Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype.

Familial hypercholesterolemia (FH) is a common genetic disorder of lipid metabolism caused by pathogenic/likely pathogenic variants in LDLR, APOB, and PCSK9 genes. Variants in FH-phenocopy genes (LDLRAP1, APOE, LIPA, ABCG5, and ABCG8), polygenic hypercholesterolemia, and hyperlipoprotein (a) [Lp(a)] can also mimic a clinical FH phenotype. We aim to present a new diagnostic tool to unravel the genetic background of clinical FH phenotype. Biochemical and genetic study was performed in 1,005 individuals with clinical diagnosis of FH, referred to the Portuguese FH Study. A next-generation sequencing panel, covering eight genes and eight SNPs to determine LDL-C polygenic risk score and LPA genetic score, was validated, and used in this study. FH was genetically confirmed in 417 index cases: 408 heterozygotes and 9 homozygotes. Cascade screening increased the identification to 1,000 FH individuals, including 11 homozygotes. FH-negative individuals (phenotype positive and genotype negative) have Lp(a) >50 mg/dl (30%), high polygenic risk score (16%), other monogenic lipid metabolism disorders (1%), and heterozygous pathogenic variants in FH-phenocopy genes (2%). Heterozygous variants of uncertain significance were identified in primary genes (12%) and phenocopy genes (7%). Overall, 42% of our cohort was genetically confirmed with FH. In the remaining individuals, other causes for high LDL-C were identified in 68%. Hyper-Lp(a) or polygenic hypercholesterolemia may be the cause of the clinical FH phenotype in almost half of FH-negative individuals. A small part has pathogenic variants in ABCG5/ABCG8 in heterozygosity that can cause hypercholesterolemia and should be further investigated. This extended next-generation sequencing panel identifies individuals with FH and FH-phenocopies, allowing to personalize each person's treatment according to the affected pathway.

Generation and validation of a classification model to diagnose familial hypercholesterolaemia in adults.

BACKGROUND AND AIMS: The early diagnosis of familial hypercholesterolaemia is associated with a significant reduction in cardiovascular disease (CVD) risk. While the recent use of statistical and machine learning algorithms has shown promising results in comparison with traditional clinical criteria, when applied to screening of potential FH cases in large cohorts, most studies in this field are developed using a single cohort of patients, which may hamper the application of such algorithms to other populations. In the current study, a logistic regression (LR) based algorithm was developed combining observations from three different national FH cohorts, from Portugal, Brazil and Sweden. Independent samples from these cohorts were then used to test the model, as well as an external dataset from Italy. METHODS: The area under the receiver operating characteristics (AUROC) and precision-recall (AUPRC) curves was used to assess the discriminatory ability among the different samples. Comparisons between the LR model and Dutch Lipid Clinic Network (DLCN) clinical criteria were performed by means of McNemar tests, and by the calculation of several operating characteristics. RESULTS: AUROC and AUPRC values were generally higher for all testing sets when compared to the training set. Compared with DLCN criteria, a significantly higher number of correctly classified observations were identified for the Brazilian (p < 0.01), Swedish (p < 0.01), and Italian testing sets (p < 0.01). Higher accuracy (Acc), G mean and F1 score values were also observed for all testing sets. CONCLUSIONS: Compared to DLCN criteria, the LR model revealed improved ability to correctly classify observations, and was able to retain a similar number of FH cases, with less false positive retention. Generalization of the LR model was very good across all testing samples, suggesting it can be an effective screening tool if applied to different populations.

Comparative study on the performance of different classification algorithms, combined with pre- and post-processing techniques to handle imbalanced data, in the diagnosis of adult patients with familial hypercholesterolemia.

Familial Hypercholesterolemia (FH) is an inherited disorder of cholesterol metabolism. Current criteria for FH diagnosis, like Simon Broome (SB) criteria, lead to high false positive rates. The aim of this work was to explore alternative classification procedures for FH diagnosis, based on different biological and biochemical indicators. For this purpose, logistic regression (LR), naive Bayes classifier (NB), random forest (RF) and extreme gradient boosting (XGB) algorithms were combined with Synthetic Minority Oversampling Technique (SMOTE), or threshold adjustment by maximizing Youden index (YI), and compared. Data was tested through a 10 × 10 repeated k-fold cross validation design. The LR model presented an overall better performance, as assessed by the areas under the receiver operating characteristics (AUROC) and precision-recall (AUPRC) curves, and several operating characteristics (OC), regardless of the strategy to cope with class imbalance. When adopting either data processing technique, significantly higher accuracy (Acc), G-mean and F1 score values were found for all classification algorithms, compared to SB criteria (p < 0.01), revealing a more balanced predictive ability for both classes, and higher effectiveness in classifying FH patients. Adjustment of the cut-off values through pre or post-processing methods revealed a considerable gain in sensitivity (Sens) values (p < 0.01). Although the performance of pre and post-processing strategies was similar, SMOTE does not cause model's parameters to loose interpretability. These results suggest a LR model combined with SMOTE can be an optimal approach to be used as a widespread screening tool.

Performance comparison of different classification algorithms applied to the diagnosis of familial hypercholesterolemia in paediatric subjects.

Familial Hypercholesterolemia (FH) is an inherited disorder of lipid metabolism, characterized by increased low density lipoprotein cholesterol (LDLc) levels. The main purpose of the current work was to explore alternative classification methods to traditional clinical criteria for FH diagnosis, based on several biochemical and biological indicators. Logistic regression (LR), decision tree (DT), random forest (RF) and naive Bayes (NB) algorithms were developed for this purpose, and thresholds were optimized by maximization of Youden index (YI). All models presented similar accuracy (Acc), specificity (Spec) and positive predictive values (PPV). Sensitivity (Sens) and G-mean values were significantly higher in LR and RF models, compared to the DT. When compared to Simon Broome (SB) biochemical criteria for FH diagnosis, all models presented significantly higher Acc, Spec and G-mean values (p < 0.01), and lower negative predictive value (NPV, p < 0.05). Moreover, LR and RF models presented comparable Sens values. Adjustment of the cut-off point by maximizing YI significantly increased Sens values, with no significant loss in Acc. The obtained results suggest such classification algorithms can be a viable alternative to be used as a widespread screening method. An online application has been developed to assess the performance of the LR model in a wider population.

Polygenic contribution for familial hypercholesterolemia (FH).

PURPOSE OF REVIEW: The present review summarizes different polygenic risk scores associated with hypercholesterolemia applied to cohorts with a genetic diagnosis of familial hypercholesterolemia (FH). RECENT FINDINGS: Several single-nucleotide polymorphisms associated with increased levels of LDL-C or Lp(a) have been genotyped in population cohorts with FH phenotype, to identify the cause of hypercholesterolemia in mutation negative individuals. In different studies, a large proportion of individuals without a monogenic causative variant (in low density lipoprotein receptor gene (LDLR), apolipoprotein B gene (APOB) or proprotein convertase subtilisin/kexin type 9 gene (PCSK9 genes) was considered to have a hypercholesterolemia with a polygenic basis. The heterogeneity in the phenotype of monogenic FH may also be explained by polygenic contributions to LDL-C. The elevated LDL-C genetic risk score (GRS) has been associated with increased risk of atherosclerotic cardiovascular disease in individuals with monogenic FH. Moreover, a poorer response to lipid lowering therapy has been associated with monogenic FH when compared to a polygenic basis. The reason why Lp(a) concentrations are raised in individuals with clinical FH is unclear, but it could be caused by a genetic variation in Lipoprotein(A) gene as a polygenic contribution. SUMMARY: Polygenic risk scores have revealed to be important tools to define the cause of hypercholesterolemia in FH mutation-negative individuals and should be included in FH diagnosis strategies, although there is still space for more specific LDL-C GRS to be developed. The use of GRS may be used to refine cardiovascular risk prediction in FH patients and could lead to a personalized approach to therapy. The identification of the genetic status of an individual with FH phenotype (monogenic or polygenic) may have implications on their risk stratification, cascade screening of relatives, disease management and therapeutic measures.

Phenotypical, Clinical, and Molecular Aspects of Adults and Children With Homozygous Familial Hypercholesterolemia in Iberoamerica.

OBJECTIVE: Characterize homozygous familial hypercholesterolemia (HoFH) individuals from Iberoamerica. Approach and Results: In a cross-sectional retrospective evaluation 134 individuals with a HoFH phenotype, 71 adults (age 39.3±15.8 years, 38.0% males), and 63 children (age 8.8±4.0 years, 50.8% males) were studied. Genetic characterization was available in 129 (96%). The majority (91%) were true homozygotes (true HoFH, n=79, 43.0% children, 46.8% males) or compound heterozygotes (compound heterozygous familial hypercholesterolemia, n=39, 51.3% children, 46.2% males) with putative pathogenic variants in the LDLR. True HoFH due to LDLR variants had higher total (P=0.015) and LDL (low-density lipoprotein)-cholesterol (P=0.008) compared with compound heterozygous familial hypercholesterolemia. Children with true HoFH (n=34) tended to be diagnosed earlier (P=0.051) and had a greater frequency of xanthomas (P=0.016) than those with compound heterozygous familial hypercholesterolemia (n=20). Previous major cardiovascular events were present in 25 (48%) of 52 children (missing information in 2 cases), and in 43 (67%) of 64 adults with LDLR variants. Children who are true HoFH had higher frequency of major cardiovascular events (P=0.02), coronary heart (P=0.013), and aortic/supra-aortic valve diseases (P=0.022) than compound heterozygous familial hypercholesterolemia. In adults, no differences were observed in major cardiovascular events according to type of LDLR variant. From 118 subjects with LDLR variants, 76 (64%) had 2 likely pathogenic or pathogenic variants. In 89 subjects with 2 LDLR variants, those with at least one null allele were younger (P=0.003) and had a greater frequency of major cardiovascular events (P=0.038) occurring at an earlier age (P=0.001). CONCLUSIONS: There was a high frequency of cardiovascular disease even in children. Phenotype and cardiovascular complications were heterogeneous and associated with the type of molecular defect.

The familial hypercholesterolaemia phenotype: Monogenic familial hypercholesterolaemia, polygenic hypercholesterolaemia and other causes.

Familial hypercholesterolaemia (FH) is a monogenic disorder characterised by high low-density lipoprotein cholesterol (LDL-C) concentrations and increased cardiovascular risk. However, in clinically defined FH cohorts worldwide, an FH-causing variant is only found in 40%-50% of the cases. The aim of this work was to characterise the genetic cause of the FH phenotype in Portuguese clinical FH patients. Between 1999 and 2017, 731 index patients (311 children and 420 adults) who met the Simon Broome diagnostic criteria had been referred to our laboratory. LDLR, APOB, PCSK9, APOE, LIPA, LDLRAP1, ABCG5/8 genes were analysed by polymerase chain reaction amplification and Sanger sequencing. The 6-SNP LDL-C genetic risk score (GRS) for polygenic hypercholesterolaemia was validated in the Portuguese population and cases with a GRS over the 25th percentile were considered to have a high likelihood of polygenic hypercholesterolaemia. An FH-causing mutation was found in 39% of patients (94% in LDLR, 5% APOB and 1% PCSK9), while at least 29% have polygenic hypercholesterolaemia and 1% have other lipid disorders. A genetic cause for the FH phenotype was found in 503 patients (69%). All known causes of the FH phenotype should be investigated in FH cohorts to ensure accurate diagnosis and appropriate management.

Further evidence of novel APOB mutations as a cause of familial hypercholesterolaemia.

BACKGROUND AMD AIMS: APOB mutations are a rare cause of familial hypercholesterolaemia (FH) and, until recently, routine genetic diagnosis only included the study of two small APOB fragments. In previous years, 5 novel functional mutations have been described in APOB fragments not routinely studied, our group having functionally characterized 2 of them. The main aim of this work was to identify and characterize novel alterations in APOB to assess the genetic cause of hypercholesterolemia in patients with a clinical diagnosis of FH. METHODS: We performed next generation sequencing of 48 Portuguese clinical FH patients, who were apparently mutation negative. All variants found in APOB were annotated. For functional studies, LDL from index patients and relatives was separated and marked with FITC-LDL for flow cytometry assays in lymphocytes and U937 growth assays. RESULTS: A total of 11 potential pathogenic variants were identified. Variants p.(Pro994Leu) and p.(Thr3826Met) in exons 19 and 26 were found in 4 patients, and in vitro analysis was performed for these variants. An exon 26 alteration (p.(Thr3826Met)) showed a decrease in binding and internalization of LDL, and in U937 growth assays that was similar to the effect with p.(Arg3527Gln). An alteration in exon 19 had a neutral effect. CONCLUSIONS: The spectrum of functional alterations in APOB outside the fragments routinely screened is slowly growing. Screening of all 29 exons of APOB is advised for FH routine diagnosis, but functional characterization is necessary for pathogenicity assessment. It is expected that the number of patients with functional APOB mutations will increase in the near future.

Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia: application of ACMG guidelines and implications for familial hypercholesterolemia diagnosis.

PurposeFamilial hypercholesterolemia (FH) is an autosomal disorder of lipid metabolism presenting with increased cardiovascular risk. Although more than 1,700 variants have been associated with FH, the great majority have not been functionally proved to affect the low-density lipoprotein receptor cycle. We aimed to classify all described variants associated with FH and to establish the proportion of variants that lack evidence to support their pathogenicity.MethodsWe followed American College of Medical Genetics and Genomics (ACMG) guidelines for the classification, and collected information from a variety of databases and individual reports. A worldwide overview of publicly available FH variants was also performed.ResultsA total of 2,104 unique variants were identified as being associated with FH, but only 166 variants have been proven by complete in vitro functional studies to be causative of disease. Additionally, applying the ACMG guidelines, 1,097 variants were considered pathogenic or likely pathogenic. Only seven variants were found in all five continents.ConclusionThe lack of functional evidence for about 85% of all variants found in FH patients can compromise FH diagnosis and patient prognosis. ACMG classification improves variant interpretation, but functional studies are necessary to understand the effect of about 40% of all variants reported. Nevertheless, ACMG guidelines need to be adapted to FH for a better diagnosis.

Lysosomal acid lipase deficiency: A hidden disease among cohorts of familial hypercholesterolemia?

BACKGROUND: Lysosomal acid lipase deficiency (LALD) is an autosomal recessive disorder and an unrecognized cause of dyslipidemia. Patients usually present with dyslipidemia and altered liver function and mutations in LIPA gene are the underlying cause of LALD. OBJECTIVE: The aim of this study was to investigate LALD in individuals with severe dyslipidemia and/or liver steatosis. METHODS: Coding, splice regions, and promoter region of LIPA were sequenced by Sanger sequencing in a cohort of mutation-negative familial hypercholesterolemia (FH) patients (n = 492) and in a population sample comprising individuals with several types of dyslipidemia and/or liver steatosis (n = 258). RESULTS: This study led to the identification of LALD in 4 children referred to the Portuguese FH Study, all with a clinical diagnosis of FH. Mild liver dysfunction was present at the age of FH diagnosis; however, a diagnosis of LALD was not considered. No adults at the time of referral have been identified with LALD. CONCLUSION: LALD is a life-threatening disorder, and early identification is crucial for the implementation of specific treatment to avoid premature mortality. FH cohorts should be investigated to identify possible LALD patients, who will need appropriate treatment. These results highlight the importance of correctly identifying the etiology of the dyslipidemia.

Preliminary spectrum of genetic variants in familial hypercholesterolemia in Argentina.

BACKGROUND: Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol and early cardiovascular disease. As cardiovascular disease is a leading cause of mortality in Argentina, early identification of patients with FH is of great public health importance. OBJECTIVE: The aim of our study was to identify families with FH and to approximate to the characterization of the genetic spectrum mutations of FH in Argentina. METHODS: Thirty-three not related index cases were selected with clinical diagnosis of FH. Genetic analysis was performed by sequencing, multiplex ligation-dependent probe amplification, and bioinformatics tools. RESULTS: Twenty genetic variants were identified among 24 cases (73%), 95% on the low-density lipoprotein receptor gene. The only variant on APOB was the R3527Q. Four were novel variants: c.-135C>A, c.170A>C p.(Asp57Ala), c.684G>C p.(Glu228Asp), and c.1895A>T p.(Asn632Ile); the bioinformatics' analysis revealed clear destabilizing effects for 2 of them. The exon 14 presented the highest number of variants (32%). Four variants were observed in more than 1 case and the c.2043C>A p.(Cys681*) was carried by 18% of index cases. Two true homozygotes, 3 compound heterozygotes, and 1 double heterozygote were identified. CONCLUSION: This study characterizes for the first time in Argentina genetic variants associated with FH and suggest that the allelic heterogeneity of the FH in the country could have 1 relative common low-density lipoprotein receptor mutation. This knowledge is important for the genotype-phenotype correlation and for optimizing both cholesterol-lowering therapies and mutational analysis protocols. In addition, these data contribute to the understanding of the molecular basis of FH in Argentina.

Clinical and molecular aspects of familial hypercholesterolemia in Ibero-American countries.

BACKGROUND: There is little information about familial hypercholesterolemia (FH) epidemiology and care in Ibero-American countries. The Ibero-American FH network aims at reducing the gap on diagnosis and treatment of this disease in the region. OBJECTIVE: To describe clinical, molecular, and organizational characteristics of FH diagnosis in Argentina, Brazil, Chile, Colombia, Mexico, Portugal, Spain, and Uruguay. METHODS: Descriptive analysis of country data related to FH cascade screening, molecular diagnosis, clinical practice guidelines, and patient organization presence in Ibero-America. RESULTS: From a conservative estimation of an FH prevalence of 1 of 500 individuals, there should be 1.2 million heterozygous FH individuals in Ibero-America and roughly 27,400 were diagnosed so far. Only Spain, Brazil, Portugal, and Uruguay have active cascade screening programs. The prevalence of cardiovascular disease ranged from 10% to 42% in member countries, and the highest molecular identification rates are seen in Spain, 8.3%, followed by Portugal, 3.8%, and Uruguay with 2.5%. In the 3 countries with more FH patients identified (Spain, Portugal, and Brazil) between 10 and 15 mutations are responsible for 30% to 47% of all FH cases. Spain and Portugal share 5 of the 10 most common mutations (4 in low density lipoprotein receptor [LDLR] and the APOB3527). Spain and Spanish-speaking Latin American countries share 6 of the most common LDLR mutations and the APOB3527. LDL apheresis is available only in Spain and Portugal and not all countries have specific FH diagnostic and treatment guidelines as well as patient organizations. CONCLUSIONS: Ibero-American countries share similar mutations and gaps in FH care.

Mutational analysis of a cohort with clinical diagnosis of familial hypercholesterolemia: considerations for genetic diagnosis improvement.

PURPOSE: Familial hypercholesterolemia (FH) is a common autosomal dominant disorder of lipid metabolism caused by mutations in LDLR, APOB, and PCSK9. To fulfill the World Health Organization recommendation, the Portuguese FH Study was established. Here, we report the results of the past 15 years and present practical considerations concerning the genetic diagnosis of FH based on our experience. METHODS: Our approach comprises a biochemical and molecular study and is divided into five phases, including the study of whole APOB and functional assays. RESULTS: A total of 2,122 individuals were enrolled. A putative pathogenic variant was identified in 660 heterozygous patients: LDLR (623), APOB (33), and PCSK9 (4); 8 patients presented with homozygous FH. A detection rate of 41.5% was observed. A stricter biochemical criteria was shown to improve patient identification. Overall, we have identified 3.4% and 80% of all heterozygous and homozygous patients, respectively, estimated to exist in our country. CONCLUSION: The Portuguese FH Study has established the genetic diagnosis of FH in Portugal and is committed to continue the investigation of the genetic complexity of FH. Genetic diagnosis of FH should be expanded to include the study of all coding/flanking regions of APOB and functional in vitro studies, to improve the correct patient identification, and to avoid misdiagnosis.Genet Med 18 4, 316-324.

Cardiovascular risk profile of high school students: a cross-sectional study.

INTRODUCTION: Disease prevention should begin in childhood and lifestyles are important risk determinants of cardiovascular disease. Awareness and monitoring of risk is essential in preventive strategies. AIM: To characterize cardiovascular risk and the relationships between certain variables in adolescents. METHODS: In a cross-sectional study, 854 adolescent schoolchildren were surveyed, mean age 16.3 ± 0.9 years. Data collection included questionnaires, physical examination, charts for 10-year relative risk of mortality, and biochemical assays. In the statistical analysis continuous variables were studied by the Student's t test and categorical variables by the chi-square test and Fisher's exact test, and each risk factor was entered as a dependent variable in logistic regression analysis. RESULTS: Physical activity was insufficient in 81% of students. The daily consumption of soup, salad or vegetables, and fruit was, respectively, 37%, 39% and 21%. A minority (6%) took ≤ 3 and 77% took ≥ 5 meals a day. The prevalence of each risk factor was as follows: overweight 16%; smoking 13%; hypertension 11%; impaired glucose metabolism 9%; hypertriglyceridemia 9%; and hypercholesterolemia 5%. Out-of-school physical activity, hypertension and overweight were more prevalent in males (p<0.001). Females had higher levels of cholesterol (p<0.005) and triglycerides (p<0.001). A quarter of the adolescents had a relative risk score for 10-year cardiovascular mortality of ≥ 2. Overweight showed a positive association with blood pressure, changes in glucose metabolism and triglycerides, and a negative association with number of daily meals. CONCLUSIONS: The results demonstrate the need for action in providing and encouraging healthy choices for adolescents, with an emphasis on behavioral and lifestyle changes aimed at individuals, families and communities.

Cardiovascular risk assessment of dyslipidemic children: analysis of biomarkers to identify monogenic dyslipidemia.

The distinction between a monogenic dyslipidemia and a polygenic/environmental dyslipidemia is important for the cardiovascular risk assessment, counseling, and treatment of these patients. The present work aims to perform the cardiovascular risk assessment of dyslipidemic children to identify useful biomarkers for clinical criteria improvement in clinical settings. Main cardiovascular risk factors were analyzed in a cohort of 237 unrelated children with clinical diagnosis of familial hypercholesterolemia (FH). About 40% carried at least two cardiovascular risk factors and 37.6% had FH, presenting mutations in LDLR and APOB. FH children showed significant elevated atherogenic markers and lower concentration of antiatherogenic particles. Children without a molecular diagnosis of FH had higher levels of TGs, apoC2, apoC3, and higher frequency of BMI and overweight/obesity, suggesting that environmental factors can be the underlying cause of their hypercholesterolem≥ia. An apoB/apoA1 ratio ≥0.68 was identified as the best biomarker (area under the curve = 0.835) to differentiate FH from other dyslipidemias. The inclusion in clinical criteria of a higher cut-off point for LDL cholesterol or an apoB/apoA1 ratio ≥0.68 optimized the criteria sensitivity and specificity. The correct identification, at an early age, of all children at-risk is of great importance so that specific interventions can be implemented. apoB/apoA1 can improve the identification of FH patients.

Familial hypercholesterolemia: Molecular characterization of possible cases from the Azores Islands (Portugal).

Familial hypercholesterolemia (FH) is an autosomal dominant disorder of the cholesterol metabolism, which constitutes a risk factor for coronary arterial disease (CAD). In the Azores Islands (Portugal), where mortality from CAD doubles its rate comparatively to the rest of the country and where a high frequency of dyslipidemia has been reported, the prevalence and distribution of FH remain unknown. The molecular characterization of a group of 33 possible cases of FH of Azorean background was undertaken in this study. A DNA array was initially used to search mutations in the LDLR, APOB and PCSK9 loci in 10 unrelated possible cases of FH. No mutations were detected in the array; after sequencing the full LDLR gene, 18 variants were identified, corresponding to two missense (c.806G > A; c.1171G > A) and sixteen synonymous alterations. Six of the synonymous variants which are consistently described in the literature as associated with altered cholesterol levels were used to build haplotypes. The most frequent haplotype corresponded to TTCGCC (45%), a "risk" haplotype, formed exclusively by alleles that were reported to increase cholesterol levels. Some of the variants detected in the full sequencing of the LDLR gene fell within the ligand-binding domain of this gene, defined by exons 2 to 6. To add information as to the role of such variants, these exons were sequenced in the remaining 23 possible FH cases. Two missense alterations (c.185C > T; c.806G > A) were found in this subset of possible FH cases. The missense alteration c.185C > T, identified in one individual, is novel for the Portuguese population. In silico analysis was not conclusive for this alteration, whose role will have to be further investigated. This study represents the first approach to the establishment of the mutational profile of FH in the Azores Islands.

Hypercholesterolemia--a disease with expression from childhood.

INTRODUCTION: Hypercholesterolemia results from an alteration, genetic or acquired, in lipoprotein metabolism. Evidence that hypercholesterolemia is associated with the atherosclerotic process from childhood justifies the screening of high-risk children and initiation of therapy at preschool ages. OBJECTIVE: To assess children referred for pediatric consultations due to hypercholesterolemia. METHODS: Children and adolescents referred for pediatric consultations with a diagnosis of hypercholesterolemia were enrolled. Information on family history and clinical, anthropometric and biochemical parameters was recorded and, when appropriate, molecular study was performed. RESULTS: A total of 168 children were assessed. Forty-six presented a familial hypercholesterolemia phenotype and in 22 of these, a mutation in the low-density lipoprotein (LDL) receptor gene was identified. The lipid profile of the group with mutations showed significantly higher values of total and non-high-density lipoprotein (HDL) cholesterol compared to the group without mutations (total cholesterol 316.5±75.9 mg/dl vs. 260.9±42,0 mg/dl; non-HDL cholesterol 268.3±72.6 mg/dl vs. 203.5±43.9 mg/dl; p<0.05). Of the total, 55 were prescribed pharmacological therapy and the others underwent diet and exercise interventions only. A greater reduction in LDL cholesterol was observed in individuals under pharmacological therapy compared to those prescribed diet and exercise only (30.3% vs. 18.1%). Drug side effects were insignificant. CONCLUSION: It is possible to maintain a normal lipid profile in most individuals with familial hypercholesterolemia in order to reduce the risk of early onset of atherosclerosis, which is associated with serious cardiovascular complications from childhood.