Family cascade screening for equitable identification of familial hypercholesterolemia: study protocol for a hybrid effectiveness-implementation type III randomized controlled trial.

BACKGROUND: Familial hypercholesterolemia (FH) is a heritable disorder affecting 1.3 million individuals in the USA. Eighty percent of people with FH are undiagnosed, particularly minoritized populations including Black or African American people, Asian or Asian American people, and women across racial groups. Family cascade screening is an evidence-based practice that can increase diagnosis and improve health outcomes but is rarely implemented in routine practice, representing an important care gap. In pilot work, we leveraged best practices from behavioral economics and implementation science-including mixed-methods contextual inquiry with clinicians, patients, and health system constituents-to co-design two patient-facing implementation strategies to address this care gap: (a) an automated health system-mediated strategy and (b) a nonprofit foundation-mediated strategy with contact from a foundation-employed care navigator. This trial will test the comparative effectiveness of these strategies on completion of cascade screening for relatives of individuals with FH, centering equitable reach. METHODS: We will conduct a hybrid effectiveness-implementation type III randomized controlled trial testing the comparative effectiveness of two strategies for implementing cascade screening with 220 individuals with FH (i.e., probands) per arm identified from a large northeastern health system. The primary implementation outcome is reach, or the proportion of probands with at least one first-degree biological relative (parent, sibling, child) in the USA who is screened for FH through the study. Our secondary implementation outcomes include the number of relatives screened and the number of relatives meeting the American Heart Association criteria for FH. Our secondary clinical effectiveness outcome is post-trial proband cholesterol level. We will also use mixed methods to identify implementation strategy mechanisms for implementation strategy effectiveness while centering equity. DISCUSSION: We will test two patient-facing implementation strategies harnessing insights from behavioral economics that were developed collaboratively with constituents. This trial will improve our understanding of how to implement evidence-based cascade screening for FH, which implementation strategies work, for whom, and why. Learnings from this trial can be used to equitably scale cascade screening programs for FH nationally and inform cascade screening implementation efforts for other genetic disorders. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05750667. Registered 15 February 2023-retrospectively registered, https://clinicaltrials.gov/study/NCT05750667 .

Familial hypercholesterolemia.

Familial hypercholesterolemia is a common genetic disorder of autosomal inheritance associated with elevated LDL-cholesterol. It is estimated to affect 1:250 individuals in general population roughly estimated to be 5 million in India. The prevalence of FH is higher in young CAD patients (<55 years in men; <60 years in women). FH is underdiagnosed and undertreated. Screening during childhood and Cascade screening of family members of known FH patients is of utmost importance in order to prevent the burden of CAD. Early identification of FH patients and early initiation of the lifelong lipid lowering therapy is the most effective strategy for managing FH. FH management includes pharmaceutical agents (statins and non statin drugs) and lifestyle modification. Inspite of maximum dose of statin with or without Ezetimibe, if target levels of LDL-C are not achieved, Bempedoic acid, proprotein convertase subtilisin/kexin type 9 (PCSK9) Inhibitors/Inclisiran can be added.

A case report of an Egyptian family with familial hypercholesterolemia and an exonic LINE-1 insertion in LDLR.

BACKGROUND: Familial hypercholesterolemia (MIM: PS143890) is a genetic disorder characterized by an increase in blood cholesterol. LDLR is one of the genes which their defect contributes to the disorder. Affected individuals may carry a heterozygous variant or homozygous/compound heterozygous variants and those with biallelic pathogenic variants present more severe symptoms. METHOD: We report an Egyptian family with familial hypercholesterolemia. Both the proband and parents have the disorder while a sibling is unaffected. Exome sequencing was performed to identify the causal variant. RESULTS: LINE-1 insertion in exon 7 of LDLR was identified. Both parents have a heterozygous variant while the proband has a homozygous variant. The unaffected sibling did not carry the variant. DISCUSSION: This insertion may contribute to the high prevalence of hypercholesterolemia in Egypt and the finding underscores the importance of implementing mobile element insertion caller in routine bioinformatics pipeline.

Evolocumab Treatment in Pediatric Patients With Homozygous Familial Hypercholesterolemia: Pooled Data From Three Open-Label Studies.

BACKGROUND: Pediatric patients with homozygous familial hypercholesterolemia (HoFH) have an increased risk of atherosclerotic cardiovascular disease and difficulty meeting low-density lipoprotein cholesterol (LDL-C) goals. In this post hoc analysis, we evaluated pooled safety and efficacy data from 3 studies in pediatric patients with HoFH treated with the PCSK9 (proprotein convertase subtilisin/kexin type 9) monoclonal antibody inhibitor evolocumab. METHODS: Patients with HoFH aged 10 to 17 years received treatment with open-label evolocumab 420 mg subcutaneously monthly or biweekly in the TAUSSIG, RAMAN, or HAUSER-OLE clinical studies. All patients received background statins with or without ezetimibe. Study duration ranged from 12 to 260 weeks. The primary end point was treatment-emergent adverse events per 100 patient-years. Efficacy end points were changes from baseline to week 12 in lipids and PCSK9. RESULTS: Of the 39 patients in the pooled analysis, 69.2% were males, median age was 13.0 years, and 79.5% (31/39) had genotyped HoFH with LDLR pathogenic variants. Overall, median exposure to evolocumab was 18.2 (Q1, Q3: 3.0, 18.5) months. Treatment-emergent adverse events with an exposure-adjusted patient incidence rate of ≥5% were upper respiratory tract infection (6.6%), influenza (5.2%), and acne (5.0%) per 100 patient-years. Exposure-adjusted patient incidence of serious treatment-emergent adverse events was 13.3% per 100 patient-years. Excluding 4 patients receiving lipoprotein apheresis, week 12 median percentage change from baseline in LDL-C was -2.9% (Q1, Q3: -21.7, 1.5); however, 42.9% (15/35) of patients achieved ≥15% reduction in LDL-C from baseline. Residual LDLR (LDL receptor) activity was not associated with a reduction in LDL-C. CONCLUSIONS: In this pooled data analysis from 3 studies in pediatric patients with HoFH, evolocumab was well tolerated, with no new safety signals reported. These safety findings are consistent with findings from previous studies of evolocumab. Patients showed marked variability in LDL-C reduction. Results from this pooled analysis support guidelines suggesting a trial of PCSK9 inhibitor therapy regardless of estimated residual LDLR function. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01624142, NCT03403374, and NCT02624869.

Genetic Counseling and Genetic Testing for Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is one of the most common autosomal codominant Mendelian diseases. The major complications of FH include tendon and cutaneous xanthomas and coronary artery disease (CAD) associated with a substantial elevation of serum low-density lipoprotein levels (LDL). Genetic counseling and genetic testing for FH is useful for its diagnosis, risk stratification, and motivation for further LDL-lowering treatments. In this study, we summarize the epidemiology of FH based on numerous genetic studies, including its pathogenic variants, genotype-phenotype correlation, prognostic factors, screening, and usefulness of genetic counseling and genetic testing. Due to the variety of treatments available for this common Mendelian disease, genetic counseling and genetic testing for FH should be implemented in daily clinical practice.

The Health History of First-Degree Relatives' Dyslipidemia Can Affect Preferences and Intentions following the Return of Genomic Results for Monogenic Familial Hypercholesterolemia.

Genetic testing is key in modern healthcare, particularly for monogenic disorders such as familial hypercholesterolemia. This Tohoku Medical Megabank Project study explored the impact of first-degree relatives' dyslipidemia history on individual responses to familial hypercholesterolemia genomic results. Involving 214 participants and using Japan's 3.5KJPN genome reference panel, the study assessed preferences and intentions regarding familial hypercholesterolemia genetic testing results. The data revealed a significant inclination among participants with a family history of dyslipidemia to share their genetic test results, with more than 80% of participants intending to share positive results with their partners and children and 98.1% acknowledging the usefulness of positive results for personal health management. The study underscores the importance of family health history in genetic-testing perceptions, highlighting the need for family-centered approaches in genetic counseling and healthcare. Notable study limitations include the regional scope and reliance on questionnaire data. The study results emphasize the association between family health history and genetic-testing attitudes and decisions.

Reproductive Carrier Screening: Identifying Families at Risk for Familial Hypercholesterolemia in the United States.

BACKGROUND: Familial hypercholesterolemia is a treatable genetic condition but remains underdiagnosed. We reviewed the frequency of pathogenic or likely pathogenic (P/LP) variants in the LDLR gene in female individuals receiving reproductive carrier screening. METHODS: This retrospective observational study included samples from female patients (aged 18-55 years) receiving a 274-gene carrier screening panel from January 2020 to September 2022. LDLR exons and their 10 base pair flanking regions were sequenced. Carrier frequency for P/LP variants was calculated for the entire population and by race/ethnicity. The most common variants and their likely functional effects were evaluated. RESULTS: A total of 91 637 tests were performed on women with race/ethnicity reported as Asian (8.8%), Black (6.1%), Hispanic (8.5%), White (29.0%), multiple or other (15.0%), and missing (33.0%). Median age was 32.8 years with 83 728 (91%) <40 years. P/LP LDLR variants were identified in 283 samples (1 in 324). No patients were identified with >1 P/LP variant. LDLR carrier frequency was higher in Asian (1 in 191 [95% CI, 1 in 142-258]) compared with White (1 in 417 [95% CI, 1 in 326-533]; P<0.001) or Black groups (1 in 508 [95% CI, 1 in 284-910]; P=0.004). The most common variants differed between populations. Of all variants, at least 25.0% were predicted as null variants. CONCLUSIONS: P/LP variants in LDLR are common. Expanding the use of reproductive carrier screening to include genes associated with FH presents another opportunity to identify people predisposed to cardiovascular disease.

High Prevalence of Familial Hypercholesterolemia Due to the Founder Effect of the LDLR c.2271del Variant in Communities of Oaxaca, Mexico.

INTRODUCTION: In Mexico, familial hypercholesterolemia (FH) is underdiagnosed, but population screening in small communities where at least one homozygous patient has already been detected results in a useful and inexpensive approach to reduce this problem. Considering that we previously reported nine homozygous cases from the state of Oaxaca, we decided to perform a population screening to identify patients with FH and to describe both their biochemical and genetic characteristics. METHODS: LDL cholesterol (LDLc) was quantified in 2,093 individuals from 11 communities in Oaxaca; either adults with LDLc levels ≥170 mg/dL or children with LDLc ≥130 mg/dL were classified as suggestive of FH and therefore included in the genetic study. LDLR and APOB (547bp fragment of exon 26) genes were screened by sequencing and MLPA analysis. RESULTS: Two hundred and five individuals had suggestive FH, with a mean LDLc of 223 ± 54 mg/dL (range: 131-383 mg/dL). Two pathogenic variants in the LDLR gene were detected in 149 individuals: c.-139_-130del (n = 1) and c.2271del (n = 148). All patients had a heterozygous genotype. With the cascade screening of their relatives (n = 177), 15 heterozygous individuals for the c.2271del variant were identified, presenting a mean LDLc of 133 ± 35 mg/dL (range: 60-168 mg/dL). CONCLUSIONS: The FH frequency in this study was 7.8% (164/2093), the highest reported worldwide. A founder effect combined with inbreeding could be responsible for the high percentage of patients with the LDLR c.2271del variant (99.4%), which allowed us to detect both significant biochemical heterogeneity and incomplete penetrance; hence, we assumed the presence of phenotype-modifying variants.

Identification of a novel LDLR p.Glu179Met variant in Thai families with familial hypercholesterolemia and response to treatment with PCSK9 inhibitor.

Familial hypercholesterolemia (FH) is a genetic disease characterized by elevated LDL-C levels. In this study, two FH probands and 9 family members from two families from northeastern Thailand were tested for LDLR, APOB, and PCSK9 variants by whole-exome sequencing, PCR-HRM, and Sanger sequencing. In silico analysis of LDLR was performed to analyse its structure‒function relationship. A novel variant of LDLR (c.535_536delinsAT, p.Glu179Met) was detected in proband 1 and proband 2 in homozygous and heterozygous forms, respectively. A total of 6 of 9 family members were heterozygous for LDLR p.Glu179Met variant. Compared with proband 2, proband 1 had higher baseline TC and LDL-C levels and a poorer response to lipid-lowering therapy combined with a PCSK9 inhibitor. Multiple sequence alignment showed that LDLR p.Glu179Met was located in a fully conserved region. Homology modelling demonstrated that LDLR p.Glu179Met variant lost one H-bond and a negative charge. In conclusion, a novel LDLR p.Glu179Met variant was identified for the first time in Thai FH patients. This was also the first report of homozygous FH patient in Thailand. Our findings may expand the knowledge of FH-causing variants in Thai population, which is beneficial for cascade screening, genetic counselling, and FH management to prevent coronary artery disease.

Recapitulating familial hypercholesterolemia in a mouse model by knock-in patient-specific LDLR mutation.

Familial hypercholesterolemia (FH) is one of the most prevalent monogenetic disorders leading to cardiovascular disease (CVD) worldwide. Mutations in Ldlr, encoding a membrane-spanning protein, account for the majority of FH cases. No effective and safe clinical treatments are available for FH. Adenine base editor (ABE)-mediated molecular therapy is a promising therapeutic strategy to treat genetic diseases caused by point mutations, with evidence of successful treatment in mouse disease models. However, due to the differences in the genomes between mice and humans, ABE with specific sgRNA, a key gene correction component, cannot be directly used to treat FH patients. Thus, we generated a knock-in mouse model harboring the partial patient-specific fragment and including the Ldlr W490X mutation. LdlrW490X/W490X mice recapitulated cholesterol metabolic disorder and clinical manifestations of atherosclerosis associated with FH patients, including high plasma low-density lipoprotein cholesterol levels and lipid deposition in aortic vessels. Additionally, we showed that the mutant Ldlr gene could be repaired using ABE with the cellular model. Taken together, these results pave the way for ABE-mediated molecular therapy for FH.

Advances in familial hypercholesterolemia.

Familial hypercholesterolemia (FH), a semi-dominant genetic disease affecting more than 25 million people worldwide, is associated with severe hypercholesterolemia and premature atherosclerotic cardiovascular disease. Over the last decade, advances in data analysis, screening, diagnosis and cardiovascular risk stratification has significantly improved our ability to deliver precision medicine for these patients. Furthermore, recent updates on guideline recommendations and new therapeutic approaches have also proven to be highly beneficial. It is anticipated that both ongoing and upcoming clinical trials will offer further insights for the care and treatment of FH patients.

[The diagnostic value of genetic testing in familial hypercholesterolemia in patients with premature myocardial infarction].

Objective: To evaluate the diagnostic value of gene testing in familial hypercholesterolemia (FH) in patients with premature myocardial infarction(PMI). Methods: This study was a single center cross-sectional study. A retrospective analysis was made on PMI patients who visited the People's Hospital of Peking University from May 1, 2015 to March 31, 2017. Clinical data of patients was collected and gene testing of FH related genes low density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein B(APOB) and low density lipoprotein receptor adaptor protein 1(LDLRAP1) was carried out. Clinical diagnosis of FH patients was performed using Simon Broome criteria, DLCN criteria, and FH Chinese expert consensus. Results: There were 188 males (83.6%) among 225 PMI patients, and the age of the first myocardial infarction was (46.6±7.2) years old. Ten patients carried FH pathogenic or possibly pathogenic mutations (4.4%). Compared with Simon Broome standard, DLCN standard and FH Chinese expert consensus, gene testing increased the diagnostic rate of FH by 53.3%, 33.3% and 42.1% respectively. Conclusion: Gene testing is helpful to improve the diagnosis of FH, and it is important to start the standard treatment of FH as early as possible in patients with premature myocardial infarction.

LDLR c.415G > A causes familial hypercholesterolemia by weakening LDLR binding to LDL.

BACKGROUND: Familial hypercholesterolemia (FH) is a prevalent hereditary disease that can cause aberrant cholesterol metabolism. In this study, we confirmed that c.415G > A in low-density lipoprotein receptor (LDLR), an FH-related gene, is a pathogenic variant in FH by in silico analysis and functional experiments. METHODS: The proband and his family were evaluated using the diagnostic criteria of the Dutch Lipid Clinic Network. Whole-exome and Sanger sequencing were used to explore and validate FH-related variants. In silico analyses were used to evaluate the pathogenicity of the candidate variant and its impact on protein stability. Molecular and biochemical methods were performed to examine the effects of the LDLR c.415G > A variant in vitro. RESULTS: Four of six participants had a diagnosis of FH. It was estimated that the LDLR c.415G > A variant in this family was likely pathogenic. Western blotting and qPCR suggested that LDLR c.415G > A does not affect protein expression. Functional studies showed that this variant may lead to dyslipidemia by impairing the binding and absorption of LDLR to low-density lipoprotein ( LDL). CONCLUSION: LDLR c.415G > A is a pathogenic variant in FH; it causes a significant reduction in LDLR's capacity to bind LDL, resulting in impaired LDL uptake. These findings expand the spectrum of variants associated with FH.

CRISPR-Cas9-guided amplification-free genomic diagnosis for familial hypercholesterolemia using nanopore sequencing.

Familial hypercholesterolemia is an inherited disorder that remains underdiagnosed. Conventional genetic testing methods such as next-generation sequencing (NGS) or target PCR are based on the amplification process. Due to the efficiency limits of polymerase and ligase enzymes, these methods usually target short regions and do not detect large mutations straightforwardly. This study combined the long-read nanopore sequencing and CRISPR-Cas9 system to sequence the target DNA molecules without amplification. We originally designed and optimized the CRISPR-RNA panel to target the low-density lipoprotein receptor gene (LDLR) and proprotein convertase subtilisin/kexin type 9 gene (PCSK9) from human genomic DNA followed by nanopore sequencing. The average coverages for LDLR and PCSK9 were 106× and 420×, versus 1.2× for the background genome. Among them, continuous reads were 52x and 307x, respectively, and spanned the entire length of LDLR and PCSK9. We identified pathogenic mutations in both coding and splicing donor regions in LDLR. We also detected an 11,029 bp large deletion in another case. Furthermore, using continuous long reads generated from the benchmark experiment, we demonstrated how a false-positive 670 bp deletion caused by PCR amplification errors was easily eliminated.

Cluster analysis and visualisation of electronic health records data to identify undiagnosed patients with rare genetic diseases.

Rare genetic diseases affect 5-8% of the population but are often undiagnosed or misdiagnosed. Electronic health records (EHR) contain large amounts of data, which provide opportunities for analysing and mining. Data mining, in the form of cluster analysis and visualisation, was performed on a database containing deidentified health records of 1.28 million patients across 3 major hospitals in Singapore, in a bid to improve the diagnostic process for patients who are living with an undiagnosed rare disease, specifically focusing on Fabry Disease and Familial Hypercholesterolaemia (FH). On a baseline of 4 patients, we identified 2 additional patients with potential diagnosis of Fabry disease, suggesting a potential 50% increase in diagnosis. Similarly, we identified > 12,000 individuals who fulfil the clinical and laboratory criteria for FH but had not been diagnosed previously. This proof-of-concept study showed that it is possible to perform mining on EHR data albeit with some challenges and limitations.

Genetic testing for familial hypercholesterolemia.

PURPOSE OF REVIEW: Despite familial hypercholesterolemia (FH) being the most common genetic cause of cardiovascular disease (CVD), genetic testing is rarely utilized in the US. This review summarizes what is known about the clinical utility of genetic testing and its role in the diagnosis and screening of FH. RECENT FINDINGS: The presence of an FH-causative variant is associated with a substantially higher risk of CVD, even when low-density lipoprotein cholesterol (LDL-C) levels are only modestly elevated. Genetic testing can facilitate the identification of FH cases who may be missed by clinical diagnostic criteria, improve risk stratification beyond LDL-C and family history, guide treatment decisions, and improve treatment initiation and adherence. Genetic testing can be incorporated into FH screening and diagnosis algorithms, including cascade, targeted, and universal screening. Integrating genetic testing into cascade screening can enhance the effectiveness of the process. Several models of universal FH screening with coordinated genetic and lipid testing are feasible and effective. SUMMARY: More systematic integration of genetic testing into FH diagnosis and screening can significantly reduce the burden of this condition through early detection and treatment. Further pragmatic implementation studies are needed to determine how to more effectively and affordably integrate genetic testing into clinical lipid screening programs.

Familial hypercholesterolemia with special focus on Japan.

Familial hypercholesterolemia (FH) is an inherited disorder characterized by increased low-density lipoprotein LDL) cholesterol and atherosclerotic cardiovascular disease. Although initial genetic analysis linked FH to LDL receptor mutations, subsequent work demonstrated that a gain-of-function mutation in the proprotein convertase subtilisin/kexin type 9 (PCSK9), which causes LDL-R degradation, was shown to be the cause of FH. In this review, we describe the history of research on FH, its clinical phenotyping and genotyping and advances in treatment with special focus on Japan.

Plasma legumain in familial hypercholesterolemia: associations with statin use and cardiovascular risk markers.

Legumain is known to be regulated in atherosclerotic disease and may have both pro- and anti-atherogenic properties. The study aimed to explore legumain in individuals with familial hypercholesterolemia (FH), a population with increased cardiovascular risk. Plasma legumain was measured in 251 subjects with mostly genetically verified FH, of which 166 were adults (≥18 years) and 85 were children and young adults (<18 years) and compared to 96 normolipidemic healthy controls. Plasma legumain was significantly increased in the total FH population compared to controls (median 4.9 versus 3.3 pg/mL, respectively, p < 0.001), whereof adult subjects with FH using statins had higher levels compared to non-statin users (5.7 versus 3.9 pg/mL, respectively, p < 0.001). Children and young adults with FH (p = 0.67) did not have plasma legumain different from controls at the same age. Further, in FH subjects, legumain showed a positive association with apoB, and markers of inflammation and platelet activation (i.e. fibrinogen, NAP2 and RANTES). In the current study, we show that legumain is increased in adult subjects with FH using statins, whereas there was no difference in legumain among children and young adults with FH compared to controls. Legumain was further associated with cardiovascular risk markers in the FH population. However the role of legumain in regulation of cardiovascular risk in these individuals is still to be determined.

The impact of SLCO1B1 rs4149056 on LDL-C target achievement after lipid lowering therapy optimization in men and women with familial hypercholesterolemia.

Background and aims: FH women are less likely to receive intensive statin treatment and to obtain a 50% reduction of LDL-C from baseline compared to men with FH. SLCO1B1 rs4149056 might influence statin therapy compliance and thus LDL-C target achievement. Our aim was to evaluate the impact of SLCO1B1 rs4149056 on LDL-C target achievement after lipid lowering therapy (LLT) optimization in men and women with FH. Methods: This was a retrospective observational study involving 412 FH subjects with a probable or defined clinical diagnosis of FH who had had genetic analysis from June 2016 to September 2022. Biochemical analysis was obtained from all subjects at baseline and at the last follow-up after LLT optimization. Results: After LLT optimization the percentage of FH subjects on high-intensity statins decreased from the M/SLCO1B1- group to the W/SLCO1B1+ group and the same was found in LDL-C target distribution (for both p for trend < 0.01). The prevalence of SASE fear increased from the M/SLCO1B1- group to the W/SLCO1B1+ group and the same was observed in reported myalgia distribution (for both p for trend < 0.01). Logistic regression analysis showed that the W/SCLO1B1-, M/SCLO1B1+ and W/SCLO1B1+ groups were inversely associated with LDL-C target achievement (p for trend < 0.001) and the W/SCLO1B1+ group exhibited the strongest association. Conclusion: A low prevalence of FH women with SLCO1B1 rs4149056 were on high intensity statins and they rarely achieved LDL-C target. The genotype effect of SLCO1B1 rs4149056 could be more pronounced in FH women than men.

A Clinical Case of Probable Sitosterolemia.

Sitosterolemia is a rare genetic lipid disorder characterized by elevated plant sterols in the serum. A 24-year-old Japanese woman was referred to our hospital due to a high serum low-density lipoprotein cholesterol (LDL-C) level of 332 mg/dL. At first, she was suspected to suffer from familial hypercholesterolemia, and thus received lipid-lowering agents. Although her LDL-C level remained high (220 mg/dL) with diet therapy plus 10 mg/day rosuvastatin, it was drastically decreased to 46 mg/dL with the addition of 10 mg/day ezetimibe. Finally, her LDL-C level was well-controlled at about 70 mg/dL with 10 mg/day ezetimibe alone. Furthermore, while her serum sitosterol level was elevated at 10.5 µg/mL during the first visit to our hospital, it decreased to 3.6 µg/mL with the 10 mg/day ezetimibe treatment alone. These observations suggest that she might probably suffer from sitosterolemia. Therefore, targeted gene sequencing analysis was performed using custom panels focusing on the exome regions of 21 lipid-associated genes, including ABCG5, ABCG8, and familial hypercholesterolemia-causing genes (LDL receptor, LDLRAP1, PCSK9, and apolipoprotein B). We finally identified a heterozygous ABCG8 variant (NM_022437.2:c.1285A>G or NP_071882.1:p.Met429Val) in our patient. The same gene mutation was detected in her mother. We report here a rare case exhibiting probable sitosterolemia caused by a heterozygous Met429Val variant in the ABCG8 gene and additional unknown variants.