Low Prevalence of Mutations in Known Loci for Autosomal Dominant Hypercholesterolemia in a Multiethnic Patient Cohort

Abstract

Background Autosomal dominant hypercholesterolemia (ADH), characterized by elevated plasma levels of low density lipoprotein-cholesterol (LDL-C), is caused by variants in at least three different genes:LDL receptor (LDLR), apolipoprotein B-100 (APOB), and proprotein convertase subtilisin-like kexin type 9 (PCSK9). There is paucity of data about the molecular basis of ADH among ethnic groups other than those of European or Japanese descent. Here, we examined the molecular basis of ADH in a multi-ethnic patient cohort from lipid clinics in a large urban U.S. city. Methods and Results A total of 38 males and 53 females, age 22 to 76 years, met modified Simon-Broome criteria for ADH and were screened for mutations in the exons and consensus splice sites of LDLR, and in selected exons of APOB and PCSK9. Deletions and duplications of LDLR exons were detected with multiplex ligation-dependent probe amplification. Heterozygous variants in LDLR were identified in 30 patients and in APOB in one patient. The remaining 60 patients (65%) had “unexplained ADH.” A higher proportion of African Americans (77%) than either non-Hispanic whites (57%) or Hispanics (53%) had “unexplained ADH.” As compared to patients with LDLR variants, those with “unexplained ADH” had lower levels of LDL-C (292 ± 47vs 239 ± 42 mg/dL, respectively; p < 0.0001) and higher levels of HDL-cholesterol (45 ± 12vs 54 ± 13 mg/dL, respectively, p = 0.003). Conclusions Our findings suggest that additional loci may contribute to ADH, especially in understudied populations such as African Americans.

Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation

“…A pathogenic mutation in one of these genes is identified in about 70% of phenotypically definite FH and 20% of phenotypically probable/possible FH [78,[84][85][86]. New molecular techniques, such as whole exome sequencing, can lead to the discovery of novel mutations [87]; this may be particularly applicable to under-studied multiethnic populations [88].…”

Cascade Screening for Familial Hypercholesterolemia: PCR Methods with Melting-Curve Genotyping for the Targeted Molecular Detection of Apolipoprotein B and LDL Receptor Gene Mutations to Identify Affected Relatives

“…Next-generation sequencing as a comprehensive genetic analysis method has demonstrated high levels of specificity and sensitivity (21)(22)(23). However, a significant drawback is the recognition that sequencing 4 genes is insufficient, and approximately 15% of people with FH do not have a mutation in LDLR, APOB, or PCSK9 genes (though estimates range from 12% to 48%) (24).…”

The panorama of familial hypercholesterolemia in Latin America: a systematic review

“…In addition, a significant percentage of FH cases do not have previously known FH mutations. Ahmed et al (59) were unable to identify a disease-causing mutation in the LDLR, APOB, or PCSK9 genes in 66% of their multi-ethnic autosomal dominant hypercholesterolemia population (53% in Hispanics). Although this could be due to methodological limitations, we must consider other explanations.…”