Genotype–phenotype correlation in a large cohort of pediatric patients with heterozygous and homozygous familial hypercholesterolemia

Abstract

BackgroundFamilial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease (CVD). Both the heterozygous form and the very severe homozygous form can be diagnosed by genetic testing and by clinical criteria. Genetic testing can discern FH in a form caused by complete absence of the LDL-receptors, the negative variant and a form leading to reduced activity of the LDL receptors, the defective variant. The aim of this study is to provide more insight in the genotype--phenotype correlation in children and adolescents diagnosed with heterozygous FH (HeFH) and with homozygous FH (HoFH), specifically in relation to the clinical and therapeutic consequences of the negative and defective variant of FH. Methods and ResultsData of 5904 children with a tentative diagnosis of FH referred to our center for genetic testing were collected. A lipid-profile was present in 3494 children, who became the study cohort. In this large cohort of children, which includes 2714 HeFH and 41 HoFH patients, it is shown that receptor negative variants are associated with significant higher LDL-C levels in HeFH patients than receptor defective variants (6.0 versus 4.9 mmol/L; p < 0.001). A negative/negative variant is associated with a significant higher LDL-C level jn HoFH patients than a negative/defective variant, which in itself has a higher LDL-C level than a defective/defective variant. Significantly more premature CVD is present in close relatives of children with HeFH with negative variants compared to close relatives of HeFH children with defective variants (75% vs 59%; p < 0.001). ConclusionsPerforming genetic testing and identifying the type of underlying genetic variant is of added value in order to distinguish between pediatric patients with higher risks of premature CVD and to identify those that will benefit most from new types of lipid-lowering therapies. Since in children the phenotype of FH is less affected by environmental factors, the study substantiates the genotype-phenotype correlation in this large pediatric population.

Genetic variants and structure-function predictions of protein models related to familial hypercholesterolemia in Vietnam

“…In recent reports, using NGS techniques, the index case rate carrying APOB mutations tended to be higher, for example, at 26.05% in FH Chinese populations 14 . Furthermore, our ndings con rmed the genotype-phenotype relationships, with a trend for more severe clinical symptoms in HoFH and cHeFH index cases, consistent with other studies 14,15 .…”

“…HoFH patients had a high prevalence of premature ASCVD and an average LDL-C level of 14.83 mmol/L, which are consistent with the typical clinical presentation of HoFH described in the 2023 updated clinical guidance of the European Atherosclerosis Society Consensus 16 . The HoFH patients also exhibited higher levels of total cholesterol (TC) and LDL-C than did the HeFH patients, consistent with the previous data on the differences between HoFH and HeFH phenotypes 15 . We observed LDL-C levels of 5-10 mmol/L in HeFH patients, consistent with recent global data on mean LDL-C levels in HeFH 17 .…”

“…Furthermore, we noted slight differences in plasma LDL-C levels among patients with different mutation sites. Plasma LDL-C levels were higher in patients with LDLR-negative mutations than in patients with LDLR-defective mutations 15 ; however, comprehensive data comparing different mutant sites are currently limited and unclear. Notably, we identi ed that some HeFH patients have slightly increased LDL-C levels (< 5 mmol/L) despite testing positive for mutations, while some patients who tested negative for mutations had plasma LDL-C levels of > 10 mmol/L.…”

How Genetic Variants in Children with Familial Hypercholesterolemia Not Only Guide Detection, but Also Treatment

“…In FH, different pathogenic variants are associated with different levels of LDL-C [ 20 ]. Patients with an LDLR -null allele present with higher average LDL-C levels than those with an LDLR-defective allele (6.0 versus 4.9 mmol/L; p < 0.001) and the more negative alleles in HoFH patients, the higher the LDL-C levels expected [ 21 ]. PCSK9 was discovered in 2003 by Seidah et al and is formed in the endoplasmic reticulum (ER) of hepatic cells [ 22 ].…”