HR]: 2.91; 95% CI: 1.82 to 4.65) and abnormal electrocardiogram (ECG) (HR: 4.02; 95% CI: 2.51 to 6.44); TNNI3 variants had the lowest risk (HR: 0.19; 95% CI: 0.07 to 0.55, compared to MYBPC3 ). Conclusions Following a first negative screening, approximately 50% of SP mutation carriers develop HCM over 15 years of follow-up. Male sex and an abnormal ECG are associated with a higher risk of developing HCM. Regular CMR should be considered in long-term screening.

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“…The patient's father had hypertrophic cardiomyopathy and died at the age of 40 and he had two uncles died with hypertrophic cardiomyopathy as well. This variant had been reported many times in association with hypertrophic cardiomyopathy, either familial [50][51][52] or sporadic 53 in both children 24 and adults. 54 Some of the previously reported patients presented with earlyonset, severe phenotype, or premature death.…”

Section: Resultsmentioning

confidence: 97%

Genetic study of pediatric hypertrophic cardiomyopathy in Egypt

et al. 2020

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Paediatric cardiomyopathy is a progressive and often lethal disorder and the most common cause of heart failure in children. Despite their severe outcomes, their genetic etiology is still poorly characterised. The current study aimed at uncovering the genetic background of idiopathic primary hypertrophic cardiomyopathy in a cohort of Egyptian children using targeted next-generation sequencing. The study included 24 patients (15 males and 9 females) presented to the cardiomyopathy clinic of Cairo University Children’s Hospital with a median age of 2.75 (0.5–14) years. Consanguinity was positive in 62.5% of patients. A family history of hypertrophic cardiomyopathy was present in 20.8% of patients. Ten rare variants were detected in eight patients; two pathogenic variants (8.3%) in MBPC3 and MYH7, and eight variants of uncertain significance in MYBPC3, TTN, VCL, MYL2, CSRP3, and RBM20. Here, we report on the first national study in Egypt that analysed sarcomeric and non-sarcomeric variants in a cohort of idiopathic paediatric hypertrophic cardiomyopathy patients using next-generation sequencing. The current pilot study suggests that paediatric hypertrophic cardiomyopathy in Egypt might have a particular genetic background, especially with the high burden of consanguinity. Including the genetic testing in the routine diagnostic service is important for a better understanding of the pathophysiology of the disease, proper patient management, and at-risk detection. Genome-wide tests (whole exome/genome sequencing) might be better than the targeted sequencing approach to test primary hypertrophic cardiomyopathy patients in addition to its ability for the identification of novel genetic causes.

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Yield of Clinical Screening for Hypertrophic Cardiomyopathy in Child First-Degree Relatives

Abstract: Supplemental Digital Content is available in the text.

Cited by 70 publications

References 23 publications

Family screening for hypertrophic cardiomyopathy: Is it time to change practice guidelines?

Family screening for hypertrophic cardiomyopathy: Is it time to change practice guidelines?

Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers

Genetic study of pediatric hypertrophic cardiomyopathy in Egypt

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