Diagnosis of Familial Hypercholesterolemia in Children: From Clinical Features Through Gene Variants to Polygenic Score

Background: Early diagnosis of familial hypercholesterolemia (FH) is crucial to improve long-term outcomes. FH diagnosis relies on elevated low-density lipoprotein cholesterol (LDL-C) levels, familial clinical characteristics, and identification of pathogenic variants in FH-related genes. Secondary factors, such as overweight and obesity, are known to influence lipid profiles in the general population. More recently, polygenic risk scores based on single-nucleotide polymorphisms (SNPs) have been proposed as additional determinants of LDL-C levels. Methods: We enrolled 214 pediatric subjects with LDL-C levels ≥95th percentile (after 6 months of dietary intervention) and with at least one parent with LDL-C levels ≥ 95th percentile. All participants underwent biochemical and auxological assessment and genetic testing for FH. In a subgroup of 60 subjects, LDL-C polygenic scores based on 6- and 12-SNPs were calculated. Results: Pathogenic variants confirming heterozygous FH were identified in 190 subjects (variant-positive, V+); 17 were variant-negative (V−), yielding a mutation detection rate of 91.8%. An additional seven patients carrying variants of uncertain significance were excluded from the primary analysis. LDL-C was modestly higher in V+ than V− subjects using both Friedewald (212 vs. 188 mg/dL; p = 0.035) and Martin–Hopkins formulas (208 vs. 187 mg/dL; p = 0.041), while the other main clinical and laboratory parameters were similar. In V+, LDL-C was higher in subjects with null variants, compared to those with defective variants. Body mass index (BMI SDS) was inversely correlated with HDL-C (p < 0.001), and obesity (BMI z-score > 2 SDS) was associated with lower HDL-C and higher LDL-C, non-HDL-C, and ApoB. With regard to the polygenic scores, 12- and 6-SNP scores showed overlap between V+ and V−, and published cut-offs did not discriminate lipid severity in our population; however, in V+ subjects, the 12-SNP score acted as a phenotype modifier, being independently associated with higher LDL-C and non-HDL-C levels after adjustment for age, sex, and BMI SDS. Conclusions: In children selected by LDL-C ≥ 95th percentile, together with autosomal dominant familial hypercholesterolemia, genetic confirmation of FH is achieved in the vast majority of cases. Variant type (null vs. defective), BMI, and polygenic background contribute to phenotypic heterogeneity, supporting the need to address other factors alongside genetic diagnosis. Further validation is needed before polygenic scores can be implemented in routine clinical practice.