Modern genetic nomenclature for the clinical homozygous familial hypercholesterolaemia phenotype
| Traditional clinical terminology . | Precise nomenclature based on genetics . | Comments . |
|---|---|---|
| Homozygous familial hypercholesterolaemia (HoFH): an umbrella term that encompasses a spectrum of genetic diagnoses | 1. Bi-allelic semi-dominant hypercholesterolaemia: monogenic (single gene) | ‘Semi-dominant’ indicates that mono-allelic (i.e. heterozygote) relatives have a less severe phenotype |
| (a) defined by causative genes: | ||
| • LDLR-related | Accounts for 85%–90% of all variants | |
| • APOB-related | Accounts for 5%–10% of all variants | |
| • PCSK9-related | Accounts for 1%–3% of all variants | |
| (b) defined by nature of variants: | ||
| · 2 copies of the identical variant | Formerly called ‘true’ or ‘simple’ HoFH | |
| · 1 copy each of 2 different variants | Formerly called ‘compound heterozygous FH’ | |
| 2. Bi-allelic semi-dominant hypercholesterolaemia: digenic (two different causal genes) | ‘Semi-dominant’ indicates that mono-allelic (i.e. heterozygote) relatives have a less severe phenotype | |
| (a) defined by causative genes: | ||
| • LDLR-related plus APOB-related | Accounts for 90%–95% of cases with digenic variants | |
| • LDLR-related plus PCSK9-related | Accounts for 2%–5% of cases with digenic variants | |
| • APOB-related plus PCSK9-related | Accounts for <2% of cases with digenic variants | |
| (b) defined by nature of variants: | ||
| · 1 copy each of 2 different variants | Formerly called ‘double heterozygous FH’ | |
| 3. Bi-allelic recessive hypercholesterolaemia: single gene | Heterozygous parents are true carriers with normal clinical and biochemical phenotypes | |
| (a) defined by causative gene: | ||
| • LDLRAP1-related | Accounts for all patients with this subtype;<1% of all cases of ‘HoFH’. | |
| (b) defined by nature of variants: | ||
| · 2 copies of the identical variant | Formerly called ‘true’ or ‘simple’ ARH | |
| · 1 copy each of 2 different variants | Formerly called ‘compound heterozygous’ ARH |
| Traditional clinical terminology . | Precise nomenclature based on genetics . | Comments . |
|---|---|---|
| Homozygous familial hypercholesterolaemia (HoFH): an umbrella term that encompasses a spectrum of genetic diagnoses | 1. Bi-allelic semi-dominant hypercholesterolaemia: monogenic (single gene) | ‘Semi-dominant’ indicates that mono-allelic (i.e. heterozygote) relatives have a less severe phenotype |
| (a) defined by causative genes: | ||
| • LDLR-related | Accounts for 85%–90% of all variants | |
| • APOB-related | Accounts for 5%–10% of all variants | |
| • PCSK9-related | Accounts for 1%–3% of all variants | |
| (b) defined by nature of variants: | ||
| · 2 copies of the identical variant | Formerly called ‘true’ or ‘simple’ HoFH | |
| · 1 copy each of 2 different variants | Formerly called ‘compound heterozygous FH’ | |
| 2. Bi-allelic semi-dominant hypercholesterolaemia: digenic (two different causal genes) | ‘Semi-dominant’ indicates that mono-allelic (i.e. heterozygote) relatives have a less severe phenotype | |
| (a) defined by causative genes: | ||
| • LDLR-related plus APOB-related | Accounts for 90%–95% of cases with digenic variants | |
| • LDLR-related plus PCSK9-related | Accounts for 2%–5% of cases with digenic variants | |
| • APOB-related plus PCSK9-related | Accounts for <2% of cases with digenic variants | |
| (b) defined by nature of variants: | ||
| · 1 copy each of 2 different variants | Formerly called ‘double heterozygous FH’ | |
| 3. Bi-allelic recessive hypercholesterolaemia: single gene | Heterozygous parents are true carriers with normal clinical and biochemical phenotypes | |
| (a) defined by causative gene: | ||
| • LDLRAP1-related | Accounts for all patients with this subtype;<1% of all cases of ‘HoFH’. | |
| (b) defined by nature of variants: | ||
| · 2 copies of the identical variant | Formerly called ‘true’ or ‘simple’ ARH | |
| · 1 copy each of 2 different variants | Formerly called ‘compound heterozygous’ ARH |
Modern genetic nomenclature for the clinical homozygous familial hypercholesterolaemia phenotype
| Traditional clinical terminology . | Precise nomenclature based on genetics . | Comments . |
|---|---|---|
| Homozygous familial hypercholesterolaemia (HoFH): an umbrella term that encompasses a spectrum of genetic diagnoses | 1. Bi-allelic semi-dominant hypercholesterolaemia: monogenic (single gene) | ‘Semi-dominant’ indicates that mono-allelic (i.e. heterozygote) relatives have a less severe phenotype |
| (a) defined by causative genes: | ||
| • LDLR-related | Accounts for 85%–90% of all variants | |
| • APOB-related | Accounts for 5%–10% of all variants | |
| • PCSK9-related | Accounts for 1%–3% of all variants | |
| (b) defined by nature of variants: | ||
| · 2 copies of the identical variant | Formerly called ‘true’ or ‘simple’ HoFH | |
| · 1 copy each of 2 different variants | Formerly called ‘compound heterozygous FH’ | |
| 2. Bi-allelic semi-dominant hypercholesterolaemia: digenic (two different causal genes) | ‘Semi-dominant’ indicates that mono-allelic (i.e. heterozygote) relatives have a less severe phenotype | |
| (a) defined by causative genes: | ||
| • LDLR-related plus APOB-related | Accounts for 90%–95% of cases with digenic variants | |
| • LDLR-related plus PCSK9-related | Accounts for 2%–5% of cases with digenic variants | |
| • APOB-related plus PCSK9-related | Accounts for <2% of cases with digenic variants | |
| (b) defined by nature of variants: | ||
| · 1 copy each of 2 different variants | Formerly called ‘double heterozygous FH’ | |
| 3. Bi-allelic recessive hypercholesterolaemia: single gene | Heterozygous parents are true carriers with normal clinical and biochemical phenotypes | |
| (a) defined by causative gene: | ||
| • LDLRAP1-related | Accounts for all patients with this subtype;<1% of all cases of ‘HoFH’. | |
| (b) defined by nature of variants: | ||
| · 2 copies of the identical variant | Formerly called ‘true’ or ‘simple’ ARH | |
| · 1 copy each of 2 different variants | Formerly called ‘compound heterozygous’ ARH |
| Traditional clinical terminology . | Precise nomenclature based on genetics . | Comments . |
|---|---|---|
| Homozygous familial hypercholesterolaemia (HoFH): an umbrella term that encompasses a spectrum of genetic diagnoses | 1. Bi-allelic semi-dominant hypercholesterolaemia: monogenic (single gene) | ‘Semi-dominant’ indicates that mono-allelic (i.e. heterozygote) relatives have a less severe phenotype |
| (a) defined by causative genes: | ||
| • LDLR-related | Accounts for 85%–90% of all variants | |
| • APOB-related | Accounts for 5%–10% of all variants | |
| • PCSK9-related | Accounts for 1%–3% of all variants | |
| (b) defined by nature of variants: | ||
| · 2 copies of the identical variant | Formerly called ‘true’ or ‘simple’ HoFH | |
| · 1 copy each of 2 different variants | Formerly called ‘compound heterozygous FH’ | |
| 2. Bi-allelic semi-dominant hypercholesterolaemia: digenic (two different causal genes) | ‘Semi-dominant’ indicates that mono-allelic (i.e. heterozygote) relatives have a less severe phenotype | |
| (a) defined by causative genes: | ||
| • LDLR-related plus APOB-related | Accounts for 90%–95% of cases with digenic variants | |
| • LDLR-related plus PCSK9-related | Accounts for 2%–5% of cases with digenic variants | |
| • APOB-related plus PCSK9-related | Accounts for <2% of cases with digenic variants | |
| (b) defined by nature of variants: | ||
| · 1 copy each of 2 different variants | Formerly called ‘double heterozygous FH’ | |
| 3. Bi-allelic recessive hypercholesterolaemia: single gene | Heterozygous parents are true carriers with normal clinical and biochemical phenotypes | |
| (a) defined by causative gene: | ||
| • LDLRAP1-related | Accounts for all patients with this subtype;<1% of all cases of ‘HoFH’. | |
| (b) defined by nature of variants: | ||
| · 2 copies of the identical variant | Formerly called ‘true’ or ‘simple’ ARH | |
| · 1 copy each of 2 different variants | Formerly called ‘compound heterozygous’ ARH |
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