Genetic Evaluation of Cardiomyopathy—A Heart Failure Society of America Practice Guideline

Authors, Journal, Affiliations, Type, DOI

• Hershberger RE, Givertz MM, Ho CY, Judge DP, Kantor PF, McBride KL, Morales A, Taylor MRG, Vatta M, Ware SM
• Journal of Cardiac Failure Vol. 24 No. 5, 2018 (pp. 281–302)
• Institutions: Ohio State University, Brigham and Women's Hospital, Medical University of South Carolina, University of Alberta, Nationwide Children's Hospital, University of Colorado, Invitae Corporation, Indiana University School of Medicine
• Type: Joint Practice Guideline (HFSA + ACMG)
• DOI: https://doi.org/10.1016/j.cardfail.2018.03.004

Overview

This 2018 joint practice guideline from the Heart Failure Society of America (HFSA) and American College of Medical Genetics and Genomics (ACMG) provides a comprehensive framework for the genetic evaluation of all major cardiomyopathy phenotypes (HCM, DCM, ARVC, RCM, LVNC). Its central principle is treating the family as the unit of care, mandating a 3-generation pedigree, cascade genetic testing of at-risk relatives for pathogenic/likely pathogenic (P/LP) variants, and serial phenotypic screening for those with unknown or positive genetic status. Nine numbered guidelines are provided covering family history, phenotypic screening intervals, referral to expert multidisciplinary centres, multigene panel genetic testing, genetic counselling, secondary/incidental ACMG findings, medical therapy, device therapy, and a gene-specific ICD exception for high-risk genes before LVEF falls below 35%.

Keywords

Cardiomyopathy, genetics, genetic analysis, practice guideline, secondary findings

Key Takeaways

Guideline 1: Family History — 3-Generation Pedigree

• A comprehensive 3-generation family history with formal pedigree creation is recommended for all patients with primary cardiomyopathy (Level A for HCM, DCM, ARVC, RCM)
• The family as the unit of care is the foundational principle: care must extend beyond the proband to at-risk relatives before a sentinel event occurs
• Most adult-onset cardiomyopathies are autosomal dominant; paediatric presentations are more frequently recessive, X-linked, or mitochondrial
• De novo variants occur in up to one-third of children with negative family history across HCM, DCM, and ARVC
• Bilineal inheritance (pathogenic variants from both parents) is seen in up to 5% of HCM and up to 20% of ARVC — associated with earlier onset and more severe disease
• Family history from patients is frequently inadequate; review of primary medical records and postmortem reports is strongly advised
• Key elements to elicit: cardiovascular symptoms (dyspnoea, syncope, presyncope, palpitations), cardiovascular diagnoses (cardiomyopathy, HF, devices, transplant, ablation), sudden death especially before age 40 (including single-vehicle accidents, drowning, SIDS), prior genetic testing, features of syndromes (skeletal muscle disease, short stature, acroparesthesias, renal failure)

Guideline 2: Clinical (Phenotypic) Screening of At-Risk Relatives

• Baseline phenotype screening recommended for all at-risk 1st-degree relatives, including those testing negative for a known familial P/LP variant (Level A)
• Serial screening recommended for clinically unaffected relatives who carry P/LP variants or whose genetic status is unknown (Level A)
• Serial screening NOT recommended for relatives confirmed genotype-negative for a known P/LP variant — can be discharged from surveillance; counsel to return if symptoms develop (Level A)
• Screening studies: ECG, 2D echocardiography ± tissue Doppler (HCM), cardiac MRI (when echo inadequate), CK-MM (if neuromuscular disease suspected), Holter monitoring (HCM, ARVC), metabolic disease screening (DCM, HCM, LVNC, RCM paediatric onset)
• Suggested screening intervals (Table 2):

Guideline 3: Referral to Expert Centres

• Expert centres with multidisciplinary teams (cardiologists + genetics professionals: genetic counsellors and/or clinical geneticists) are recommended for genetic evaluation
• Paediatric presentations require specialist expertise due to much higher rates of syndromic and metabolic causes (~10% of children with cardiomyopathy have an underlying genetic syndrome; >100 syndromes described)
• Infancy-specific investigations: Pompe disease — enzyme assay for acid alpha-glucosidase (HCM in any infant mandates this; enzyme replacement therapy is time-critical); fatty acid oxidation defects (acylcarnitine profile, amino acids, urine organic acids, serum lactate); RASopathies (Noonan syndrome — HCM in up to 20–30%, may improve over time)
• Childhood neuromuscular disease: Duchenne/Becker muscular dystrophy, laminopathies, desminopathies, sarcoglycanopathies; Barth syndrome (boys: TAZ, mitochondrial, X-linked); Friedreich ataxia; myotonic dystrophy
• Selected syndromic causes with specific management: Danon disease (LAMP2 — severe HCM + preexcitation + intellectual disability; cardiac transplant often required); Fabry disease (GLA — HCM phenocopy, early ERT for males; cardiac variant at age ≥40); PRKAG2-related glycogenosis (HCM + WPW + heart block)
• Telemedicine-based genetic counselling and telephone consultation are legitimate alternatives when travel to expert centres is not feasible

Guideline 4: Genetic Testing

• Genetic testing recommended for all major cardiomyopathy types at the time of diagnosis; testing should be initiated on the most clearly affected family member
• Multigene panel testing is the standard of care — superior to serial single-gene testing due to genetic heterogeneity, cost-effectiveness, and ability to detect co-existing variants
• Cascade genetic testing of at-risk family members is recommended for P/LP variants
• VUS cannot be used for predictive cascade testing in family members
• Retesting reasonable if test sensitivity has increased by 5–10% since prior testing

Genetic testing yields by phenotype:

Test selection principles:

• Large multigene cardiomyopathy panels are preferred; composition varies by laboratory — review carefully before ordering
• DCM panels typically include all HCM and ARVC genes due to substantial gene/phenotype overlap
• Panels may also include metabolic/syndromic genes (GLA-Fabry, LAMP2-Danon, GAA-Pompe) — advantage of identifying mixed phenotypes but increases VUS burden
• For HCM: expanded panels beyond sarcomeric genes do not currently increase sensitivity — keep panels targeted
• For DCM: TTN and BAG3 inclusion add >10% yield; warranted in all DCM panels
• Copy number variants (large insertions/deletions, structural variants) account for <1% of cardiomyopathy cases; may be underdetected by standard panels

Variant interpretation:

• ACMG/AMP 2015 classification: Pathogenic (P), Likely Pathogenic (LP), VUS, Likely Benign, Benign
• Novel variants will often initially be VUS even in well-established genes — segregation data from family members is crucial for reclassification
• VUS can be reclassified to LP/P as additional cases and family co-segregation data accumulate (e.g., in ClinVar/ClinGen)
• Variants previously classified as P/LP may be downgraded to VUS as larger datasets from diverse populations become available — carries major clinical implications (relatives may require return to surveillance)
• Interpretation particularly challenging in non-European populations where reference databases are underrepresented (ExAC, gnomAD)

Guideline 5: Genetic Counselling

• Genetic counselling recommended for all patients with cardiomyopathy and their family members (Level A)
• Scope: pedigree creation, family education on inheritance patterns, evaluation of genetic testing options, pre- and post-test consent and counselling, result interpretation and communication, psychosocial support, coordination of cascade testing
• Board-certified genetic counsellors or clinical geneticists with cardiovascular expertise are the preferred providers
• Addressing family dynamics that may impede dissemination of genetic information to at-risk relatives is an active focus

Guideline 6: Secondary and Incidental ACMG Findings

• Of the ACMG's 59 medically actionable genes (2016 update), 30 (51%) have cardiovascular phenotypes; 16 (27%) include cardiomyopathy phenotypes
• Focused cardiovascular phenotyping is recommended when ACMG-listed cardiomyopathy gene P/LP variants are identified incidentally (e.g., on exome sequencing performed for a non-cardiac indication)
• If phenotype confirmed: full genetic evaluation including family-based approaches
• If no phenotype: surveillance screening at intervals; cascade evaluation of relatives may be considered (tempered by strength of evidence, usual age of onset, and pedigree data)
• Most incidental cardiomyopathy variants will remain VUS due to lack of prior case data — actionability is limited to confirmed P/LP findings

Guideline 7–8: Medical and Device Therapy

• Medical therapy follows phenotype-specific consensus guidelines (HCM, DCM/HF, ARVC)
• ICD for secondary prevention of VT/VF regardless of cardiomyopathy type or degree of LV dysfunction
• ICD for primary prevention: standard threshold LVEF ≤35% + NYHA II–III after ≥3 months OMT (Class I/IIa)
• Gene-specific exceptions apply — see Guideline 9

Guideline 9: Early ICD Before LVEF 35% for Gene-Specific Risk

• In patients with cardiomyopathy and significant arrhythmia or known risk of arrhythmia, an ICD may be considered before the LVEF falls below 35% (Level C)
• Primarily addresses LMNA cardiomyopathy: progressive conduction disease (PR prolongation → AV block) + supraventricular and ventricular arrhythmias commonly precede or coincide with early DCM before LVEF falls to ≤35% — leaving patients unprotected by standard thresholds
• Also applies to: DES, SCN5A, FLNC, and other genes with prominent lethal arrhythmia risk before advanced LV dysfunction
• When pacemaker indication exists in LMNA (or similar high-risk) cardiomyopathy: implant ICD with pacing capability rather than pacemaker alone
• For patients with reduced EF requiring chronic ventricular pacing: CRT-defibrillator should be considered

Limitations of the Document

• Essentially no randomised controlled trial evidence underpins the recommendations; most are expert consensus or observational data
• The guideline explicitly acknowledges that "well-designed clinical studies have routinely shown that conventional wisdom may be simply wrong" — RCT evidence is needed but has not been generated
• Variant interpretation in non-white, non-northern European populations is particularly problematic; most reference databases are European-derived
• VUS reclassification: no outcome data on the clinical consequences of downgrading a previously P/LP variant to VUS for families already managed based on that result
• Clinical infrastructure for systematic variant reclassification notification does not yet exist
• Writing group included a member employed by a for-profit genetic testing company (Invitae), managed by recusal from relevant discussions

Key Concepts Mentioned

• concepts/Genetic-Testing-in-Cardiomyopathy — systematic framework established by this guideline
• concepts/Cascade-Family-Screening — 3-generation pedigree, serial phenotypic screening intervals, cascade genetic testing rules
• concepts/Variant-Reclassification — VUS cannot be used for predictive testing; downgrading P/LP to VUS has major clinical implications; segregation data essential for reclassification
• concepts/Cardiogenetic-Centers — expert multidisciplinary centres recommended; telemedicine as alternative
• concepts/Phenotypic-Approach-to-Cardiomyopathy — phenotype-first classification drives gene panel selection and interpretation

Key Entities Mentioned

• entities/HCM — 30–60% genetic testing yield; MYH7/MYBPC3 account for ~80% of solved cases; sarcomere-first but genocopies important in paediatric cases
• entities/DCM — 10–40% yield; TTNtv most common (10–20%); LMNA second most common (5.5%); BAG3 and RBM20 each ~2%
• entities/ARVC — 10–50% yield; desmosomal gene panel; digenic inheritance and compound heterozygosity frequent; exercise role in pathogenesis
• entities/RCM — 10–60% yield; often shares HCM genes; TTR amyloidosis important differential
• entities/LMNA — Guideline 9: early ICD before LVEF <35% due to progressive conduction disease + early VA risk
• entities/TTN — TTNtv 10–20% of DCM; interpretation challenging due to large gene size and frequency in reference populations; not all TTNtv are disease-causing
• entities/ATTR-Amyloidosis — TTR p.Val142Ile in 10% of African Americans >65 yr with severe HF; differentiated from RCM by different management
• entities/Anderson-Fabry-Disease — GLA mutations cause HCM phenocopy; early enzyme replacement indicated; cardiac variant presents >40 yr
• entities/PKP2 — most common ARVC gene; desmosomal + Nav1.5 + Cx43 disruption
• entities/MYBPC3 — most common HCM gene; ~50% of HCM; combined with MYH7 accounts for ~80%

Wiki Pages Updated

• wiki/sources/genetic-cmp-jcf-2018.md (created)
• wiki/concepts/Genetic-Testing-in-Cardiomyopathy.md (created)
• wiki/concepts/Cascade-Family-Screening.md (updated — HFSA 2018 phenotypic screening intervals added)
• wiki/concepts/Variant-Reclassification.md (updated — VUS clinical implications and segregation guidance added)
• wiki/entities/LMNA.md (updated — Guideline 9 early ICD language added)
• wiki/entities/DCM.md (updated — HFSA 2018 genetic testing yield and gene-specific guidance added)
• wiki/entities/ARVC.md (updated — HFSA 2018 genetic testing yield and digenic inheritance data added)
• wiki/wikiindex.md (updated)
• log.md (updated)