Comprehensive Gene Lists for Monogenic Hypertension, Inborn Errors of Metabolism, and Cardiomyopathy
Monogenic Hypertension Genes
The established monogenic hypertension genes include those affecting renal sodium transport and mineralocorticoid pathways, with at least 9-10 distinct genetic syndromes identified. 1, 2
Genes with Definitive Evidence:
Epithelial Sodium Channel (ENaC) Genes:
- SCNN1B (β-subunit) - Liddle syndrome (gain-of-function)
- SCNN1G (γ-subunit) - Liddle syndrome (gain-of-function)
- SCNN1A (α-subunit) - Can cause both hypertension and hypotension depending on mutation type
Mineralocorticoid-Related Genes:
- CYP11B1/CYP11B2 - Familial hyperaldosteronism type I (glucocorticoid-remediable aldosteronism/GRA)
- HSD11B2 - Apparent mineralocorticoid excess (AME) syndrome (loss-of-function)
- NR3C2 (MCR) - Mineralocorticoid receptor activating mutations
- NR3C1 - Glucocorticoid receptor mutations (loss-of-function)
WNK Kinase Family:
- WNK1 - Gordon syndrome (pseudohypoaldosteronism type II)
- WNK4 - Gordon syndrome (pseudohypoaldosteronism type II)
Adrenal Steroidogenesis:
- CYP11B1 - Congenital adrenal hyperplasia type IV (11β-hydroxylase deficiency)
- CYP17A1 - Congenital adrenal hyperplasia type V (17α-hydroxylase deficiency)
Other Identified Genes:
- CYP3A5 - Associated with treatment-resistant hypertension, particularly in African-Americans 3
- Gene for hypertension with brachydactyly - Mapped to chromosome 12p (specific gene not yet identified) 4
The current tabulation includes more than 25 rare mutations across these genes 5, 6, 5. These monogenic forms manifest with suppressed plasma renin activity, increased distal tubular sodium absorption, and variable presentations including serum potassium abnormalities and metabolic acid-base disturbances 1.
Inborn Errors of Metabolism (IEM) Genes
IEM encompasses approximately 270 metabolic disorders spanning diverse disease categories, with lysosomal storage diseases showing the highest cardiac involvement (61.4%). 7, 8
Categories and Representative Genes:
Lysosomal Storage Diseases (highest cardiac involvement at 61.4%):
- GLA - Fabry disease (also causes left ventricular hypertrophy mimicking HCM) 9, 10
- LAMP2 - Danon disease (causes HCM phenotype) 9
- Multiple other lysosomal enzyme genes causing storage disorders with cardiac manifestations
Fatty Acid Oxidation Disorders:
- SLC22A5 - Carnitine transporter defect (causes cardiomyopathy, treatable with oral carnitine) 10
- Multiple acyl-CoA dehydrogenase genes
- Carnitine palmitoyltransferase genes
Amino Acid Metabolism:
- Multiple genes affecting amino acid pathways
- Organic acidemias genes
Carbohydrate Metabolism:
- PRKAG2 - Glycogen storage disease causing HCM phenotype 9
- Other glycogen storage disease genes
Mitochondrial Disorders:
- Multiple mitochondrial DNA and nuclear genes affecting oxidative phosphorylation
Lipoprotein Disorders:
- LDLR - Familial hypercholesterolemia 9
- APOB - Familial hypercholesterolemia 9
- PCSK9 - Familial hypercholesterolemia 9
- LDLRAP1, LIPA, ABCG5, ABCG8, APOE - Phenotypic overlap with FH 9
- Lipoprotein(a) gene on chromosome 6 10
Connective Tissue Metabolism:
- FBN1 - Marfan syndrome (>200 mutations identified, affects aorta) 10
The evidence indicates that biochemical genetic testing is performed for approximately 270 metabolic disorders, with lysosomal storage diseases showing particularly high rates of cardiac involvement, especially valvular disease (56.6% of affected patients) 7, 8.
Cardiomyopathy Genes
Genetic testing should include 8 genes with definitive evidence for hypertrophic cardiomyopathy, with sarcomeric genes MYBPC3 and MYH7 being most commonly affected. 9, 11, 12
Hypertrophic Cardiomyopathy (HCM):
Definitive Evidence (8 genes):
- MYBPC3 - Cardiac myosin binding protein C (most common)
- MYH7 - β-myosin heavy chain (second most common)
- TNNT2 - Cardiac troponin T
- TNNI3 - Cardiac troponin I
- TPM1 - α-tropomyosin
- ACTC1 - Cardiac actin
- MYL2 - Regulatory myosin light chain
- MYL3 - Essential myosin light chain
Moderate Evidence (3 genes):
- CSRP3 - Muscle LIM protein
- TNNC1 - Cardiac troponin C
- JPH2 - Junctophilin-2
Additional Genes (recently validated):
- ALPK3 - Demonstrated significant association in large biobank studies 11
- FHOD3 - Formin homology 2 domain containing 3 11
Definitive Syndromic Genes (12 genes causing isolated LVH):
- PLN - Phospholamban
- CACNA1C - Calcium channel
- DES - Desmin
- FHL1 - Four and a half LIM domains 1
- FLNC - Filamin C
- GLA - α-galactosidase A (Fabry disease)
- LAMP2 - Lysosomal-associated membrane protein 2 (Danon disease)
- PRKAG2 - AMP-activated protein kinase
- PTPN11 - Protein tyrosine phosphatase, non-receptor type 11
- RAF1 - RAF proto-oncogene
- RIT1 - Ras-like without CAAX 1
- TTR - Transthyretin (amyloidosis)
Dilated Cardiomyopathy (DCM):
Primary DCM Genes:
- TTN - Titin (most common)
- LMNA - Lamin A/C
- MYH7 - β-myosin heavy chain
- TNNT2 - Cardiac troponin T
- BAG3 - BCL2-associated athanogene 3
- RBM20 - RNA binding motif protein 20
- TNNC1 - Cardiac troponin C
- TNNI3 - Cardiac troponin I
- TPM1 - α-tropomyosin
- SCN5A - Sodium channel
- PLN - Phospholamban
Note: Testing should include all HCM and ARVC genes when evaluating DCM 9
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC):
Primary ARVC Genes:
- PKP2 - Plakophilin-2 (most common)
- DSP - Desmoplakin
- DSG2 - Desmoglein-2
- DSC2 - Desmocollin-2
- JUP - Junction plakoglobin
- DES - Desmin
- LMNA - Lamin A/C
- PLN - Phospholamban
- RYR2 - Ryanodine receptor 2
- SCN5A - Sodium channel
- TMEM43 - Transmembrane protein 43
- TTN - Titin
Consider full DCM panel when evaluating ARVC 9
Restrictive Cardiomyopathy:
Primary Gene:
- TTR - Transthyretin (amyloidosis)
Consider HCM or DCM panel for comprehensive evaluation 9
Left Ventricular Non-Compaction (LVNC):
Use the gene panel for the cardiomyopathy identified in association with the LVNC phenotype 9
Ion Channel Genes (Arrhythmia Syndromes with Cardiomyopathy):
Somatic Mutations in Aldosterone-Producing Adenomas:
- KCNJ5 - Potassium channel
- CACNA1D - Calcium channel
- ATP1A1 - Sodium-potassium ATPase
- ATP2B3 - Calcium ATPase
Long QT Syndrome:
- KCNQ1 - Potassium channel
- KCNH2 - Potassium channel
- SCN5A - Sodium channel
Short QT Syndrome:
- KCNH2 - Potassium channel
- KCNQ1 - Potassium channel
- KCNJ2 - Potassium channel
Brugada Syndrome:
- SCN5A - Sodium channel
Catecholaminergic Polymorphic Ventricular Tachycardia:
- RYR2 - Ryanodine receptor 2
- CASQ2 - Calsequestrin 2
Key Clinical Considerations
For monogenic hypertension: The incidence is unknown but genetic testing confirms mutations in approximately 3% of select hypertensive children without known etiology 1. All manifest with suppressed plasma renin activity and increased distal tubular sodium absorption.
For IEM: Cardiac involvement occurs in 34.3% of children with IEM, with valvular disease being most common (25.2% overall, 56.6% in lysosomal storage diseases). Valvular involvement increases significantly after age 6 years (34.3% vs younger ages, p<0.001) 8.
For cardiomyopathy: Approximately 70% of adult HCM cases are polygenic/multifactorial rather than monogenic 13. The yield of identifying a definitive pathogenic variant varies based on family history, age of onset, location of hypertrophy, and presence of additional risk factors 13. Large biobank studies confirm that 67% of definitive HCM genes show nominally significant associations, with 42% remaining significant after Bonferroni correction 11.