Rolf Andersen

Examining barriers to cascade screening for familial hypercholesterolemia in the United States

• Cascade screening for familial hypercholesterolemia (FH) in the US is hindered by privacy law.

Familial defective apolipoprotein B-100: a tale of twin mutations.

The recent review article by Drs Chiou and Charng, ‘‘Genetic diagnosis of familial hypercholesterolemia in Han Chinese,’’ recently published in the Journal of Clinical Lipidology poses significant implications for the field of cardiovascular genetics related to familial defective apolipoprotein B-100 (FDB). The authors have described the p.Arg3527Trp mutation, commonly known as R3500 W, as the most common single mutation causing familial forms of hypercholesterolemia (FH) among 66 studies including Han Chinese participants, causing 10.6% of genetically diagnosed FH cases. Although the population prevalence of R3500 W is currently unknown, the current evidence of its high frequency relative to other genetic causes of hyperlipidemia in Han Chinese indicates a significant challenge to a variety of standard FH treatment guidelines including that of the National Lipid Association (NLA) and the European Atherosclerosis Society (EAS). The 2011 NLA consensus scientific statement on FH posits that ‘‘The Arg3500Gln (R3500Q) mutation in APOB is the most common cause of hypercholesterolemia due to an APOB mutation (FDB), accounting for 5%–10% of FH cases in Northern European populations (rare in other populations).’’ The 2013 EAS FH consensus statement further states that ‘‘Arg3500Gln is the only common FH-related mutation in APOB,’’ citing a distribution of ‘‘.90, w5, and w1%’’ for LDLR, APOB, and PCSK9 mutations, respectively. As Chiou and Charng demonstrate, the similar R3500 W mutation is another frequent cause of FH; owing to the large size of the Han Chinese population (approximately 1.267 billion persons compared with about 598 million in European countries), R3500 W mutation carriers likely outnumber those of R3500Q. Furthermore, the geographic limitation described in 2011 NLA guidelines fails to recognize the prevalence of FDB due to R3500 W in East Asia consistently reported since 1998. The described work further illustrates a unique tale of twin mutations, R3500Q and R3500 W, both frequent

PCSK9 inhibitor therapy in homozygous familial defective apolipoprotein B-100 due to APOB R3500Q: A case report

Identification of a patient homozygous for familial defective apolipoprotein B-100(FDB) and successful treatment with PCSK9 inhibition.

Current familial hypercholesterolemia diagnostic criteria underdiagnose APOB mutations: Lessons from the Amish community

The NLA Expert Panel on familial hypercholesterolemia (FH) defines three known genes that, when mutated, cause autosomal dominant FH, an inherited illness characterized by the severe elevation of serum low-density lipoprotein (LDL) concentration. In the order of most to least common, these are LDLR, APOB, and PCSK9. Approximately 70% of ‘‘definite’’ FH patients will show a mutation in one of these genes, and genetic testing serves as the ‘‘gold standard’’ of diagnosis in families suspected of having FH. Despite the identification of these mutations, FH largely remains a clinically diagnosed disease under several diagnostic systems; the NLA Expert Panel states, ‘‘.genetic screening for FH is generally not needed for diagnosis or clinical management.’’ Following the results of a 1993 Dutch study, pathogenic mutations in LDLR and APOB have been considered ‘‘clinically indistinguishable’’ and thus able to be identified using the same clinical criteria. However, wider scale genetic population sampling or testing of patients with ‘‘general’’ hypercholesterolemia has shown defects in APOB to be frequent in certain ethnic populations and appears at variable LDL-C levels often lower than those accepted as phenotypically diagnostic of FH, an effect accentuated in younger patients. Of 297 German patients with LDL-C levels .146 mg/dL, 7.1% were found to carry R3500Q (the most common pathogenic mutation in APOB identified to date), whereas a smaller cohort of Belgian patients with LDL-C over 160 mg/dL and no tendon xanthomas showed a rate of 8%. Universal pediatric screening in Slovenia recently showed that 18.7% of severely hyperlipidemic children carried R3500Q, about half the number carrying LDLR mutations. Cohorts of clinical FH patients in Poland as well as hypercholesterolemic and CADsuffering adults in Latvia showed similar ratios of R500Q to LDLR mutation detection. Approximately 0.4% of