Hypertrophic Cardiomyopathy: Genetic Testing and Risk Stratification

Stafford, F.; Thomson, Kate; Butters, Alexandra; Ingles, Jodie

doi:10.1007/s11886-020-01437-4

Cited by 12 publications

(11 citation statements)

References 64 publications

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“…Genetic testing predicts adverse clinical outcomes and becomes an essential part of guiding risk stratification as genetics grows. In the future, genotype may play a more significant role in risk stratification, management, treatment, and prognosis, offering improved outcomes for patients and their families with HCM ( Stafford et al, 2021 ). A recent study proposes that rare variants associated with the inherited arrhythmic syndrome should be reanalyzed within 5 years, if already classified following ACMG recommendations, since it seems to be adequate to manage the rapid obsolescence of genetic data interpretations ( Campuzano et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Case Report: A Chinese Family of Hypertrophic Cardiomyopathy Caused by a Novel Splicing Mutation in the FLNC Gene

Huang¹,

Zheng²,

Zhang³

et al. 2022

Front. Genet.

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Hypertrophic cardiomyopathy (HCM) is a type of primary cardiomyopathy with genetic etiology, and it carries a high risk of diastolic dysfunction, heart failure, and malignant arrhythmias. We reported the first familial HCM in China, caused by a novel FLNC splicing mutation. We performed duo exome sequencing (ES) to examine the genome of the proband and his mother. For 10 days, a 15-year-old boy was presented to our hospital due to non–exercise-associated chest tightness and asthma. He was diagnosed with HCM [end-diastolic interventricular septal thickness was about 18 mm by transthoracic echocardiography (TTE)]. His mother and sister performed TTE to screen familial cardiomyopathy, which revealed hypertrophic cardiomyopathy only in the proband’s mother. In ES of the mother–son duo, we identified a novel heterozygous mutation of the FLNC gene (chr7:128492808, NM_001127487, c.5905+2T>C, rs1808874360) as the candidate cause of autosomal dominant HCM. Sanger sequencing confirmed this novel mutation in the proband and his mother but absent in the proband’s sister. The potential impact of the novel mutation was predicted by MutationTaster, dbscSNV_ADA_SCORE, dbscSNV_RF_SCORE, CADD_phred, PhyloP20way_mammalian, PhyloP100way_vertebrate, SiPhy_29way_logOdds, and GERP++_RS software. After the administration of furosemide, spironolactone, and metoprolol, the proband’s heart function was improved, and symptoms were alleviated. We presented the first familial HCM caused by a novel FLNC splicing mutation via exome sequencing in China. Therefore, it is necessary that familial screening for patients with HCM should be performed for the early detection of HCM intervention in malignant cardiac events in advance and block genes.

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Section: Discussionmentioning

confidence: 99%

Case Report: A Chinese Family of Hypertrophic Cardiomyopathy Caused by a Novel Splicing Mutation in the FLNC Gene

Huang¹,

Zheng²,

Zhang³

et al. 2022

Front. Genet.

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“…Multiple studies indicate that in adults some gene mutations predict earlier disease onset and more severe phenotypes in HCM ( 21 – 25 ). Although gene mutations and phenotypes are heterogeneously influenced by modifier genes, environmental factors, and other influences ( 16 ), current evidence suggests that HCM patients with multiple variants are more likely to suffer malignant outcomes and SCD, potentially justifying early ICD implantation ( 26 – 29 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic Clues on Implantable Cardioverter-Defibrillator Placement in Young-Age Hypertrophic Cardiomyopathy: A Case Report of Novel MYH7 Mutation and Literature Review

Xing

Tang

et al. 2021

Front. Cardiovasc. Med.

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Background: Hypertrophic cardiomyopathy (HCM) is the second most common cardiomyopathy in childhood with a life-threatening risk. Implantable cardioverter-defibrillator (ICD) placement is recommended for early prevention if there are two or more clinical risk factors. Pediatric patients with HCM are at a higher risk of sudden cardiac death (SCD), but there are limited reports on indications for ICD implantation in children. Herein we describe the case of Myh7 mutation-induced HCM and cardiac arrest in a patient and evaluated information originating from genetic background to guide ICD administration.Case Presentation: The patient was a girl aged 7 years and 8 months who had been diagnosed with cardiomyopathy in utero 8 years prior. She had had recurrent cardiac arrests within the last 4 years. Electrocardiography indicated abnormalities in conduction, and ST segment changes. Echocardiography indicated significant left ventricular hypertrophy and hypertrophic systolic interventricular septum. Cardiac magnetic resonance imaging depicted general heart enlargement with hypertrophy, and delayed enhancement in myocardium with perfusion defect was also evident. Whole exon sequencing identified a de novo c.2723T>C (p.L908P) heterozygous mutation in the MYH7 gene. MYH7 p.L908P predicted unstable protein structure and impaired function. The patient was scheduled for ICD implantation. There were no complications after ICD implantation, and she was discharged from hospital on the 10th day. Regular oral beta-blockers, amiodarone, spironolactone, and enalapril were administered, and she was required to attend hospital regularly for follow-up. During follow-up there were no cardiac arrests. Literature review of clinical prognoses associated with genetic mutations of MYH7, MYBPC3, TNNI3, TNNT2, and TPM1 in pediatric HCM patients with and without ICD implantation indicated that they were totally differently. Previous reports also indicated that gene mutations predicted earlier onset of cardiac hypertrophy, and increase likelihood of SCD.Conclusion: Variant burden and variant type contribute to the risk of adverse events in pediatric HCM. Early recognition and intervention are vital in children. Gene mutation could be considered an indication for early ICD placement during standard risk stratification of HCM patients. Whether this extends to the majority of pediatric patients requires further investigation.

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“…Massively parallel sequencing Targeted massively parallel sequencing of the index patient’s genomic DNA was performed with an Agilent SureSelect custom library covering 251 genes that constitute our current cardiomyopathy panel. This panel is detailed in Supplementary Table S1 and includes the following gene categories: (1) sarcomeric genes with definitive clinical evidence that they cause HCM: the eight core sarcomeric genes ( MYBPC3 , MYH7 , ACTC1 , MYL2 , MYL3 , TNNT2 , TNNI3 and TPM1 ) that account for more than 99% 4 of pathogenic or likely pathogenic HCM variants , and the TNNC1 gene, with moderate evidence 6 , 37 , 38 ; (2) non-sarcomeric genes 4 , 6 , 38 with definitive clinical, strong or moderate evidence: ACTN2 , PLN , CACNA1C , CSRP3 , DES , FLNC , FHL1 , FHOD3 , JHP2 , RIT1 and ALPK3 ; (3) HCM syndromic genes 6 , 37 – 39 : LAMP2 , PRKAG2 , GLA , TTR , PTPN11 , RAF1 , DTNA , TAFAZZIN , FXN , SOS1 and AGL ; (4) genes relevant to other cardiomyopathies, cardiac arrhythmias and sudden death; and (5) genes with weak clinical evidence and for research purposes only.…”

Section: Methodsmentioning

confidence: 99%

Identification of an elusive spliceogenic MYBPC3 variant in an otherwise genotype-negative hypertrophic cardiomyopathy pedigree

Torrado

Maneiro

Lamounier

et al. 2022

Sci Rep

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The finding of a genotype-negative hypertrophic cardiomyopathy (HCM) pedigree with several affected members indicating a familial origin of the disease has driven this study to discover causative gene variants. Genetic testing of the proband and subsequent family screening revealed the presence of a rare variant in the MYBPC3 gene, c.3331−26T>G in intron 30, with evidence supporting cosegregation with the disease in the family. An analysis of potential splice-altering activity using several splicing algorithms consistently yielded low scores. Minigene expression analysis at the mRNA and protein levels revealed that c.3331−26T>G is a spliceogenic variant with major splice-altering activity leading to undetectable levels of properly spliced transcripts or the corresponding protein. Minigene and patient mRNA analyses indicated that this variant induces complete and partial retention of intron 30, which was expected to lead to haploinsufficiency in carrier patients. As most spliceogenic MYBPC3 variants, c.3331−26T>G appears to be non-recurrent, since it was identified in only two additional unrelated probands in our large HCM cohort. In fact, the frequency analysis of 46 known splice-altering MYBPC3 intronic nucleotide substitutions in our HCM cohort revealed 9 recurrent and 16 non-recurrent variants present in a few probands (≤ 4), while 21 were not detected. The identification of non-recurrent elusive MYBPC3 spliceogenic variants that escape detection by in silico algorithms represents a challenge for genetic diagnosis of HCM and contributes to solving a fraction of genotype-negative HCM cases.

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Hypertrophic Cardiomyopathy: Genetic Testing and Risk Stratification

Cited by 12 publications

References 64 publications

Case Report: A Chinese Family of Hypertrophic Cardiomyopathy Caused by a Novel Splicing Mutation in the FLNC Gene

Case Report: A Chinese Family of Hypertrophic Cardiomyopathy Caused by a Novel Splicing Mutation in the FLNC Gene

Genetic Clues on Implantable Cardioverter-Defibrillator Placement in Young-Age Hypertrophic Cardiomyopathy: A Case Report of Novel MYH7 Mutation and Literature Review

Identification of an elusive spliceogenic MYBPC3 variant in an otherwise genotype-negative hypertrophic cardiomyopathy pedigree

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