JIMD Reports, Volume 35

S. Varma, A. D. McIntyre, R. A. Hegele, Varma, S., McIntyre, A. D., Hegele, R. A.

Familial hypercholesterolemia (FH) is an autosomal codominantly inherited disease. The severity of clinical presentation depends on the zygosity of the mutations in the LDLR, APOB, or PCSK9 genes. The homozygous form (HoFH) is associated with high mortality rate by third decade of life, while individuals with HeFH begin to suffer from premature cardiovascular disease in fourth or fifth decade of life. Statin drugs have helped to improve the biochemical profile and life expectancy in HeFH, while they are only minimally effective in HoFH. LDL apheresis remains an effective treatment option in HoFH, though limited by its availability and affordability issues. We present the case that highlights a few novel aspects of clinical and genetic heterogeneity in FH, wherein a child presented with features of both HeFH and HoFH. His clinical picture was that of HoFH; however he responded well clinically and biochemically to pharmacologic treatment only. DNA sequencing showed a novel heterozygous rare splicing variant in the LDLR gene in addition to a relatively high polygenic trait score comprised of LDL-C raising alleles from common polymorphic sites. Interestingly his normolipemic mother showed the same heterozygous mutation. Thus this novel splicing variant in LDLR showed nonclassical co-segregation with the disease phenotype and was associated with a high polygenic trait score comprised of common LDL-C raising polymorphic alleles in the affected proband. Thus it indicates the phenotypic heterogeneity of FH and suggests that secondary causes, such as polygenic factors and possibly as yet undetermined genetic or environmental factors, can exacerbate the metabolic phenotype in an individual who is genotypically heterozygous for FH.