Abstract 17368: The Diagnosis of Heterozygous Familial Hypercholesterolemia: Genotype versus Phenotype

Abstract

Background: Heterozygous familial hypercholesterolemia (HeFH) is the most common dominantly-inherited disorder in man, affecting between 1:250 and 1:300 persons worldwide and estimates of more than 3 million with HeFH in the USA and Europe alone. Diagnosis is usually made by clinical criteria and confirmed with genetic testing. Despite next-generation gene sequencing, a causative mutation cannot be identified in up to 20% of patients even with a clinical diagnosis of definite HeFH. Given the prevalence, clinical diagnostic criteria are important tools for detection and early treatment of HeFH patients, particularly for clinicians outside of referral centers. Methods: The RUTHERFORD-1 and -2 studies enrolled patients with a clinical and/or genetic diagnosis of HeFH. All consenting patients in this analysis underwent FH genotyping. We compare the accuracy of clinical and genetic diagnosis of HeFH. Results: Of the 416 patients enrolled who consented to genetic testing, 342 (82%) were found to have genetically-confirmed HeFH. Of these patients, 288 (84%) met the Simon Broome criteria for definite and 54 (16%) for probable HeFH; 250 (75%) met the MEDPED clinical criteria for 100%, and 301 (90%) the 80% likelihood for a diagnosis of HeFH (Table). Conclusion: Although the optimal method to diagnose HeFH remains unclear, from these two trials there was close agreement between the two clinical classifications and genetic criteria. There were only a relatively small number of patients in whom genetic testing could not confirm the clinical diagnosis. Clinical criteria offer an inexpensive, low-technology ability for widespread screening in patients suspected of having HeFH. The advantage of genetic testing is that it allows for cascade testing of family members for the identified mutation who may not fulfill clinical criteria for the diagnosis of HeFH and application of family-oriented preventive strategies.