The formal diagnosis of FH
FH is a dominantly inherited disorder, affected individuals having a 50% chance of passing the causative mutation to each offspring.
The majority of cases of FH are due to mutations in the LDL-receptor (LDLR), apolipoprotein B-100 (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. A pathogenic mutation in one of these genes is identified in about 70% of phenotypically definite FH and 20% of phenotypically probable/possible FH. New molecular techniques, such as whole exome sequencing, can lead to the discovery of novel mutations; this may be particularly applicable to under-studied multi-ethnic populations.
Absence of a pathogenic mutation in the presence of a high LDL-cholesterol gene score may indicate polygenic hypercholesterolaemia, and this may be used to limit further search for novel FH causing mutations. About 95% of the identified mutations are in the LDLR gene, 4 -5% in the APOB gene and 1% in the PCSK9 gene. Detection of a mutation in a family member allows the definite diagnosis of FH to be made. However, failure to detect a mutation does not exclude a diagnosis of FH, particularly if the clinical phenotype is highly suggestive of FH. To optimize the use of resources, DNA testing may only be offered to index patients with DLCNS›5 or meeting the Simon Broome possible criteria, especially those with a personal history of early onset (60 years) CVD or imaging evidence of significant subclinical atherosclerosis. If a pathogenic mutation is identified in an index case, genetic testing is a cost-effective, accurate and acceptable approach for detecting new cases.
The average Family Doctor is likely to 'see' one FH patient each year, but is unlikely to diagnose FH in that patient
FH will most likely be identified initially in cardiology services
Untreated FH is likely to cause premature death from heart attack
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