RT Journal Article
SR Electronic
T1 Diagnostic validity and clinical utility of genetic testing for hypertrophic cardiomyopathy: a systematic review and meta-analysis
JF Open Heart
JO Open Heart
FD British Cardiovascular Society
SP e001815
DO 10.1136/openhrt-2021-001815
VO 9
IS 1
A1 Susan Christian
A1 Allison Cirino
A1 Brittany Hansen
A1 Stephanie Harris
A1 Andrea M Murad
A1 Jaime L Natoli
A1 Jennifer Malinowski
A1 Melissa A Kelly
YR 2022
UL http://openheart.bmj.com/content/9/1/e001815.abstract
AB Objective This study summarises the diagnostic validity and clinical utility of genetic testing for patients with hypertrophic cardiomyopathy (HCM) and their at-risk relatives.Methods A systematic search was performed in PubMed (MEDLINE), Embase, CINAHL and Cochrane Central Library databases from inception through 2 March 2020. Subgroup and sensitivity analyses were prespecified for individual sarcomere genes, presence/absence of pathogenic variants, paediatric and adult cohorts, family history, inclusion of probands, and variant classification method. Study quality was assessed using the Newcastle-Ottawa tool.Results A total of 132 articles met inclusion criteria. The detection rate based on pathogenic and likely pathogenic variants was significantly higher in paediatric cohorts compared with adults (56% vs 42%; p=0.01) and in adults with a family history compared with sporadic cases (59% vs 33%; p=0.005). When studies applied current, improved, variant interpretation standards, the adult detection rate significantly decreased from 42% to 33% (p=0.0001) because less variants met criteria to be considered pathogenic. The mean difference in age-of-onset in adults was significantly earlier for genotype-positive versus genotype-negative cohorts (8.3 years; p<0.0001), MYH7 versus MYBPC3 cohorts (8.2 years; p<0.0001) and individuals with multiple versus single variants (7.0 years; p<0.0002). Overall, disease penetrance in adult cohorts was 62%, but differed significantly depending on if probands were included or excluded (73% vs 55%; p=0.003).Conclusions This systematic review and meta-analysis is the first, to our knowledge, to collectively quantify historical understandings of detection rate, genotype-phenotype associations and disease penetrance for HCM, while providing the answers to important routine clinical questions and highlighting key areas for future study.Data are available upon reasonable request. Data are available from Susan Christian at smc12@ualberta.ca.