Cardiomyopathies

Hypertrophic Cardiomyopathy (HCM)

Dilated Cardiomyopathy (DCM)

Arrhythmogenic Cardiomyopathy (ACM)

Restrictive Cardiomyopathy (RCM)

Non-Dilated LV Cardiomyopathy (NDLVC)

Channelopathies

Long QT Syndrome (LQTS)

Short QT Syndrome (SQTS)

Brugada Syndrome (BrS)

Catecholaminergic Polymorphic VT (CPVT)

Metabolic & Storage Diseases

Fabry Disease (Anderson-Fabry)

Danon Disease (LAMP2)

Cardiac Amyloidosis (TTR/AL)

Pompe Disease (GSD-II)

Aortopathies & Connective Tissue

Marfan Syndrome (MFS)

Loeys-Dietz Syndrome (LDS)

Vascular Ehlers-Danlos Syndrome (vEDS)

Bicuspid Aortic Valve (BAV)

Neuromuscular & Syndromic

Duchenne/Becker Muscular Dystrophy (DMD/BMD)

Myotonic Dystrophy (DM1/DM2)

Friedreich Ataxia (FRDA)

Mitochondrial Disorders

21 conditions · 5 categories · 47+ primary references · ESC / HRS / BHRS aligned

Aetiology

Genetics

Prevalence

Diagnosis

Investigations

Treatments

Complications

Risk Stratification

Pregnancy Management

Follow-up

Key Points

References & Review Date

Cardiomyopathies

2023 ESC Guidelines for Management of Cardiomyopathies

European Society of Cardiology, 2023

View Guideline →

AHA/ACC/HFSA Guideline on HCM

American Heart Association / American College of Cardiology / Heart Failure Society of America, 2024

View Guideline →

HRS Expert Consensus on ARVC

Heart Rhythm Society, 2019

View Guideline →

Arrhythmias & Channelopathies

ESC Guidelines on Ventricular Arrhythmias and SCD

European Society of Cardiology, 2022

View Guideline →

HRS/EHRA/APHRS/LAHRS Expert Consensus on Arrhythmia Management in Inherited Primary Arrhythmia Syndromes

Heart Rhythm Society / EHRA / APHRS / LAHRS, 2022

View Guideline →

Aortopathies

2024 ESC Guidelines for the Management of Aortic Diseases

European Society of Cardiology, 2024

View Guideline →

Sports Cardiology & Exercise

ESC Guidelines on Sports Cardiology and Exercise in Patients with Cardiovascular Disease

European Society of Cardiology, 2020

View Guideline →

Device Therapy

ESC Guidelines on Cardiac Pacing and CRT

European Society of Cardiology, 2021

View Guideline →

Genetic Testing

ACMG Standards and Guidelines for Genetic Testing

American College of Medical Genetics, 2024

View Guideline →

UK National Genomic Test Directory (Version 8.1, July 2025^[1])

General Requirements for All Tests

All testing should be:

Performed in parallel with expert phenotypic assessment in an Inherited Cardiac Clinic (ICC)
With clinical genetics support
Targeted at those where genetic/genomic diagnosis will guide management for proband or family

Full guidelines: National Genomic Test Directory v8.1

Cardiomyopathy

R131 Hypertrophic Cardiomyopathy

▼

Testing Method: WES or Medium Panel | Requesting Specialties: Cardiology, Clinical Genetics

Testing criteria (meet ONE OR MORE):

Adult with wall thickness ≥15 mm in ≥1 LV segment, NOT explained solely by loading conditions (e.g. hypertension), AND age of onset <60 years
Child <18 years with LV wall thickness >2 standard deviations above predicted mean (z-score >2)
Increased LV wall thickness ≥13 mm in ≥1 LV segment, in patient with 1st degree relative with unequivocal disease (LVH ≥15 mm), where affected family member unavailable for testing
Deceased individual with pathologically confirmed HCM (post-mortem DNA analysis)

Additional requirements:

Testing recommended when relatives will benefit from cascade testing using genetic diagnosis
Testing in parallel with expert phenotypic assessment in ICC, including clinical genetics support

Genes Tested (Hypertrophic Cardiomyopathy Panel - 49 genes)

MYBPC3 MYH7 TNNT2 TNNI3 TPM1 ACTC1 MYL2 MYL3 + 41 others

Note: R135 Paediatric/syndromic cardiomyopathy should be used where atypical features suggest broader gene testing needed

R132 Dilated and Arrhythmogenic Cardiomyopathy

▼

Testing Method: WES or Medium Panel | Requesting Specialties: Cardiology, Clinical Genetics

Testing criteria (meet ONE OR MORE):

LVEDD >2 SD AND/OR reduced EF <45% (age/sex adjusted), AND age of onset <65 years
Criterion 2 (DCM with conduction): DCM with conduction defects, age of onset <65 years
Left and/or biventricular cardiomyopathy with variable myocardial dysfunction/fibrosis PLUS ventricular arrhythmias, after excluding inflammatory causes
Deceased individual with pathologically confirmed DCM/ACM, age of onset <65 years
Patient with DCM/ACM at ANY age if 1st degree relative has confirmed DCM/ACM

Main Genes Tested (DCM/ACM Panel)

TTN LMNA MYH7 BAG3 FLNC RBM20 SCN5A DSP PLN DES + others

Exclusions: DCM secondary to coronary disease or pressure/volume overload. Consult expert before testing DCM due to myocarditis, alcohol, peripartum, chemotherapy.

R133 Arrhythmogenic Cardiomyopathy (ACM/ARVC)

▼

Testing Method: Small Panel (134 genes) | Requesting Specialties: Cardiology, Clinical Genetics

Testing criteria (meet ONE OR MORE):

DEFINITE diagnosis by Modified Task Force Criteria (Marcus 2010^[3]), age of onset <50 years
Deceased with pathologically confirmed ARVC, relatives will benefit from cascade testing
Identification of P/LP variant would complete diagnostic Task Force Criteria

Desmosomal Genes

PKP2 DSG2 DSC2 DSP JUP TMEM43 PLN FLNC + 126 others

Arrhythmia

R127 Long QT Syndrome

▼

Testing Method: Small Panel (76 genes) | Requesting Specialties: Cardiology, Clinical Genetics

Testing criteria (meet ONE OR MORE):

QTc ≥500ms in repeated 12-lead ECGs
LQTS risk score ≥3.5 (Schwartz 2011)
QTc ≥480ms in repeated ECGs AND unexplained syncope
QTc ≥480ms AND sudden unexplained death <60 years in 1st/2nd degree relative

Main Genes (LQTS Panel)

KCNQ1 KCNH2 SCN5A CALM1 CALM2 CALM3 CACNA1C KCNE1 KCNE2 + 67 others

Secondary causes must be excluded before testing

R128 Brugada Syndrome

▼

Testing Method: Small Panel (13 genes) | Requesting Specialties: Cardiology, Clinical Genetics

Testing criteria (meet ONE):

Spontaneous Type 1 ST elevation ≥2mm in ≥1 right precordial lead
Type 1 ST elevation with Na-channel blocker, AND ONE OR MORE of: VF/VT, syncope, FH of SCD <45y, coved ECG in family, agonal respiration, atrial arrhythmias <30y
Sodium channel disease suspicion (atrial arrhythmias, sinus/conduction disease, QT prolongation)

Genes Tested

SCN5A GPD1L CACNA1C CACNB2 SCN1B + 8 others

R129 Catecholaminergic Polymorphic VT

▼

Testing Method: Small Panel (214 genes) | Requesting Specialties: Cardiology, Clinical Genetics

Structurally normal heart, normal ECG, AND:

Exercise/catecholamine-induced bidirectional VT or polymorphic PVCs/VT/VF in patient <40 years, OR
Exercise-induced arrhythmias with positive FH of CPVT (symptomatic family member unavailable), OR
Same as above but age >40 years

Main Genes

RYR2 CASQ2 CALM1-3 TRDN TECRL + 209 others

R130 Short QT Syndrome

▼

Testing Method: Small Panel (224 genes) | Requesting Specialties: Cardiology, Clinical Genetics

QTc ≤330ms, OR
QTc <360ms AND (FH of SQTS OR FH of SCD ≤40y OR VT/VF survival)

Main Genes

KCNH2 KCNQ1 KCNJ2 + 221 others

Other

R138 Molecular Autopsy / Idiopathic VF

▼

Testing Method: WES/Medium Panel (841 genes) | Requesting Specialties: Cardiology, Clinical Genetics

Post-mortem testing:

Sudden death with normal PM <40 years, OR
Sudden death with normal PM <60y with FH unexplained SCD <40y in 1st/2nd degree relative, OR
Sudden death with normal PM <60y with FH unexplained SCD <60y (relative also had normal PM)

Cardiac arrest survivors (idiopathic VF):

No phenotype on comprehensive evaluation (coronary, imaging, ECG provocation) AND age <45 years

Panel: 841 genes covering all ICC, channelopathies, cardiomyopathies, SCD-associated genes

About These Criteria

These criteria are from the NHS England National Genomic Test Directory.^[1] Tests must be delivered by a Genomic Laboratory Hub and should only be requested where results are highly likely to change clinical management.

Important: Criteria use "OR" / "AND" logic. When multiple criteria are listed with "OR", meeting ANY ONE is sufficient. When "AND" is used, ALL criteria must be met.

Genetic Counselling

When to Refer for Genetic Counselling^[1]^[2]

Confirmed diagnosis of inherited cardiac condition
Family history of inherited cardiac condition or sudden cardiac death
Prior to genetic testing (predictive or diagnostic)^[3]
After receiving genetic test results (positive, negative, or uncertain, especially variants of uncertain significance (VUS)^[4])
Family cascade screening
Reproductive planning in affected individuals

Important Notes on Genetic Counselling

Who provides genetic counselling: Certified genetic counsellors or clinicians with appropriate training in genetics^[3]

Pre-test counselling is mandatory before genetic testing for inherited cardiac conditions^[1]

Post-test counselling should be provided regardless of result (positive, negative, or VUS). VUS should be interpreted using ACMG/AMP 5-tier classification.^[4]

References & Review Date

Last reviewed: May 2026

Gene panels & eligibility

NHS England. National Genomic Test Directory v8.1. July 2025. Available at: england.nhs.uk/publication/national-genomic-test-directories/
Arbelo E, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503–3626. DOI: 10.1093/eurheartj/ehad194
Marcus FI, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Circulation. 2010;121(13):1533–1541. DOI: 10.1161/CIRCULATIONAHA.108.840827
Zeppenfeld K, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43(40):3997–4126. DOI: 10.1093/eurheartj/ehac262
Sturm AC, et al. Clinical Genetic Testing for the Cardiomyopathies and Arrhythmias. Genet Med. 2019;21(3):694–711. DOI: 10.1038/s41436-018-0386-3

Genetic counselling

Charron P, et al. Genetic counselling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2010;31(22):2715–2728. DOI: 10.1093/eurheartj/ehq271
Sturm AC, et al. Clinical Genetic Testing for the Cardiomyopathies and Arrhythmias. Genet Med. 2019;21(3):694–711. DOI: 10.1038/s41436-018-0386-3
Arbelo E, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503–3626. DOI: 10.1093/eurheartj/ehad194
Richards S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–424. DOI: 10.1038/gim.2015.30
Zeppenfeld K, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43(40):3997–4126. DOI: 10.1093/eurheartj/ehac262

Testing Methods

How ICC genetic investigation is done, in a top-down flow: the tiered escalation strategy, then the individual assays and analyses, then the key cross-cutting strategies. Term definitions are in the Glossary tab.

Tiered testing strategy

ICC genetic investigation follows a tiered approach, escalating to broader and more expensive tests only when simpler methods are insufficient. The guide below outlines when to move between tiers and what decisions follow a positive result at each stage.

First-Line, Targeted NGS Gene Panel

All suspected ICC probands. Select a condition-matched panel (HCM, ARVC, LQTS, DCM, etc.).

Pathogenic / Likely Pathogenic: proceed to genetic counselling and cascade testing of first-degree relatives
VUS: pursue segregation studies; do not use VUS alone to drive clinical decisions
Negative: consider MLPA add-on if CNV suspected; escalate to Tier 2 if clinical suspicion remains high

↓ panel negative or inconclusive with ongoing clinical suspicion

Second-Line, Whole Exome Sequencing (WES)

Broadens search to all protein-coding genes. Reflex to trio WES if any of the following apply:

Paediatric / severe early-onset phenotype
Suspected de novo variant (no family history, normal parental phenotypes)
Syndromic features or intellectual disability
Consanguineous family (biallelic variants suspected)

Also consider CMA if syndromic features suggest a microdeletion syndrome.

↓ WES negative or non-coding / structural variant strongly suspected

Third-Line, Whole Genome Sequencing (WGS)

Includes non-coding regions, structural variants, and repeat expansions. Primarily via national genomics programmes (e.g. NHS Genomic Medicine Service).

Add trio design if de novo variant still suspected in a paediatric or unresolved case
Consider RNA-seq alongside if a splice-disrupting variant is suspected but unconfirmed by DNA analysis

↓ pathogenic or likely pathogenic result identified at any tier

→

Post-Result Pathways

Cascade testing: offer targeted single-variant testing to all first-degree relatives; coordinate through cardiac genetics clinic
Genetic counselling: discuss implications for family planning, employment, insurance; MDT approach
Reproductive options: preimplantation genetic testing (PGT-M via IVF) or invasive prenatal testing (CVS / amniocentesis)
VUS ongoing review: segregation studies, functional evidence, periodic database reanalysis

Assay & analysis methods

Grouped by what they analyse (DNA then RNA) and ordered by the scale of change they detect, from single DNA bases up to whole chromosomes. Expand a category for indications, what it detects, the technical approach, limitations, and ICC applications.

DNA analysis · by scale of change

Sequencing-based assayssingle bases to whole genome

Detect single nucleotide variants (SNVs) and small insertions/deletions across a range of genomic scope, from condition-specific gene panels to whole genome. Trio testing (proband + both parents sequenced simultaneously) falls within this category.

Assay	When to Order	What It Detects	Technical Approach	Key Limitations	ICC Application
Targeted Gene Panel (NGS)	First-line in clinically suspected ICC Proband with HCM, DCM, ARVC, LQTS, CPVT, Brugada Cascade testing when family variant is unknown	SNVs and small indels in a curated set of disease-associated genes (typically 50–300 genes)	NGS of enriched target regions; bioinformatic variant calling against reference genome	Misses variants outside the gene panel Generally cannot detect large CNVs Non-coding variants missed	HCM panel (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, ACTC1); LQTS panel (KCNQ1, KCNH2, SCN5A); ARVC panel (PKP2, DSP, DSC2, DSG2, JUP)
Sanger Sequencing	Confirming a variant identified on NGS panel Cascade testing when family variant is already known (single-site)	Point mutations and small indels in a single amplicon (~200–1000 bp)	Dideoxy chain termination; fluorescent capillary electrophoresis of a single PCR product	Very low throughput, one amplicon per run Cannot detect CNVs Not suitable for novel discovery	Confirming MYH7 p.Arg403Gln in at-risk relatives of a known HCM family; validating a KCNH2 variant before cascade testing
Whole Exome Sequencing (WES)	Panel-negative with strong clinical suspicion Atypical or syndromic phenotype Rare or undiagnosed cardiomyopathy Paediatric cases where diagnosis is uncertain	SNVs and indels across all ~20,000 protein-coding exons (~1–2% of genome)	Hybridisation capture enriches exome; NGS library sequenced to ~100× depth; phenotype-driven gene prioritisation	Misses non-coding regions (introns, promoters) Limited CNV detection Repeat expansions not reliably called Higher VUS burden than targeted panels	Novel truncating RBM20 variant in panel-negative familial DCM; FLNC truncating variant in NDLVC after negative panel
Trio Exome Sequencing Proband + both parents	Severe early-onset or paediatric phenotype Suspected de novo variant Syndromic features of unknown cause Consanguineous family (biallelic variants suspected) Solo WES inconclusive	De novo variants; compound heterozygous variants with phasing; inherited variants with one-step segregation data	WES on proband and both biological parents simultaneously; de novo calling compares child VCF against parental VCFs; increases diagnostic yield vs solo WES	Requires both biological parents to provide samples Higher cost than solo WES Still misses non-coding variants and repeat expansions	De novo KCNQ1 in neonatal LQTS; de novo PTPN11 in Noonan-associated HCM; compound heterozygous MYH7/MYBPC3 in severe paediatric HCM
Whole Genome Sequencing (WGS)	Unresolved after panel + WES Suspected non-coding, intronic, or structural variant Repeat expansion disorder (Friedreich, myotonic dystrophy) Research or national genomics programme	SNVs, indels, CNVs, structural variants, non-coding variants, and repeat expansions across the entire genome	NGS without prior target enrichment; ~30–50× depth; structural variant callers (Manta, DELLY); repeat expansion callers (ExpansionHunter)	High cost and large data volumes Very high VUS burden in non-coding regions Non-coding variant interpretation remains limited clinically	Non-coding LMNA promoter variant in familial DCM; FXN GAA repeat expansion in Friedreich-associated HCM; DMPK CTG expansion in myotonic dystrophy cardiomyopathy
Trio Genome Sequencing Proband + both parents	Most complex unresolved cases where trio WES is insufficient Suspected non-coding or structural de novo variant NHS Genomic Medicine Service or equivalent programme	Full genome of proband + both parents; de novo SNVs, CNVs, SVs, and non-coding variants with parental phasing; maximum diagnostic resolution	WGS on three individuals simultaneously; de novo calling against parental backgrounds; phasing detects compound heterozygous events across all variant classes	Very high cost (≈3× WGS); requires both parents Complex bioinformatics Primarily available in research or national genomic programmes	De novo non-coding regulatory variant in severe unexplained paediatric cardiomyopathy; structural PKP2 rearrangement after negative trio WES in ARVC

Copy number & structural analysisexon to gene level

Detect exon-level or gene-level deletions and duplications. Used as an adjunct when standard sequencing is negative but a copy number change is suspected based on clinical features or incomplete co-segregation.

Assay	When to Order	What It Detects	Technical Approach	Key Limitations	ICC Application
MLPA Multiplex Ligation-dependent Probe Amplification	Suspected exon-level CNV after negative sequencing PKP2 deletions in sequence-negative ARVC LDLR exon CNVs in severe familial hypercholesterolaemia LMNA or DMD CNVs in familial DCM / muscular dystrophy	Exon-level deletions and duplications in targeted genes (typically 40–50 probes covering one or a few genes)	Probe pairs flanking each exon ligated and PCR-amplified; capillary electrophoresis quantifies relative probe copy number	Only detects CNVs within pre-designed probe regions Cannot detect point mutations or balanced rearrangements Requires gene-specific kit (e.g. P082 for PKP2)	PKP2 exon 1–5 deletion in sequence-negative ARVC; LDLR CNV (~15% of pathogenic FH variants); LMNA exon deletion in conduction-system DCM
qPCR / ddPCR Quantitative / Digital Droplet PCR	Targeted CNV confirmation after CMA or MLPA Known family variant follow-up where MLPA unavailable	Relative copy number of specific targeted loci; gene expression levels via RT-qPCR	Fluorescent probe quantification relative to reference gene; ddPCR partitions reaction into droplets for absolute digital counting	Only analyses pre-defined target regions Requires prior knowledge of variant Not suitable for discovery	LMNA exon deletion quantification in familial DCM before cascade testing; DMD exon copy number confirmation in Duchenne cardiomyopathy

Cytogenetic analysischromosome level

Detect chromosomal-scale abnormalities, from whole-chromosome aneuploidies (karyotyping) to sub-megabase copy number changes (microarray). Indicated for syndromic presentations, congenital heart disease, or prenatal screening contexts.

Assay	When to Order	What It Detects	Technical Approach	Key Limitations	ICC Application
Chromosomal Microarray (CMA)	Syndromic ICC with dysmorphic features, intellectual disability, or congenital heart disease Suspected microdeletion/duplication syndrome (22q11, Williams, Noonan region) Panel and WES negative with syndromic features persisting	CNVs (microdeletions and microduplications) at ≥50 kb resolution genome-wide; regions of homozygosity (ROH)	SNP or CGH array; patient DNA hybridised against reference; signal intensity ratios indicate copy number; ROH from B-allele frequency patterns	Cannot detect balanced translocations or point mutations UPD without LOH not detected CNVs below ~50 kb missed	22q11.2 deletion (DiGeorge) + DCM + congenital heart defect; 7q11.23 deletion (Williams) + supravalvular aortic stenosis; NF1 microdeletion in Noonan-related HCM
Karyotyping G-banded chromosome analysis	Suspected aneuploidy with cardiomyopathy (Down, Turner, Klinefelter) Congenital heart disease + dysmorphic features Suspected balanced translocation disrupting a cardiac gene	Whole-chromosome abnormalities: aneuploidies, large structural rearrangements, balanced and unbalanced translocations (>5–10 Mb resolution)	Blood lymphocytes cultured and arrested in metaphase; G-banding stain; microscopic karyogram of 22 autosomes + sex chromosomes	Poor resolution (~5–10 Mb); misses microdeletions detectable by CMA Largely superseded by CMA for most syndromic indications	Turner syndrome (45,X) + bicuspid aortic valve; trisomy 21 + AVSD + dilated cardiomyopathy; balanced t(1;3) disrupting FLNC in unexplained RCM
FISH Fluorescence In Situ Hybridisation	Confirming a specific known deletion (e.g. 22q11.2) after clinical suspicion or CMA screen Rapid aneuploidy detection in prenatal samples	Specific chromosomal deletions, amplifications, or translocations at a single targeted locus	Fluorescent probes hybridise to denatured chromosomal DNA; fluorescence microscopy detects copy number at the specific locus	Requires prior knowledge of region, cannot discover novel abnormalities Single-locus; replaced by CMA for genome-wide analysis	22q11.2 deletion confirmation in DiGeorge syndrome + DCM; rapid trisomy 21 detection in fetal cardiac sample
Non-Invasive Prenatal Testing (NIPT)	Prenatal screening in families at risk of chromosomal syndrome with cardiac involvement Note: cannot diagnose monogenic ICC variants, use PGT-M or invasive testing for known family variants	Fetal aneuploidies (trisomy 21, 18, 13; sex chromosome abnormalities) from cell-free fetal DNA (cffDNA) in maternal blood; selected microdeletion syndromes on extended panels	Cell-free DNA from maternal plasma (~10–15% fetal fraction); massively parallel sequencing; statistical over/under-representation of chromosomal regions infers fetal copy number	Screening only, positive requires confirmatory CVS or amniocentesis Cannot diagnose monogenic ICC family variants False positives on microdeletion panels	Trisomy 21 screening in fetus at risk of AVSD; 22q11.2 screening in family with DiGeorge syndrome; not suitable for monogenic HCM/LQTS family variant

RNA analysis

Transcriptomic analysisRNA & splicing

Analyses RNA rather than DNA. Used to confirm whether a DNA variant disrupts normal splicing or gene expression, primarily in specialist or research settings. Requires tissue in which the gene of interest is actively expressed.

Assay	When to Order	What It Detects	Technical Approach	Key Limitations	ICC Application
RNA Sequencing (RNA-seq)	VUS with predicted splicing effect Deep intronic or cryptic splice-site variant Discordance between phenotype and genetic findings Research investigation of cardiac gene expression	Aberrant splicing, exon skipping, cryptic exon use, allele-specific expression, fusion transcripts, and RNA expression levels	RNA isolated from relevant tissue; reverse-transcribed to cDNA; NGS library sequenced; splice junctions and expression compared to reference transcriptome	Gene must be expressed in available tissue, many cardiac genes not expressed in blood Requires fresh/frozen tissue; FFPE unsuitable Not routine clinical practice; primarily research	TTN deep intronic variant causing exon skipping in DCM (cardiac biopsy RNA); PKP2 aberrant splice isoform in ARVC; SCN5A splice variant reclassification in Brugada syndrome

Testing strategies & workflows

How testing is used in practice: testing relatives, reproductive options, and making sense of the results.

Testing approaches

Trio Testing

Proband + both biological parents

Simultaneous sequencing of affected individual and both parents. Directly identifies de novo variants; phases compound heterozygous variants; improves VUS classification by providing segregation data in a single test.

Example: Infant with severe HCM, normal parental echocardiograms → trio WES identifies de novo PTPN11 p.Thr73Ile, confirming Noonan syndrome.

Cascade Testing

Systematic family screening after a positive proband

First-degree relatives offered targeted single-variant testing (not a panel). 50% prior probability for autosomal dominant conditions. Negative result discharges from cardiac surveillance. Requires pre-test counselling on insurance and employment implications.

Example: MYBPC3 p.Trp792* in proband → 2 of 4 first-degree relatives gene-positive → enter annual echo surveillance programme.

Reproductive options

Preimplantation Genetic Testing (PGT-M)

IVF-based embryo selection before implantation

Unaffected embryos selected at blastocyst stage before IVF transfer. Avoids transmission without requiring termination. Requires full IVF cycle. Regulated by HFEA in UK; eligibility requires high penetrance and significant morbidity/mortality.

Example: Couple with KCNQ1 LQT1 pathogenic variant → PGT-M selects unaffected embryos; unaffected pregnancy achieved.

Prenatal Genetic Testing

CVS or amniocentesis for a known family variant

CVS: ≥10 weeks; miscarriage risk ~0.5–1%. Amniocentesis: ≥15 weeks; miscarriage risk ~0.1–0.5%. Most relevant for severe early-onset conditions (Pompe, Danon, neonatal LQTS). Counselling must be non-directive.

Example: Known RYR2 pathogenic variant → amniocentesis confirms fetal genotype; if positive, neonatal surveillance and early beta-blocker planned pre-delivery.

Variant interpretation & follow-up

VUS Management

Variant of Uncertain Significance, principles

Do not use a VUS alone to drive ICD implantation, sport restriction, or cascade testing. Build evidence through: segregation, functional studies, population frequency (gnomAD), and computational predictors (SIFT, PolyPhen, SpliceAI).

Example: MYH7 missense VUS → found in 3/4 affected relatives, absent from 2 unaffected → reclassified likely pathogenic (PP1 + PS3 criteria met).

Genetic Reanalysis

Revisiting stored data as knowledge evolves

Periodic reanalysis of stored WES/WGS data against updated databases (ClinVar, gnomAD) and expanded gene lists. Diagnostic yield ~10–15% of previously unsolved cases. Driven by new gene–disease associations (ALPK3, FLNC) and VUS reclassifications.

Example: FLNC VUS in 2019 → reclassified likely pathogenic in 2023 reanalysis (new NDLVC evidence) → diagnosis without re-sequencing.

Gene Variants in Inherited Cardiac Conditions

An interactive reference of clinically significant variants across inherited cardiac conditions. Each entry summarises the inheritance pattern, mutation type, molecular mechanism, and key genotype–phenotype relationships. Use the filters below to isolate variants by category, for example all X-linked disorders, all truncating variants, or all gain-of-function mechanisms.^[1]^[2]

Gene	Condition	Affected Component	Inheritance	Mutation Type	Molecular Effect	Genotype–Phenotype Relationships

References & Review Date

Last reviewed: May 2026

Walsh R, et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017;19(2):192–203. DOI: 10.1038/gim.2016.90
Richard P, et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003;107(17):2227–2232. DOI: 10.1161/01.CIR.0000066323.15244.54
Herman DS, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012;366(7):619–628. DOI: 10.1056/NEJMoa1110186
Schwartz PJ, et al. Inherited cardiac arrhythmias. Nat Rev Dis Primers. 2020;6(1):58. DOI: 10.1038/s41572-020-0188-7
Priori SG, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2015;36(41):2793–2867. DOI: 10.1093/eurheartj/ehv316
McKenna WJ, et al. Diagnosis of arrhythmogenic cardiomyopathy: the Padua criteria. Eur Heart J. 2020;41(48):4617–4631. DOI: 10.1093/eurheartj/ehaa540
Nordestgaard BG, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population. Eur Heart J. 2013;34(45):3478–3490. DOI: 10.1093/eurheartj/eht273
Loeys BL, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010;47(7):476–485. DOI: 10.1136/jmg.2009.072785
Elliott PM, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503–3626. DOI: 10.1093/eurheartj/ehad194
Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol. 2013;10(9):531–547. DOI: 10.1038/nrcardio.2013.105
van der Zwaag PA, et al. Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy. Eur Heart J. 2012;33(10):1241–1248. DOI: 10.1093/eurheartj/ehr466
Brugada R, et al. Brugada syndrome. Nat Rev Dis Primers. 2018;4:28. DOI: 10.1038/s41572-018-0029-y
Priori SG, et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation. 2001;103(2):196–200. DOI: 10.1161/01.CIR.103.2.196
Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30. DOI: 10.1186/1750-1172-5-30
Nishino I, et al. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature. 2000;406(6798):906–910. DOI: 10.1038/35022604
El-Hattab AW, et al. MELAS syndrome: clinical manifestations, pathogenesis, and treatment options. Mol Genet Metab. 2015;116(1–2):4–12. DOI: 10.1016/j.ymgme.2015.06.004
Loeys BL, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005;37(3):275–281. DOI: 10.1038/ng1511
Byers PH, et al. Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome. Am J Med Genet C Semin Med Genet. 2000;93(1):80–90. DOI: 10.1002/AJMG.C.15

Genetics Glossary

A single reference glossary of molecular genetics, inheritance, and laboratory terms used across the genetic-testing tab. Definitions are shown in full, no clicking required.

Variant & Mutation Types

Copy Number Variant (CNV)Large-scale deletion or duplication

Structural genomic variants involving deletion or duplication of segments typically >1 kb, affecting one or more exons or entire genes. CNVs account for ~15% of pathogenic LDLR variants in FH and are not reliably detected by standard Sanger sequencing, MLPA or whole-genome sequencing is required.

Example: LDLR exon 1–6 deletion → complete loss of LDL receptor in affected exons → severe FH phenotype.

Frameshift VariantReading frame disrupted by indel

Insertion or deletion of a number of nucleotides not divisible by three, shifting the downstream reading frame. Every codon after the indel is altered, producing a completely different amino acid sequence and almost always a premature stop codon, the resulting transcript typically undergoes NMD. One of the most common truncating variant types in ICC genes.

Example: MYBPC3 c.2373insG, single cytosine insertion shifts the reading frame → premature stop → NMD → haploinsufficiency → HCM.

Missense Variant (SNP)Single amino acid substitution

A single nucleotide change alters one codon, substituting a different amino acid. The resultant protein is full-length but structurally or functionally abnormal. Pathogenicity depends on the amino acid position and physicochemical change introduced.

Example: MYH7 p.Arg403Gln, glutamine substitution at the myosin motor domain disrupts cross-bridge cycling in HCM.

Nonsense Variant (Stop-Gain)Single nucleotide change creates stop codon

A single nucleotide substitution changes a coding codon to a premature stop codon (UAA, UAG, or UGA). If located >50–55 nt upstream of the last exon-exon junction, the resulting mRNA is targeted by NMD. If located near the C-terminus or in the last exon, the truncated protein may escape NMD and accumulate, potentially with dominant negative properties.

Example: PKP2 p.Arg79*, early stop codon → NMD → haploinsufficiency of plakophilin-2 → desmosomal failure → ARVC.

Repeat ExpansionPathological tandem repeat enlargement

Abnormal expansion of repetitive DNA sequences beyond a pathological threshold. While not represented among the core ICC genes in this table, repeat expansions underlie Friedreich's ataxia (FXN GAA repeat → hypertrophic cardiomyopathy + peripheral neuropathy) and myotonic dystrophy (DMPK CTG repeat → conduction disease and cardiomyopathy).

Example: FXN intron 1 GAA expansion >66 repeats → frataxin deficiency → HCM + progressive ataxia.

Splice-site VariantDisruption of exon–intron boundary signals

Variants at the canonical splice donor (GT) or acceptor (AG) dinucleotides, or within nearby intronic/exonic splicing regulatory sequences. Consequences range from exon skipping, intron retention, or activation of a cryptic splice site, all producing an aberrant mRNA. Most canonical splice-site variants result in a truncated protein and NMD, but exon-skipping variants may produce in-frame products with partial function.

Example: TTN splice-site variants in A-band exons with high PSI are among the most prevalent DCM variants; exon skipping produces non-functional titin isoforms.

Truncating VariantFrameshift, nonsense, or essential splice-site

Introduces a premature termination codon via frameshift insertion/deletion, nonsense substitution, or disruption of an essential splice site. This produces a shortened protein or triggers nonsense-mediated mRNA decay (NMD), which degrades the aberrant transcript before translation. NMD is the predominant outcome, resulting in reduced protein output (haploinsufficiency).

Example: MYBPC3 frameshift → NMD → ~50% reduction in cMyBP-C → haploinsufficiency → HCM.

Molecular Mechanisms

Altered RNA SplicingDysregulation of transcript isoform production

Some pathogenic variants do not change the protein sequence directly but instead disrupt the normal regulation of pre-mRNA splicing, altering which exons are included in the final transcript. This produces abnormal isoform ratios with downstream functional consequences. A distinct category from splice-site variants, the causal variant may be in the coding region yet its effect is entirely on splicing.

Example: RBM20 RSRSP-domain missense variants prevent correct titin mRNA splicing → giant, non-compliant titin isoforms → impaired sarcomere mechanics in DCM.

Dominant Negative EffectMutant protein sabotages wild-type function

The abnormal protein actively interferes with the function of the normal wild-type protein produced from the remaining allele. Mechanistically more damaging than haploinsufficiency because total functional protein falls below 50%. Common in proteins forming multi-subunit complexes, the mutant subunit "poisons" the assembly.

Example: MYH7 missense variants incorporate into myosin thick filaments as "poison peptides", impairing cross-bridge cycling disproportionately.

Gain of Function (GoF)Novel or enhanced pathological activity

The variant confers a new or amplified activity not present in the wild-type protein. In ion channel diseases, GoF commonly means the channel fails to fully inactivate, generating persistent current that prolongs the action potential or causes abnormal spontaneous depolarisations.

Example: SCN5A GoF → persistent late INa → prolonged QT → LQT3; RYR2 GoF → abnormal SR Ca²⁺ release at rest → triggered VT in CPVT.

HaploinsufficiencyOne functional copy is insufficient

When a single functional copy of a gene cannot produce sufficient protein for normal cellular function, disease results. Typical of dosage-sensitive structural proteins. Most commonly caused by truncating variants where the mutant allele undergoes NMD, leaving only ~50% protein output from the remaining wild-type allele.

Example: MYBPC3, TTN, PKP2, DSP, LMNA, all cause disease primarily through haploinsufficiency.

Increased Ca²⁺ SensitivityThin filament hyperactivation at rest

A molecular mechanism specific to thin filament HCM variants. Normally, troponin acts as an "off switch" that keeps the thin filament inactive during diastole in the absence of calcium. Pathogenic variants in TNNT2, TNNI3, and TPM1 shift this equilibrium toward the "on" state, the sarcomere remains partially active even at low Ca²⁺, causing incomplete relaxation, energy wastage, and diastolic dysfunction, even with minimal or no hypertrophy.

Example: TNNT2 variants cause disproportionate SCD risk with near-normal wall thickness because hyperactivated sarcomeres consume ATP excessively, causing cardiomyocyte death without gross hypertrophy.

Loss of Function (LoF)Reduced or absent normal protein activity

A broad mechanistic category encompassing any variant that reduces or abolishes the normal biological activity of a protein, through reduced expression (haploinsufficiency), impaired folding, defective protein trafficking, or disruption of the active/binding site. Includes both truncating and missense variants.

Example: KCNQ1 LoF reduces IKs (slow delayed rectifier) current → prolonged action potential → LQT1.

Nonsense-Mediated Decay (NMD)mRNA quality-control surveillance

A cellular pathway that recognises and degrades mRNA containing a premature termination codon (PTC) located >50–55 nucleotides upstream of the last exon-exon junction. NMD prevents translation of truncated proteins and is a key phenotype modifier, variants that escape NMD may produce toxic truncated peptides with dominant negative properties.

Relevant to: MYBPC3, TTN, PKP2, DSP, NMD of the mutant transcript is the primary mechanism driving haploinsufficiency in these genes.

Protein Trafficking DefectFailure to reach the cell membrane

Missense variants may produce a structurally near-normal protein that is incorrectly folded and retained in the endoplasmic reticulum (ER) rather than being trafficked to the cell surface. The protein is then degraded, reducing functional surface expression. This is a major mechanism of LoF for KCNH2 variants in LQT2.

Example: Many KCNH2 missense variants in LQT2 cause ER retention of the hERG channel, functional consequence is LoF despite a structurally near-complete protein.

Triggered Activity (DADs)Spontaneous depolarisations from Ca²⁺ overload

Delayed afterdepolarisations (DADs) are abnormal depolarisation events that occur during phase 4 of the action potential, driven by spontaneous release of calcium from the sarcoplasmic reticulum (SR). If the DAD amplitude is sufficient to reach the action potential threshold, a triggered beat is initiated outside the normal conduction cycle, the cellular mechanism of ventricular arrhythmias in CPVT and PLN cardiomyopathy.

Example: RYR2 GoF variants → spontaneous SR Ca²⁺ sparks during adrenergic stimulation → DADs → triggered bidirectional VT, the pathognomonic arrhythmia of CPVT1.

Inheritance & Population Genetics

Allelic HeterogeneityDifferent variants cause different phenotypes

When different variants within the same gene produce distinct clinical phenotypes, different diseases, different severities, or even opposite functional mechanisms. Allelic heterogeneity is common in ICC genes and is clinically relevant because it means gene identification alone does not fully determine prognosis.

Example: SCN5A, GoF missense variants → LQT3; LoF variants → Brugada syndrome; severe LoF → DCM with conduction disease. Same gene, opposite mechanisms.

Compound HeterozygosityTwo different variants in the same gene

In autosomal recessive disease, compound heterozygosity describes carrying two distinct pathogenic variants in the same gene, one on each chromosome, rather than the same variant on both chromosomes (homozygosity). Each parent carries one variant and is typically unaffected. Together the two variants produce severely reduced or absent protein function.

Example: CASQ2 compound heterozygous variants cause CPVT2 with earlier onset than heterozygous carrier parents.

De Novo VariantNew mutation absent in both parents

A pathogenic variant arising for the first time in the proband, not inherited from either parent. De novo variants are identified in ~4–5% of ICC cases, particularly in severe early-onset presentations without a family history. Their identification is clinically important: the proband's siblings and parents are at very low risk (only relevant if gonadal mosaicism is possible), but offspring have a 50% transmission risk.

Example: Severe neonatal Marfan syndrome is frequently caused by de novo FBN1 variants, the absence of affected parents does not exclude a genetic aetiology.

Digenic InheritanceVariants in two genes required for disease

A pattern where pathogenic variants in two distinct genes, each individually insufficient to cause severe disease, combine to produce a more severe phenotype or clinical disease. Seen particularly in ARVC, where compound heterozygosity across two desmosomal genes (e.g., PKP2 + DSG2) amplifies disease penetrance and severity beyond either variant alone.

Example: ARVC patients carrying variants in both PKP2 and DSP have significantly higher penetrance, earlier onset, and greater arrhythmia burden than carriers of a single desmosomal variant.

Founder VariantPopulation-enriched pathogenic allele

A pathogenic variant present at relatively high frequency in a specific population due to descent from a common ancestor who carried it (founder effect). Important for population-specific diagnostic panels, targeted assays for founder variants can provide efficient first-line screening before full gene sequencing.

Example: MYBPC3 c.2373insG (~4% of HCM in South Asians); PLN p.Arg14del (Dutch/N. European DCM); JUP c.2157del2 (Greek island ARVC).

PenetranceProportion of carriers who develop disease

The probability that a variant carrier will manifest clinical disease. Complete penetrance means virtually all carriers are affected. Incomplete penetrance is common in ICCs, some pathogenic variant carriers remain phenotype-negative throughout life. Penetrance is age-dependent and modified by sex, physical activity, and modifier genes.

Example: MYBPC3 HCM variants have strongly age-related penetrance, many carriers are unaffected until the 4th–5th decade; TTN DCM variants have ~40% penetrance in males.

PhasingDetermining which parental chromosome a variant is on

Establishing whether a variant is on the maternally or paternally inherited copy of a gene. Critical when two variants are found in the same gene: in trans (one on each chromosome = biallelic = AR disease) versus in cis (both on same chromosome = monoallelic).

ProbandIndex case in a family

The first affected individual in a family to undergo genetic testing. Results from the proband guide which specific variant is used in subsequent cascade testing of relatives.

SegregationVariant co-occurrence with disease in a family

The pattern of a variant being present in affected family members and absent from unaffected ones. Each additional affected relative carrying the variant increases the LOD score, building evidence towards LP reclassification for a VUS.

Variable ExpressivitySame variant, different severity

Even when a pathogenic variant is penetrant, the severity and features of the phenotype vary considerably between carriers of the same variant, including within the same family. Modifier genes, lifestyle (e.g., exercise load), sex hormones, and epigenetic factors all contribute to expressivity.

Example: FBN1 Marfan variants, one family member may have severe aortic root aneurysm while another has only ectopia lentis with a normal aorta.

X-inactivation (Lyonisation)Random silencing of one X in female cells

Early in female embryogenesis, each somatic cell randomly inactivates one of its two X chromosomes, creating a mosaic in which approximately half the cells express each parental allele. In X-linked dominant disease, if the pathogenic X is preferentially silenced (skewed inactivation), a female carrier may remain clinically unaffected; if it is preferentially expressed, she may develop a phenotype approaching that of an affected male.

Example: Female LAMP2 carriers who happen to express the mutant allele predominantly may develop significant cardiomyopathy; those with skewed inactivation favouring the wild-type allele remain phenotype-negative into middle age.

X-linked InheritanceGene located on the X chromosome

X-linked dominant (XLD): one pathogenic allele is sufficient to cause disease in both males and females, but males typically have more severe disease as they lack a second X chromosome to buffer the effect. X-linked recessive (XLR): females are usually unaffected carriers; hemizygous males (one X allele) are clinically affected. Pedigree patterns show no male-to-male transmission in either form.

Example: GLA (Fabry) and LAMP2 (Danon) → XLD, both sexes affected, males severely; EMD (Emery-Dreifuss) → XLR, only males clinically affected.

Mitochondrial Genetics

HeteroplasmyMitochondrial variant allele fraction

Each cell contains hundreds of mitochondria, each with multiple mtDNA copies. Heteroplasmy describes the proportion of mitochondria carrying the pathogenic variant. Higher heteroplasmy generally correlates with greater disease severity. Heteroplasmy levels differ between tissues (blood may underestimate muscle/cardiac load) and can shift across generations.

Example: m.3243A>G, blood heteroplasmy >60% correlates with cardiac and neurological involvement in MELAS; lower levels may cause only diabetes or deafness.

HomoplasmyAll mitochondria carry the same mtDNA

When all copies of mtDNA within a cell or tissue carry the same sequence, either entirely wild-type (normal) or entirely the pathogenic variant. Homoplasmy for a pathogenic variant generally produces more severe, fully penetrant disease than heteroplasmy. Some mtDNA variants causing cardiomyopathy can be homoplasmic, as they may be relatively tolerated in tissues outside the heart and muscle.

Example: Certain MT-TL1 and MT-ATP6 variants associated with hypertrophic cardiomyopathy are transmitted and expressed homoplasmatically, resulting in predictable and fully penetrant cardiac involvement.

Maternal InheritanceMitochondrial DNA is maternally transmitted

Mitochondrial DNA (mtDNA) is inherited exclusively through the maternal lineage, sperm mitochondria are degraded after fertilisation. All children of an affected mother are at risk of inheriting the variant; no children of an affected father are at risk. Pedigree analysis should identify strictly maternal transmission when a mitochondrial disorder is suspected.

Example: m.3243A>G is transmitted by affected mothers to all offspring; an affected father does not transmit, paternal transmission effectively rules out an mtDNA disorder.

Threshold EffectMinimum heteroplasmy required for disease

Mitochondrial disease only manifests once the proportion of pathogenic mtDNA exceeds a tissue-specific threshold, below which residual wild-type mitochondria provide sufficient oxidative phosphorylation capacity to maintain function. Thresholds vary by tissue: cardiac and skeletal muscle have higher energy demands and lower thresholds than other organs. This explains why some carriers with the same variant remain entirely asymptomatic while others develop severe multisystem disease.

Example: m.3243A>G blood heteroplasmy of 10–30% may cause only diabetes or deafness; levels above ~60–70% in affected tissues typically produce full MELAS with cardiomyopathy and stroke-like episodes.

Sequencing & Laboratory Concepts

Allele-Specific ExpressionImbalanced expression from one parental allele

When one allele of a gene is expressed at significantly lower levels than the other, due to a regulatory or splicing variant on that allele. Detectable by RNA-seq; can support pathogenicity reclassification of a VUS affecting transcription or splicing efficiency.

AneuploidyAbnormal chromosome number

Presence of an abnormal number of chromosomes. ICC-relevant examples: trisomy 21 / Down syndrome (AVSD, DCM), Turner syndrome 45,X (bicuspid aortic valve, aortic coarctation), Klinefelter 47,XXY (DCM).

Coverage / Sequencing DepthTimes each base is read

The average number of times each DNA base is sequenced. Higher depth (~100× for WES, ~30–50× for WGS) increases confidence in variant calls and reduces false negatives.

Cryptic ExonNormally silent intronic sequence included in mRNA

An intronic sequence aberrantly included in mature mRNA when a nearby variant activates a cryptic splice site. Typically creates a frameshift or premature stop codon. Invisible to standard WES/WGS without RNA-seq functional follow-up.

CytogeneticsStudy of chromosomes and chromosome-scale changes

Analysis of chromosome number and large-scale structural organisation. Encompasses karyotyping (microscopy), FISH (fluorescent probe hybridisation), and chromosomal microarray (genome-wide copy number). Used for syndromic and congenital presentations.

Diagnostic YieldProportion receiving a genetic diagnosis

The proportion of tested individuals in whom a P/LP variant is identified. Varies by condition: ~60% HCM, ~30–40% DCM, ~50–60% LQTS, ~50% ARVC. Lower yields reflect incomplete knowledge of causative genes.

ExomeProtein-coding portion of the genome

The ~1–2% of the genome that encodes proteins, comprising ~20,000 genes. Whole exome sequencing (WES) captures and sequences this region to ~100× depth.

NGS (Next-Generation Sequencing)High-throughput DNA sequencing

Produces millions of short DNA reads simultaneously, enabling rapid sequencing of many genes at once. The technology underlying gene panels, WES, and WGS.

ROH (Regions of Homozygosity)Identical alleles on both chromosomes

Stretches of identical alleles on both chromosome copies, detected by SNP microarray. Extensive ROH indicates consanguinity; isolated ROH can indicate uniparental disomy (UPD), relevant for imprinting disorders affecting the heart.

TranscriptomeComplete RNA output of a cell

The full set of RNA molecules expressed by a cell or tissue. Tissue-specific, cardiac genes (TTN, PKP2, SCN5A) may not be expressed in blood, limiting RNA-seq utility to biopsy samples in ICC.

VCF (Variant Call Format)Bioinformatic output file

Standard file listing all differences between a patient's DNA and the reference genome after sequencing analysis. Clinical filtering narrows hundreds of thousands of raw variants to a small number of candidates.

Variant Classification (ACMG)

ACMG ClassificationFive-tier variant classification framework

Standard framework used by clinical laboratories: Pathogenic (P), Likely Pathogenic (LP), VUS, Likely Benign (LB), Benign (B). Based on population frequency, functional data, segregation, and computational evidence criteria.

VUS (Variant of Uncertain Significance)Inconclusive genetic finding

A variant with insufficient evidence to classify as pathogenic or benign. Common with WES/WGS. Should not alone drive major clinical decisions; requires ongoing evidence accumulation and review.

About These Recommendations

Exercise recommendations are based on ESC and AHA/ACC guidelines. The matrix below provides a quick reference for condition-specific recommendations. Detailed guidance follows.

Exercise Recommendation Matrix

Condition	Low Intensity	Moderate Intensity	Vigorous Intensity	Competitive Sport
HCM	Permitted	Restricted Low-risk only	Restricted Low-risk, shared decision	Contraindicated
DCM	Permitted	Permitted If LVEF >35-40%	Restricted Stable, LVEF >50%	Contraindicated LVEF <50%
ACM	Permitted	Contraindicated	Contraindicated	Contraindicated
LQTS	Permitted	Restricted Depends on type	Restricted Type & treatment dependent	Contraindicated
Brugada	Permitted	Permitted Avoid dehydration	Restricted If asymptomatic	Restricted Asymptomatic: shared decision
CPVT	Permitted	Contraindicated	Contraindicated	Contraindicated
Marfan/TAAD	Permitted	Restricted Root <40mm, non-contact	Contraindicated All root sizes (ESC 2020)	Contraindicated Contact/collision
Gene +ve / Pheno -ve	Permitted	Permitted Annual review	Permitted Annual review	Restricted Shared decision

Sources: ESC 2020 Guidelines on Sports Cardiology and Exercise in Patients with Cardiovascular Disease (Pelliccia A et al. Eur Heart J. 2021;42:17–96) · AHA/ACC 2015 Eligibility and Disqualification Recommendations for Competitive Athletes with Cardiovascular Abnormalities (Maron BJ et al. Circulation. 2015;132:e256–e261) · ESC 2023 Guidelines for the Management of Cardiomyopathies · ESC 2022 Guidelines on Ventricular Arrhythmias and SCD. Recommendations should be interpreted in the context of individual clinical assessment and local multidisciplinary team guidance.

Exercise Intensity Definitions

Light/Low Intensity

MET: <3 METs
Heart rate: <50% max HR
Examples: Walking slowly, bowling, golf (with cart), light housework
Can hold conversation easily

Moderate Intensity

MET: 3-6 METs
Heart rate: 50-70% max HR
Examples: Brisk walking, recreational swimming, cycling on flat terrain, doubles tennis, golf (carrying clubs)
Can talk but not sing

Vigorous Intensity

MET: >6 METs
Heart rate: 70-85% max HR
Examples: Running, singles tennis, competitive cycling, football, basketball, vigorous swimming
Difficult to talk comfortably

Competitive Sport

Organized team or individual sports
Regular training and competition
Performance-focused
Examples: Any sport at club, regional, or national level

Detailed Condition-Specific Recommendations

Hypertrophic Cardiomyopathy (HCM)

PERMITTED

Low intensity recreational exercise (walking, golf with cart, bowling)
Moderate intensity if low-risk (recreational swimming, doubles tennis, recreational cycling)
Light resistance training (<50% MVC)

CONTRAINDICATED

All competitive sports
High intensity exercise (running, intense cycling, vigorous swimming)
High static component sports (weightlifting, gymnastics)
Marathon, triathlon, CrossFit

Special considerations: Avoid activities that worsen LVOT gradient (Valsalva, post-exercise). Low-risk patients (no LVOTO, thinner walls, no high-risk features) may engage in moderate-intensity activities after shared decision-making.

High-risk features (any of the following warrant exercise restriction): Prior exertional syncope/presyncope, sustained VAs or cardiac arrest, family history of SCD in young relatives, severe LVH (≥30mm), extensive LGE (≥15% LV mass), severe LVOT obstruction (>50mmHg), apical aneurysm, LVEF <50%, NSVT, abnormal BP response to exercise, or HCM Risk-SCD ≥6%.

Dilated Cardiomyopathy (DCM)

PERMITTED

Low intensity exercise (all patients)
Moderate intensity if LVEF >35-40% and stable
Vigorous exercise if LVEF >50%, stable, no arrhythmias
Competitive sport only if LVEF >50%, no LGE, normal exercise test

CONTRAINDICATED

Competitive sport if LVEF <50%
Vigorous exercise if LVEF <45% or symptomatic
Any exercise during acute decompensation

Special considerations: Exercise capacity improves with appropriate medical therapy. Annual assessment recommended. LMNA mutations require careful monitoring regardless of LVEF.

Arrhythmogenic Cardiomyopathy (ACM)

PERMITTED

Low intensity recreational exercise only (walking, golf with cart)

CONTRAINDICATED

All competitive sports
Moderate-vigorous intensity exercise
Endurance exercise (running, cycling, swimming)

Special considerations: Exercise accelerates disease progression in ARVC ("exercise paradox"). Even moderate exercise may worsen phenotype. Strictest restrictions of all cardiomyopathies.

Long QT Syndrome (LQTS)

PERMITTED

Low intensity exercise (all genotypes)
Moderate intensity if on therapy, asymptomatic, QTc <500ms
LQT3: Generally more permissive (avoid rest/sleep triggers)

CONTRAINDICATED

All competitive sports
Swimming (especially LQT1)
High intensity exercise (especially LQT1)
Exercise with auditory stimuli (LQT2)

Genotype-specific: LQT1 avoid swimming/diving. LQT2 avoid loud alarms/auditory triggers. LQT3 more permissive for exercise (events at rest/sleep). All must be on adequate beta-blocker therapy.

Brugada Syndrome

PERMITTED

Low-moderate intensity exercise if asymptomatic
Vigorous exercise if asymptomatic Type 1 pattern only
Competitive sport possible if asymptomatic, shared decision-making

CONTRAINDICATED

Competitive sport if history of syncope or VF
Exercise in febrile illness (aggressive fever management essential)
Avoid dehydration and excessive alcohol

Special considerations: Events typically at rest/sleep (not during exercise). More permissive than other channelopathies for asymptomatic patients. Fever is major trigger - treat aggressively.

Catecholaminergic Polymorphic VT (CPVT)

PERMITTED

Low intensity exercise only if well-controlled on therapy

CONTRAINDICATED

All competitive sports (absolute contraindication)
Moderate-vigorous exercise
Swimming
Any intense physical or emotional stress

Special considerations: CPVT is exercise/catecholamine-triggered - strictest exercise restrictions. Even on high-dose beta-blockers + flecainide, avoid moderate-vigorous exercise. Compliance with therapy is critical.

Marfan Syndrome & Thoracic Aortic Aneurysm Disease (TAAD)

PERMITTED

Low intensity exercise (all patients)
Moderate intensity if aortic root <40mm
Non-contact sports if aortic dimensions stable

CONTRAINDICATED

Contact/collision sports (rugby, boxing, martial arts)
Isometric exercise (weightlifting)
Competitive sport if aortic root >40mm
Vigorous intensity if aortic root >40mm

Special considerations: Exercise restrictions based on aortic dimensions. Annual imaging essential. Loeys-Dietz more aggressive (lower thresholds). Avoid Valsalva maneuvers and activities that spike blood pressure.

Genotype-Positive / Phenotype-Negative (G+/P-)

PERMITTED

All exercise intensities if truly phenotype-negative
Competitive sport with shared decision-making and annual review

REQUIRES MONITORING

Annual cardiac assessment (ECG, echo/MRI, exercise test)
Shared decision-making for competitive sport
Some variants higher risk (e.g., specific LMNA, RYR2 mutations)

Special considerations: True phenotype-negative carriers can exercise. Annual review essential as phenotype may develop. Competitive sport decision should involve patient, cardiologist, and sports physician. Specific gene/variant risk stratification important.

General Exercise Guidance

Shared decision-making: All recommendations individualized with patient and specialist input.

Regular review: Annual reassessment of exercise capacity and recommendations.

Adequate treatment: Optimize medical therapy before exercise.

Warning signs: Stop immediately if chest pain, palpitations, breathlessness, dizziness, or syncope.

Emergency plan: Patients and families should know CPR and have access to emergency services.

Key References:

2020 ESC Guidelines on Sports Cardiology and Exercise in Patients with Cardiovascular Disease
2015 Eligibility and Disqualification Recommendations for Competitive Athletes (Maron et al)
2020 AHA/ACC Guideline for the Diagnosis and Treatment of HCM

UK Driving - Patient Responsibilities

Group 1 = Car/Motorcycle | Group 2 = Bus/Lorry (HGV/PCV)

It is the PATIENT's legal responsibility to:

Notify DVLA of diagnosis (online or by post)
Stop driving if told to do so or if condition worsens
Attend reviews as required (typically 1-3 years)
Inform car insurance of medical condition

Failure to notify DVLA invalidates insurance and is a criminal offence (up to £1000 fine, with possible prosecution if an accident occurs). Clinicians can advise but cannot notify the DVLA on the patient's behalf.

Driving Rules at a Glance

Group 1 = car / motorcycle · Group 2 = bus / lorry (HGV/PCV).

Cells: may drive conditional / restrictions barred / must not drive

Condition	Group 1: Car / Motorcycle	Group 2: Bus / Lorry (HGV/PCV)
HCM	May drive if asymptomatic, notify DVLA, review 1–3 yr.Symptomatic: cease until 3 months symptom-free, EF >40%, no LVOT gradient >50 mmHg.	Permitted only if LVOT <30 mmHg, wall <30 mm, no syncope, no NSVT, normal BP response to exercise, LVEF ≥45%.
DCM	May drive if asymptomatic & LVEF >40%, annual review.Symptomatic / LVEF ≤40%: notify DVLA, cease if symptomatic.	LVEF ≥45%, no symptomatic heart failure, no significant arrhythmia; annual review.
ARVC	May drive if asymptomatic (no VT/VF/syncope, LVEF >40%).Symptomatic (VT/VF/syncope): cease until 3 months post-ablation or ICD.	Barred if VT/VF, cardiac syncope, or LVEF <45%.
LQTS	May drive if asymptomatic on therapy.Symptomatic: cease 3 months.	No syncope/arrest, QTc <500 ms, on effective therapy; annual review.
Brugada	May drive if asymptomatic.Symptomatic (syncope/arrest): cease, see ICD rules.	Barred if any history of syncope or cardiac arrest.
CPVT	May drive if asymptomatic.Symptomatic (syncope/arrest): cease, see ICD rules.	Barred if any history of syncope or cardiac arrest.
Marfan / Aortopathy	Individually assessed, BP control, aortic dimensions, no dissection history.	Individually assessed, aortic size, BP control, absence of dissection history.
ICD (in situ)	Primary prevention: 1 week off. After appropriate shock (secondary prevention): 6 months off. Inappropriate shock: 2 weeks (if cause fixed).	Any ICD = permanent disqualification.

Summary of UK DVLA standards, each case is assessed individually. Always check the full DVLA cardiovascular fitness-to-drive guidance.

Group 2 Licensing (HGV/PCV): General Principles

Group 2 (HGV/PCV/Bus): Higher Threshold

Group 2 licences (buses, lorries, HGV, PCV) require a higher medical standard than Group 1, reflecting the greater public safety risk. Key principles:

Burden of proof is on the applicant: must demonstrate fitness, not merely absence of disqualifying features
No syncope or near-syncope: any episode within 5 years is generally disqualifying
No symptomatic arrhythmia: must be controlled and stable
LVEF ≥45% required for most conditions (some require ≥50%)
Regular specialist review: typically annual; DVLA may issue 1-year licences
Any ICD = permanent disqualification (Group 2)
Pacemaker alone: may be compatible with Group 2 if underlying condition allows, subject to DVLA assessment

Key Points:

Returning to driving: DVLA will issue new licence when medical criteria met. No re-test required unless told otherwise. Patient must reapply if licence expired.
Temporary licences: DVLA may issue 1, 2, or 3-year licences requiring regular review rather than standard 10-year (Group 1) or 5-year (Group 2) licences.
Individual variation: These are general rules - DVLA assesses each case individually. Always check current guidance.

→ Full DVLA Guidance (Official)

→ Contact DVLA (Drivers Medical Group)

mWHO Classification of Cardiovascular Risk in Pregnancy (ESC 2018^[1])

Class	Risk	Management
mWHO I	No detectable increased maternal mortality; no/mild morbidity increase	Local obstetric care; annual or once per pregnancy cardiology review
mWHO II	Small increased risk of maternal mortality; moderate morbidity	Specialist centre; cardiology review each trimester
mWHO III	Significantly increased risk; expert counselling essential	Expert multidisciplinary team (MDT); monthly or more frequent review; delivery in tertiary centre
mWHO IV	Extremely high; pregnancy contraindicated	Counsel against pregnancy; if pregnant, discuss termination; if continuing, expert tertiary centre

All women with ICC should have pre-pregnancy counselling from a specialist cardiac obstetric MDT.^[1]

Cardiomyopathies

Condition	mWHO Class	Key Risks	Medications: Continue	Medications: STOP / Avoid	Delivery / Monitoring
HCM	II (non-obstructive) III (obstructive/severe)	LVOTO worsens with reduced preload; high-risk if LVEF <30%, obstructive HCM with symptoms, prior arrhythmia.^[1]^[2]	Beta-blockers (bisoprolol/metoprolol preferred); verapamil if beta-blocker intolerant	Disopyramide (1st trimester, uterotonic); vasodilators; mavacamten (no data)	Echo every trimester ± more if obstructive. Vaginal delivery preferred; shortened 2nd stage. Avoid hypovolaemia. Epidural preferred.
DCM	III (LVEF 30–45%) IV (<30%)	Risk proportional to LVEF; peripartum deterioration; thromboembolic risk if LVEF <30%; AF; PPCM overlap.^[1]^[3]	Beta-blocker; diuretic (furosemide) if pulmonary oedema; LMWH if LVEF <30%; digoxin for rate control	ACEi/ARB/ARNI (teratogenic, stop pre-conception); spironolactone (antiandrogenic); SGLT2i (limited data); amiodarone (last resort)	Echo every 4–6 weeks. MDT delivery planning. Caesarean if haemodynamically unstable or LVEF <30%. Invasive monitoring in labour if severe.
ACM / ARVC	II–III	Arrhythmia risk increases; catecholamine surges in labour trigger VT. Exercise restriction essential throughout.^[1]^[2]^[4]	Beta-blockers (continue, max tolerated); sotalol if required (monitor QTc)	Flecainide (limited safety data, use only if essential); amiodarone (last resort)	Echo + Holter each trimester. Epidural strongly preferred (minimise catecholamines). Avoid GA if possible. Defibrillator available at delivery.
Cardiac Amyloidosis	III–IV	Restrictive physiology worsens; systemic disease involvement; rare in women of childbearing age (ATTR).^[1]	Diuretics (careful); rate control	Tafamidis (no safety data, stop pre-conception); diflunisal; patisiran/inotersen (no data)	Expert MDT; individual assessment. Very rare scenario.

Channelopathies

Condition	mWHO Class	Key Risks	Medications: Continue	Medications: STOP / Avoid	Delivery / Monitoring
LQTS	I–II	Generally well tolerated. Postpartum HIGH RISK, LQT2 in particular (within 9 months).^[5]^[6] Risk increases with QTc >500ms or prior arrest.^[1]	Beta-blockers, ESSENTIAL; do NOT stop. Nadolol or propranolol preferred. Continue into postpartum (increased risk). Monitor neonate for bradycardia/hypoglycaemia.	QT-prolonging drugs (check crediblemeds.org): ondansetron (use metoclopramide/cyclizine), erythromycin, azithromycin, some antifungals, droperidol	Continuous ECG monitoring in labour. Avoid hypokalaemia (IV K⁺ supplementation). Epidural preferred (reduces catecholamines). Defibrillator immediately available.
Brugada	II–III	Fever (common peripartum) can precipitate VF. Vagal predominance in labour may unmask Brugada pattern. Higher risk if prior cardiac arrest or spontaneous type 1 ECG.^[1]^[4]	Treat ALL fever aggressively with paracetamol. ICD if high-risk, should be implanted pre-pregnancy.	Sodium channel blockers (bupivacaine, use ropivacaine instead); propofol (avoid as sole anaesthetic); avoid drugs at brugadadrugs.org	Continuous ECG monitoring. Defibrillator available. Epidural with ropivacaine preferred. Temperature monitoring throughout labour and postpartum.
CPVT	II–III	Labour pain/catecholamine surges may trigger VT/VF. Must avoid sympathetic activation. Compliance with beta-blocker critical.^[1]^[4]	Beta-blockers (nadolol/propranolol), do NOT stop; maximise dose. Flecainide if already established add-on therapy.	Avoid catecholamine-releasing GA agents (ketamine, ephedrine). Avoid adrenaline-containing dental/local anaesthetics.	Epidural analgesia strongly recommended, primary strategy to blunt sympathetic response. Continuous ECG + defibrillator. Avoid 2nd stage prolongation.
Short QT Syndrome	II	Limited data; arrhythmia risk possible during labour/postpartum. Rare condition.^[4]	Quinidine if established; avoid drugs shortening QT	Drugs shortening QT interval	Continuous ECG; defibrillator available; expert MDT. Very limited evidence base.

Aortopathies & Connective Tissue Disorders

Condition	mWHO Class	Aortic Thresholds	Medications	Delivery	Key Points
Marfan syndrome	III (<40mm) IV (>45mm or dissection)	>45mm: pregnancy contraindicated, prophylactic surgery first. 40–45mm: individual risk assessment + expert MDT. <40mm: pregnancy may proceed with close monitoring.^[1]^[7]^[8]	Continue: beta-blocker (bisoprolol/atenolol/propranolol). Stop pre-conception: losartan/ACEi (teratogenic).	Echo every 4–6 weeks. Vaginal delivery with epidural + shortened 2nd stage (avoid Valsalva) if stable. Caesarean if root >40mm or rapid growth.	Postpartum aortic imaging at 6 weeks and 6 months. Dissection risk persists postpartum. Breastfeeding: beta-blockers acceptable (monitor infant).
Loeys-Dietz syndrome	IV, almost always contraindicated	Dissection can occur at <40mm (unlike Marfan). Entire arterial tree at risk. If considering pregnancy: root must be <40mm AND no prior dissection AND fully informed consent re: 25–50% maternal mortality risk in some series.^[1]^[9]	Continue: beta-blocker. Stop pre-conception: losartan/ACEi. ARB beneficial (TGF-β suppression) but teratogenic.	Tertiary expert centre only. Delivery mode individual; avoid Valsalva. Full MDT including aortic surgery on standby.	Pregnancy strongly discouraged. Even with prophylactic surgery pre-pregnancy, residual risk high (non-root dissections). Pan-arterial imaging post-delivery.
Bicuspid aortic valve (BAV)	I–III (depends on severity)	Aortic root >50mm: significant risk. >55mm with BAV: prophylactic surgery before pregnancy recommended.^[7]	Beta-blocker if aortopathy. Stop ACEi/ARB pre-conception if used.	Echo each trimester. If severe AS or AR: discuss valve intervention pre-pregnancy. Vaginal delivery possible in mild-moderate disease.	Screen for coarctation (increased BP in pregnancy if coarctation present). FBN1/SMAD3 testing if family history.
Turner syndrome	III–IV (if aortic disease)	BAV in ~30%; coarctation ~10%; aortic dilatation, use aortic size index (ASI >2.5 cm/m² = high risk). ASI >2.5 cm/m²: pregnancy not advised.^[1]	Antihypertensives; avoid ACEi/ARB	Aortic imaging pre-pregnancy and each trimester. If ASI >2 cm/m²: tertiary centre delivery.	Pregnancy usually via oocyte donation. Obstetric complications high (hypertension, pre-eclampsia). Postpartum aortic monitoring.

Storage & Infiltrative Conditions

Condition	mWHO Class	Key Risks	Medications	Monitoring & Delivery
Fabry disease	II (if stable cardiac/renal function)	Generally well tolerated if no significant cardiac or renal involvement. CKD increases obstetric risk. Neuropathic pain may worsen.^[12]	Continue: ERT (agalsidase alfa 0.2mg/kg q2wks or agalsidase beta 1mg/kg q2wks, considered safe; case series support continuation^[12]). Avoid: migalastat (inadequate safety data). Stop ACEi/ARB pre-conception.	Echo + renal function each trimester. Vaginal delivery generally possible. Monitor neonate if ERT continued (no known neonatal effects).
Pompe disease	II–III	Respiratory involvement may compromise pregnancy, assess FVC. Cardiac involvement usually mild in late-onset forms.	Alglucosidase alfa (ERT), limited data; generally continued in specialist centres. Respiratory support if needed.	Respiratory function assessment essential. May require assisted ventilation. MDT including respiratory medicine.

Neuromuscular Conditions

Condition	mWHO Class	Key Risks	Medications	Monitoring & Delivery
DMD/BMD female carriers	II–III (if LV dysfunction)	~30% of female DMD carriers have LV dysfunction (often subclinical).^[10] Pregnancy can unmask or worsen cardiomyopathy. Obstetric complications higher if NMD involvement.^[1]	Continue: beta-blocker if LV dysfunction present. Stop pre-conception: ACEi/ARB/eplerenone. SGLT2i: avoid (limited data).	Echo at booking + each trimester. Vaginal delivery generally possible; epidural preferred. Monitor respiratory function if skeletal myopathy present.
Myotonic dystrophy type 1 (DM1)	II–III	Cardiac arrhythmias (AV block, VT), uterine atony (prolonged labour), respiratory compromise.^[11] Maternal and congenital myotonic dystrophy risk in infant (anticipation, maternal transmission worse).^[1]	ICD/pacemaker if indicated pre-pregnancy. Avoid drugs worsening myotonia.	ECG/Holter each trimester. Anaesthetic risk, detailed assessment essential. Oxytocin for uterine atony. PPH risk. Neonatal assessment for congenital DM1.
Friedreich ataxia	II–III	Hypertrophic or dilated cardiomyopathy; arrhythmias. Neurological disease affects mobility and labour management.^[1]	Continue cardiac medications (beta-blocker if LV dysfunction). Omaveloxolone, stop pre-conception (no safety data).	Cardiology + neurology MDT. Echo each trimester. Regional anaesthesia may be limited by scoliosis, anaesthetic assessment essential.

Cardiac Drug Safety in Pregnancy: Quick Reference^[1]

Drug / Class	ICC Indications	Pregnancy Safety	Recommendation
Beta-blockers (bisoprolol, metoprolol, propranolol, nadolol, atenolol)	HCM, DCM, ARVC, LQTS, CPVT, Marfan, DCM	Generally safe. Cross placenta, monitor neonate for bradycardia, hypoglycaemia. Atenolol associated with IUGR (avoid in 1st trimester).^[1] Bisoprolol/metoprolol/propranolol preferred.	Continue, do not stop
Verapamil	HCM (if beta-blocker intolerant)	Generally acceptable. May cause neonatal bradycardia/hypotension near term. Avoid high doses.	Acceptable if beta-blocker not tolerated; lowest effective dose
Sotalol	ARVC	Acceptable safety profile in pregnancy. Monitor foetal HR. QTc monitoring required.	Acceptable, monitor foetal and maternal QTc
Diuretics (furosemide)	DCM, HF	Safe if used judiciously. Avoid excessive dose, may reduce uteroplacental perfusion.	Acceptable for pulmonary oedema; use minimum effective dose
LMWH (enoxaparin, dalteparin)	DCM, AF, mechanical valves	Drug of choice for anticoagulation in pregnancy, does not cross placenta	Safe, preferred anticoagulant throughout pregnancy
Disopyramide	HCM	Uterotonic, may stimulate contractions (especially 1st trimester). Limited data overall.	Avoid in 1st trimester; use only if benefit > risk with expert advice
Flecainide	ARVC, CPVT	Limited human data. Used for foetal arrhythmias, some foetal safety data. Avoid unless essential.	Use only if essential; specialist advice required
Spironolactone	DCM	Antiandrogenic, animal studies show feminisation of male foetus at high doses	Avoid; switch to eplerenone (less antiandrogenic) or stop if safe
SGLT2 inhibitors (dapagliflozin, empagliflozin)	DCM	No adequate human data; animal embryotoxicity concerns	Stop pre-conception or as soon as pregnancy confirmed
Migalastat (Galafold)	Fabry disease	No human data	Stop pre-conception; switch to ERT if treatment required
Warfarin	Mechanical heart valves, AF	Warfarin embryopathy <12 weeks; foetal intracranial haemorrhage risk. Acceptable weeks 14–34 for mechanical valves if dose ≤5mg/day.	Mechanical valve specific use only; avoid <12 weeks and near term; switch to LMWH peripartum
ACE inhibitors (ramipril, lisinopril, perindopril)	DCM, Duchenne	Teratogenic, renal agenesis, oligohydramnios, neonatal renal failure, skull ossification defects (2nd/3rd trimester).^[1]	STOP pre-conception; switch to alternative
ARBs (losartan, candesartan, valsartan)	Marfan, DCM, Fabry	Same fetotoxicity as ACEi, contraindicated from conception.^[1]	STOP pre-conception
Sacubitril/valsartan (ARNI)	DCM	Valsartan component fetotoxic; sacubitril, no human data	STOP pre-conception; switch to beta-blocker ± diuretic
Amiodarone	ARVC, DCM	Foetal hypothyroidism, goitre, IUGR, premature birth, neonatal bradycardia. High iodine content. Last resort only.^[1]	Avoid, use only for life-threatening arrhythmia uncontrolled by other agents
Mavacamten	HCM (obstructive)	No human data; animal reproductive toxicity.^[2]	Stop pre-conception; effective contraception required (CYP2C19 metabolism, drug holidays)
DOACs (apixaban, rivaroxaban, edoxaban, dabigatran)	AF in various conditions	Foetal and embryo toxicity in animal studies; no human safety data; cross placenta.^[1]	Contraindicated in pregnancy, switch to LMWH pre-conception

Pre-Pregnancy Genetic Counselling

Key Principles

Genetic counselling should be offered to all patients with an ICC and their partners before conception.^[1]^[13]
Ideally initiated at diagnosis, not at point of pregnancy planning (allows time for family decisions)
Involves: inheritance pattern, risk to offspring, available reproductive options, implications for family members
Refer to regional clinical genetics service; joint cardiac-genetics clinic optimal

Inheritance Patterns & Offspring Risk by Condition

Condition	Inheritance	Risk to Offspring	Penetrance	Notes
HCM (MYBPC3, MYH7)	Autosomal dominant	50% per child	Variable, MYBPC3 ~65% by age 50; MYH7 >95%.^[2]	De novo mutations ~5%. Cascade testing of 1st-degree relatives.
DCM (LMNA, TTN, FLNC etc.)	Autosomal dominant (most)	50% per child	LMNA >90%; TTN 30–40%; variable by gene.^[2]	Early cardiac surveillance in gene-positive offspring. LMNA/FLNC, early ICD consideration.
ACM / ARVC (PKP2, DSP etc.)	Autosomal dominant (most); AR (Naxos/Carvajal)	50% per child (AD); 25% (AR)	30–50% (PKP2); >90% males (TMEM43)	Exercise restriction advice for gene-positive offspring. Clinical screening from childhood.
LQTS (KCNQ1, KCNH2, SCN5A)	Autosomal dominant (Romano-Ward); AR (Jervell-Lange-Nielsen, deaf)	50% per child	25–75% (AD); ~100% (AR)	Neonatal ECG ± genetic testing. Beta-blocker started promptly if QTc prolonged. JLN: if both parents carry KCNQ1/KCNE1 variants, 25% risk of severe phenotype in offspring.
Brugada (SCN5A)	Autosomal dominant; incomplete penetrance	50% per child	15–35%; male-predominant expression	~70% genetically elusive. Cascade ECG ± genetic testing in family. Fever protocols for gene-positive children.
CPVT (RYR2, CASQ2)	RYR2: autosomal dominant; CASQ2: autosomal recessive	50% (RYR2); 25% affected, 50% carrier (CASQ2)	>80% (RYR2)	Exercise stress test in gene-positive children. Start beta-blocker immediately if symptomatic.
Fabry disease (GLA)	X-linked (GLA on Xq22)	Sons: 100% unaffected (receive Y chr); daughters: 100% obligate carriers. If mother affected: 50% sons affected, 50% daughters carriers.	Males: near 100%. Females: variable (lyonisation).	Female carriers have variable expression, many develop significant disease. Neonatal/early testing recommended for male carriers.
Marfan (FBN1)	Autosomal dominant	50% per child	Near 100% (high penetrance, variable expressivity).^[8]	~25% de novo. Clinical assessment of offspring at birth and periodically. Early beta-blocker if aortic dilation.^[8]
Loeys-Dietz (TGFBR1/2, SMAD3, TGFB2/3)	Autosomal dominant	50% per child	High but variable by gene and variant	Full aortic imaging of gene-positive offspring from early childhood. More aggressive than Marfan.
Duchenne (DMD)	X-linked recessive	Female carrier: 50% of sons affected, 50% of daughters carrier	Males: ~100%. Females: carriers may have cardiac involvement (~30%).	Carrier females: cardiac surveillance. PGT-M available. Pre-implantation or prenatal diagnosis (CVS/amniocentesis) important option.

Reproductive Options for Couples with ICC

Option	Description	Considerations
Natural conception + postnatal testing	Conceive naturally; test child after birth (or at appropriate age)	Simple; no intervention. Child will require surveillance if gene-positive. Discuss age of testing (respect child autonomy for adult-onset conditions).
Prenatal diagnosis (PND): CVS or amniocentesis	Chorionic villus sampling (10–13 wks) or amniocentesis (15–20 wks) for foetal genetic testing	Enables decision whether to continue pregnancy. Risk of miscarriage ~0.5–1%. Available on NHS. Psychological impact of result significant.
Preimplantation genetic testing, monogenic (PGT-M)	IVF with embryo biopsy + genetic testing before transfer; only unaffected embryos implanted.^[13]	Avoids pregnancy termination decision. Requires IVF (cycles, cost, success rate ~25–40%/cycle). HFEA licensed centre required. Lead time ~12 months. NHS-funded in some regions for high-penetrance conditions.
Donor gametes (sperm or egg donation)	Use unaffected donor, removes genetic transmission risk from one parent	Eliminates transmission from carrier parent. Requires donor services; legal and psychological counselling. Not suitable if both parents carry pathogenic variants.
Adoption / fostering	Parenting without genetic transmission	Valid option, discuss without bias. Process can be lengthy. No medical contraindication from ICC itself.

PGT-M requires identification of the familial pathogenic variant in advance. Couples should be referred to clinical genetics and reproductive medicine well before planned conception. NHS funding criteria vary by region and condition penetrance.

References & Review Date

Last reviewed: May 2026

Regitz-Zagrosek V, et al. 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy. Eur Heart J. 2018;39(34):3165–3241. DOI: 10.1093/eurheartj/ehy340
Arbelo E, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503–3626. DOI: 10.1093/eurheartj/ehad194
McDonagh TA, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599–3726. DOI: 10.1093/eurheartj/ehab368
Zeppenfeld K, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43(40):3997–4126. DOI: 10.1093/eurheartj/ehac262
Seth R, et al. Long QT syndrome and pregnancy. J Am Coll Cardiol. 2007;49(10):1092–1098. DOI: 10.1016/j.jacc.2006.09.054
Rashba EJ, et al. Influence of pregnancy on the risk for cardiac events in patients with hereditary long QT syndrome. Circulation. 1998;97(5):451–456. DOI: 10.1161/01.CIR.97.5.451
Erbel R, et al. 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases. Eur Heart J. 2014;35(41):2873–2926. DOI: 10.1093/eurheartj/ehu281
Loeys BL, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010;47(7):476–485. DOI: 10.1136/jmg.2009.072785
MacCarrick G, et al. Loeys-Dietz syndrome: a primer for diagnosis and management. Genet Med. 2014;16(8):576–587. DOI: 10.1038/gim.2014.11
McNally EM, et al. Contemporary Cardiac Issues in Duchenne Muscular Dystrophy. Circulation. 2015;131(18):1590–1598. DOI: 10.1161/CIRCULATIONAHA.114.015151
Groh WJ, et al. Electrocardiographic abnormalities and sudden death in myotonic dystrophy type 1. N Engl J Med. 2008;358(25):2688–2697. DOI: 10.1056/NEJMoa062800
Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30. DOI: 10.1186/1750-1172-5-30
Sturm AC, et al. Clinical Genetic Testing for the Cardiomyopathies and Arrhythmias. Genet Med. 2019;21(3):694–711. DOI: 10.1038/s41436-018-0386-3

Clinical Decision Calculators

HCM Risk-SCDHCM

ESC HCM Risk-SCD model estimating 5-year sudden cardiac death risk to guide primary-prevention ICD decisions in hypertrophic cardiomyopathy (≥6% high risk, <4% low). Variables: age, maximal wall thickness, left atrial diameter, LVOT gradient, family history of SCD, NSVT, unexplained syncope. Built into this site, opens on the HCM page.

Open Calculator →

ARVC Risk CalculatorARVC

Validated tool predicting 5-year risk of sustained ventricular arrhythmia in arrhythmogenic cardiomyopathy. Derived and externally validated by Cadrin-Tourigny et al. (NEJM Evidence 2022; n=864). Endorsed in ESC 2023 cardiomyopathy guidelines for ICD decision-making. Variables: sex, age at diagnosis, prior VT/VF, syncope, Holter NSVT, QRS duration, epsilon wave, RV function, and pathogenic variant carrier status.

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Cardiac Amyloidosis Staging (ATTR-CM)Amyloidosis

Gillmore / National Amyloidosis Centre stages I–III for transthyretin cardiac amyloidosis from NT-proBNP (>3000 ng/L) and eGFR (<45 mL/min), guiding prognosis and therapy discussions; the Grogan system stages wild-type ATTR. AL amyloidosis is staged separately by the revised Mayo system (troponin T + NT-proBNP).

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Seattle Heart Failure ModelDCMHeart Failure

Validated prognostic tool estimating 1-, 2-, and 5-year survival in patients with heart failure (including DCM and advanced cardiomyopathy). Incorporates clinical, haemodynamic, medication, and device variables. Widely used to guide timing of transplant assessment, LVAD consideration, and referral to advanced heart failure services. Derived from PRAISE-1 trial (n=1,125); validated in multiple external cohorts.

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Corrected QT Interval (QTc) CalculatorLQTSDrug Safety

Calculates QTc using Bazett, Fridericia, Framingham, and Hodges correction formulas from measured QT interval and heart rate. Essential for LQTS diagnosis (QTc ≥480 ms diagnostic in symptomatic patients), drug-induced QT monitoring, and pre-prescription safety checks. Fridericia preferred at heart rates <50 or >90 bpm; Bazett most widely used in clinical practice.

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Aortic Root Z-score CalculatorMarfanAortopathy

Body surface area–adjusted aortic root Z-scores, essential for applying 2010 revised Ghent criteria in Marfan syndrome and for monitoring aortic dilation in paediatric patients and adults of varying habitus. Z-score ≥2 = dilated (≥2 SD above mean for BSA). Based on normative data from Devereux et al. BSA calculated by DuBois formula from height and weight.

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Professional Societies

British Inherited Cardiac Conditions Society (BICCS)

Professional society for healthcare professionals working with inherited cardiac conditions

Visit Website →

European Society of Cardiology

Clinical practice guidelines and educational resources

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American College of Cardiology

Clinical guidelines, tools, and educational content

Visit Website →

Heart Rhythm Society

Professional organisation for cardiac electrophysiology and arrhythmia management

Visit Website →

British Cardiovascular Society

UK professional body for cardiovascular healthcare professionals

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Patient & Charity Organisations

Cardiomyopathy UK

Patient support charity providing information and support for people affected by cardiomyopathy

Visit Website →

Cardiac Risk in the Young (CRY)

Charity working to reduce deaths from young sudden cardiac death

Visit Website →

SADS UK

Support for families affected by Sudden Arrhythmic Death Syndrome

Visit Website →

The Marfan Foundation

Resources for patients and clinicians on Marfan syndrome and related connective tissue disorders

Visit Website →

Genetics Resources

NHS England National Genomic Test Directory

Official directory of all NHS-funded genomic tests for rare and inherited conditions in England

Visit Website →

ClinGen: Clinical Genome Resource

Authoritative resource for gene–disease validity and variant interpretation

Visit Website →

ClinVar

Database of genomic variation and its relationship to human health

Visit Website →

OMIM: Online Mendelian Inheritance in Man

Comprehensive catalogue of human genes and genetic disorders with molecular basis

Visit Website →

ICCnotes is an independent, free educational resource on inherited cardiac conditions (ICC), covering genetics, diagnosis, risk stratification, follow-up, exercise and UK driving (DVLA) guidance, pregnancy, and practical management across 21 conditions. It is written for healthcare professionals and trainees, and draws on current ESC, NICE, AHA/ACC, HRS and BHRS guidance with primary-source citations throughout.

It is intended as a point-of-care reference, not a substitute for specialist assessment, local protocols, or the full current guideline text.

Important: educational use only

ICCnotes is an educational resource for healthcare professionals. It does not replace independent clinical judgement, specialist advice, local policies, or current national and international guidelines. Drug doses, thresholds and recommendations must be verified against the current SmPC/BNF and the full guideline before use in patient care. Do not enter patient-identifiable data into any linked external calculator.

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If you spot a factual error, an outdated recommendation, or a broken link, please get in touch, confirmed errors are corrected promptly.

iccnotes@protonmail.com

No commercial sponsorship. ICCnotes receives no pharmaceutical or commercial funding, and no commercial party influences its content.

Version 1.0 · Last reviewed June 2026 · Next scheduled review June 2027

ICCnotes

Aetiology

Genetics

Prevalence

Diagnostic Criteria

Diagnosis

Investigations

Treatments

Complications

Risk Stratification

Pregnancy Management

Follow-up

Key Points

References & Review Date

Clinical Guidelines

2023 ESC Guidelines for Management of Cardiomyopathies

AHA/ACC/HFSA Guideline on HCM

HRS Expert Consensus on ARVC

ESC Guidelines on Ventricular Arrhythmias and SCD

HRS/EHRA/APHRS/LAHRS Expert Consensus on Arrhythmia Management in Inherited Primary Arrhythmia Syndromes

2024 ESC Guidelines for the Management of Aortic Diseases

ESC Guidelines on Sports Cardiology and Exercise in Patients with Cardiovascular Disease

ESC Guidelines on Cardiac Pacing and CRT

ACMG Standards and Guidelines for Genetic Testing

Genetic Testing

UK National Genomic Test Directory (Version 8.1, July 2025[1])

Cardiomyopathy

R131 Hypertrophic Cardiomyopathy

Genes Tested (Hypertrophic Cardiomyopathy Panel - 49 genes)

R132 Dilated and Arrhythmogenic Cardiomyopathy

Main Genes Tested (DCM/ACM Panel)

R133 Arrhythmogenic Cardiomyopathy (ACM/ARVC)

Desmosomal Genes

Arrhythmia

R127 Long QT Syndrome

Main Genes (LQTS Panel)

R128 Brugada Syndrome

Genes Tested

R129 Catecholaminergic Polymorphic VT

Main Genes

R130 Short QT Syndrome

Main Genes

Other

R138 Molecular Autopsy / Idiopathic VF

Genetic Counselling

When to Refer for Genetic Counselling[1][2]

References & Review Date

Testing Methods

Tiered testing strategy

Assay & analysis methods

Testing strategies & workflows

Gene Variants in Inherited Cardiac Conditions

References & Review Date

Genetics Glossary

Exercise Recommendations

Exercise Recommendation Matrix

Exercise Intensity Definitions

Light/Low Intensity

Moderate Intensity

Vigorous Intensity

Competitive Sport

Detailed Condition-Specific Recommendations

Hypertrophic Cardiomyopathy (HCM)

Dilated Cardiomyopathy (DCM)

Arrhythmogenic Cardiomyopathy (ACM)

Long QT Syndrome (LQTS)

Brugada Syndrome

Catecholaminergic Polymorphic VT (CPVT)

Marfan Syndrome & Thoracic Aortic Aneurysm Disease (TAAD)

Genotype-Positive / Phenotype-Negative (G+/P-)

UK Driving Guidance

Driving Rules at a Glance

Group 2 Licensing (HGV/PCV): General Principles

Pregnancy in Inherited Cardiac Conditions

Cardiomyopathies

Channelopathies

Aortopathies & Connective Tissue Disorders

Storage & Infiltrative Conditions

Neuromuscular Conditions

Cardiac Drug Safety in Pregnancy: Quick Reference[1]

UK National Genomic Test Directory (Version 8.1, July 2025^[1])

When to Refer for Genetic Counselling^[1]^[2]

Cardiac Drug Safety in Pregnancy: Quick Reference^[1]