Molecular characterization of a Chinese woman homozygous for the familial hypercholesterolemia LDLR c.1474G>A (p.Asp492Asn) mutation

Abstract

Aims: We investigated family members of a Hong Kong Chinese woman with severe hypercholesterolemia due to homozygosity for the LDLR c.1474G>A, p.(Asp492Asn) mutation. She had surprisingly survived to 67 years without any cardiac event. Methods: Six microsatellite markers surrounding the LDLR locus on chromosome 19 were analyzed in this three-generation pedigree. DNA microarray analysis was used to investigate the chromosomal recombination history of the proband and calculate her degree of parental consanguinity. Results: In six of the seven affected family members, one disease haplotype predominated. Several extensive homozygous regions were identified in the proband’s genome with the LDLR in one spanning 21.7 Mb and her inbreeding coefficient estimated at 8.57%. Conclusion: An FH microsatellite haplotype unique for this family was found with extensive regions of homozygosity in the proband’s genome speculated to harbor cardioprotective gene variants that have let her reach 67 years despite her very high LDL-cholesterol levels.

Keywords:

• consanguinity
• familial hypercholesterolemia
• haplotype
• identity-by-descent
• microsatellite analysis
• runs of homozygosity