APOB Mutations Research Articles

Clinical reality and challenges with familial hypercholesterolemia patients management. 2024 results from the Regional Center for Rare Diseases (RCRD) Registry in Poland

Abstract Background HeFH is one of the most prevalent genetic diseases significantly increasing the risk of CVD events and mortality. Despite new achievements with earlier diagnosis and new effective drugs, most of heFH patients do not achieve LDL-C goal and are still on residual CVD risk. Purpose We aimed to present the most recent data from the regional FH registry in Poland to show the challenges and reality of everyday clinical management with FH patients. Methods The registry is conducted at the RCRD in the 2nd largest, supraregional hospital in Poland. The main inclusion criteria were being phenotypically or genetically diagnosed with FH. Nonadherence was investigated based on detailed interview, monitoring the treatment’s effects and purchasing prescribed medications. For this analysis we investigated only adult FH patients from the registry. Due to small number of cases (n=5), patients treated with inclisiran were not included in this analysis. Results We included 142 consecutive heFH patients at mean age 45,8±14,9 years (min/max 18-75 years; 60% women). Mean BMI was 29.6±5.52 kg/m2, mean baseline TC was 282.9±80 mg/dl (the highest observed was 600 mg/dl), LDL-C 204.2±72.5 mg/dL (the highest observed -762 mg/dl), TG - 151.1±123.4 mg/dl, Lp(a) 37.6±41.5 mg/dl and HDL-C - 52.3±14.2 mg/dl. Most patients were diagnosed with LDLR (72%) or APOB (24%) mutations. High intensity statin therapy was used in 74.3% of patents, ezetimibe (mostly as a part of combination LLT) in 47.2%, and PCSK9 inhibitors in all those that met the reimbursement criteria – 25.6% of FH patients. Non-adherence to statin therapy and ezetimibe in the follow up of 2 years was 27%. In patients treated with statin therapy and ezetimibe mean achieved LDL-C was 153.6±82.82 mg/dl and on triple therapy - 64.5±43.73 mg/dl. Mean achieved LDL-C in the investigated population was 87.9±55.5 mg/dl. LDL-C goal was achieved in 39% of patients – in those treated with triple therapy with PCSK9 inhibitors it was 57.14%, and in those on statins and ezetimibe only 27.1%. Combination therapy of statins and ezetimibe did not significantly change baseline Lp(a) level (p=0.109), but when PCSK9 inhibitors were introduced the mean Lp(a) reduction by 34.2% (p=0.049) was observed. Based on the multivariable regression analysis, the following factors played the most important role for FH patients to be on LDL-C target: DLCN total score (OR 1.21, 95%CI: 1.04-1.40; p=0.013), DLCN category (10.39, 1.43-75.29; p=0.021), ezetimibe use (4.78, 1.15-19.92; p=0.031), and PCSK9 inhibitors use (4.56; 1.40-14.86; p=0.012). Conclusions FH patients in Poland are diagnosed definitely too late (45 years) and most of them are still not on LDL-C goal. Double and especially triple therapy significantly, even 5 times, increase the chance of achieving LDL-C goal, therefore PCSK9 inhibitors should be available for all FH patients, without the limitations existing currently e.g., within B101 drug program in Poland.

The impact of interplay between LDLR and apoB mutations on familial hypercholesterolemia

The impact of interplay between LDLR and apoB mutations on familial hypercholesterolemia

Insights into the Vietnam familial hypercholesterolemia registry: Characterizing mutations in LDLR, APOB and PCSK9 proteins at a structural and functional level

Insights into the Vietnam familial hypercholesterolemia registry: Characterizing mutations in LDLR, APOB and PCSK9 proteins at a structural and functional level

Genetic Analyses of Primary Liver Cancer Cell Lines: Correspondence With Morphological Features of Original Tumors.

Advancements in genetic analysis technologies have led to establishment of molecular classifications systems for primary liver cancers. The correlation between pathological morphology and genetic mutations in hepatocellular carcinoma (HCC) is becoming increasingly evident. To construct appropriate experimental models, it is crucial to select cell lines based on their morphology and genetic mutations. In this study, we conducted comprehensive genetic analyses of primary liver cancer cell lines and examined their correlations with morphology. Thirteen primary liver cancer cell lines established in our Department were investigated. Eleven cell lines were HCC cell lines, whereas 2 were combined hepatocellular-cholangiocarcinoma (CHC) cell line characteristics. Whole exome sequencing and fusion gene analyses were conducted using a next generation sequencing platform. We also examined correlations between cell mutations and morphological findings and conducted experiments to clarify the association between morphological findings and genetic alterations. Mutations in TP53, HMCN1, PCLO, HYDIN, APOB, and EYS were found in 11, 5, 4, 4, 3, and 3 cell lines, respectively. CTNNB1 mutation was not identified in any cell line. The original tumor of four cell lines (KYN-1, KYN-2, KYN-3, and HAK-6) showed morphologically macrotrabecular massive patterns and these cell lines harbor TP53 mutations. Two cell lines (KYN-2 and KMCH-2) showed an extremely high tumor mutation burden. These two cell lines possess ultra-mutations associated with DNA repair and/or DNA polymerase. The study identified correlations between morphological findings and genetic mutations in several HCC cell lines. Cell lines with unique genetic mutations were found. This information will be a valuable tool for the selection of suitable experimental models in HCC research.

A Case Report of Two Youthful Brothers: The Spine Combines with Multiple Butterfly Vertebrae and Hemivertebrae

Butterfly vertebrae (BV) and Hemivertbrae (HV) are all rare congenital spinal abnormality and usually reported in the literature as an isolated finding. As far as the authors know, cases with multiple butterfly deformities and hemivertebra deformities of the spine are very rare. The condition of two brothers suffering from this disease at the same time has not been reported in the literature. We report two youthful brothers, the young brother, 14-year-old, who has butterfly vertebrae at T6-T11, L1, L3, and a hemivertebrae at L4; the old brother, 18-year-old, who has butterfly vertebrae at T5, T6, T8, T10, T11, T12, L1, L3, L4, L5, S1. They all have scoliosis and low back pain, and a 46, XY karyotype. The old brother performed TBX6 and APOB mutation.

Abstract 18931: A PCSK9 and APOB Double Heterozygote Presenting Phenotypically Similar to Homozygous Familial Hypercholesterolemia

Introduction: Familial hypercholesterolemia (FH) is an inherited disorder associated with mutations in APOB, PCSK9 and LDLR genes. Heterozygous FH (HeFH) generally has one gene mutation. Homozygous FH (HoFH) has two mutations in the same gene and is characterized by vastly elevated plasma LDL-C, accelerated ASCVD and resistance to standard lipid-lowering therapy. Combinations of mutations can present with a phenotype similar to HoFH. We present a double heterozygous patient with unreported mutations in PCSK9 and APOB genes, exhibiting clinical features of HoFH. Hypothesis: Patients with multiple gene mutations for FH can present clinically similar to HoFH and would benefit from novel lipid lowering therapies Methods: 73-year-old female with a history of diabetes and hyperlipidemia presented in 2018 with dyspnea on exertion. Cholesterol (TC) and triglycerides (TG) were 430 and 715 mg/dl respectively, on rosuvastatin 40 mg and omega 3 fatty acids. Physical exam showed arcus senilis. A nuclear stress test showed ST depressions in inferolateral leads but normal scintigraphy. Genetic testing revealed APOB and PCSK9 mutations. She was then treated with rosuvastatin, icosapentyl ethyl, ezetimibe and fenofibrate. TC, LDL, TG and ApoB levels were 463, 236, 747 and >240 mg/dl respectively. Evolocumab was added, with reduction of TC, TG and ApoB levels to 326, 432 and 182mg/dl, despite maximal available therapy. Results: Genetic testing revealed APOB variant NP_000375.2:p.Gln3378His and PCSK9 variant NP_777596.2:pAla544Thr, which were unreported mutations with unknown clinical significance. Genetically, this patient is a double heterozygote but expresses a phenotype similar to HoFH due to a poor response to maximum therapy. Conclusions: Although usually genetically defined, the phenotype of HoFH can present with different genetic variations. Chaudhry et al established genetic diagnosis of HoFH in 0.9% of patients initially diagnosed as HeFH, of which 3 were true homozygotes and 3 were compound heterozygotes. These findings support the idea that various heterozygous combinations of mutations in the genes for LDLR, APOB and PCSK9, may present clinically similar to HoFH. Patients with these mutations could benefit from novel agents such as evinacumab.

Identification and Functional Analysis of APOB Variants in a Cohort of Hypercholesterolemic Patients.

Mutations in APOB are the second most frequent cause of familial hypercholesterolemia (FH). APOB is highly polymorphic, and many variants are benign or of uncertain significance, so functional analysis is necessary to ascertain their pathogenicity. Our aim was to identify and characterize APOB variants in patients with hypercholesterolemia. Index patients (n = 825) with clinically suspected FH were analyzed using next-generation sequencing. In total, 40% of the patients presented a variant in LDLR, APOB, PCSK9 or LDLRAP1, with 12% of the variants in APOB. These variants showed frequencies in the general population lower than 0.5% and were classified as damaging and/or probably damaging by 3 or more predictors of pathogenicity. The variants c.10030A>G;p.(Lys3344Glu) and c.11401T>A;p.(Ser3801Thr) were characterized. The p.(Lys3344Glu) variant co-segregated with high low-density lipoprotein (LDL)-cholesterol in 2 families studied. LDL isolated from apoB p.(Lys3344Glu) heterozygous patients showed reduced ability to compete with fluorescently-labelled LDL for cellular binding and uptake compared with control LDL and was markedly deficient in supporting U937 cell proliferation. LDL that was carrying apoB p.(Ser3801Thr) was not defective in competing with control LDL for cellular binding and uptake. We conclude that the apoB p.(Lys3344Glu) variant is defective in the interaction with the LDL receptor and is causative of FH, whereas the apoB p.(Ser3801Thr) variant is benign.

Construction and validation of chemoresistance-associated tumor- infiltrating exhausted-like CD8+ T cell signature in breast cancer: cr-TILCD8TSig.

Accumulating evidence has revealed that CD8+ T cell exhaustion (Tex) results in worse immunotherapy outcomes. However, the molecular functions and mechanisms of action of Tex in chemoresistance needed to be elucidated. The populations of tumor-infiltrating CD8+ T cells (TILCD8Ts) in chemoresistant and chemosensitive groups of the GSE25066 dataset were calculated using CIBERSORT. Differentially expressed genes (DEGs) between TILCD8Ts and other immune cells were explored by integrating 16 immune cell datasets downloaded from the gene expression omnibus (GEO) database. Gene ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, univariate and multivariate Cox regression, and least absolute shrinkage and selection operator (LASSO) regression of TILCD8T-specific upregulated genes were used to construct a chemoresistant TILCD8T signature (cr-TILCD8TSig). Clinical prognostic data, genomic alterations, chemotherapy response, and immunotherapy response were compared between the different cr-TILCD8TSig subgroups in the GSE25066 and the cancer genome atlas breast cancer (TCGA-BRCA) cohorts. A cr-TILCD8TSig with exhausted features was identified, consisting of seven genes (TCF7, RARRES3, ARL4C, ITK, CDH3, GZMB, and KLRD1), which were identified from 104 TILCD8Ts-specific DEGs. Our results showed that compared to the cr-TILCD8TSig-low subgroup, the -high subgroup had a poorer distant relapse-free survival (DRFS) in the GSE25066 cohort and worse progression-free survival (PFS) in the TCGA-BRCA cohort. Univariate and multivariate Cox regression analyses also demonstrated that cr-TILCD8TSig was an independent prognostic factor in the two independent cohorts. Furthermore, cr-TILCD8TSig-low patients benefited more from chemotherapy and immunotherapy than cr-TILCD8TSig-high patients. Besides, we found cell transmembrane signal transduction and the ECM may provide the molecular basis for resistance to antitumor agents in the cr-TILCD8Sig-high subgroup. For genomic alterations, we revealed that mutations in PIK3CA, DMD, and APOB were more common in the cr-TILCD8Sig-high subgroup than in the cr-TILCD8Sig-low subgroup. A nomogram was finally constructed with good discrimination and calibration. cr-TILCD8TSig is a useful tool to independently predict prognosis, chemotherapy response, and immunotherapy outcomes in patients with breast cancer.

Engineered human hepatocyte organoids enable CRISPR-based target discovery and drug screening for steatosis

The lack of registered drugs for nonalcoholic fatty liver disease (NAFLD) is partly due to the paucity of human-relevant models for target discovery and compound screening. Here we use human fetal hepatocyte organoids to model the first stage of NAFLD, steatosis, representing three different triggers: free fatty acid loading, interindividual genetic variability (PNPLA3 I148M) and monogenic lipid disorders (APOB and MTTP mutations). Screening of drug candidates revealed compounds effective at resolving steatosis. Mechanistic evaluation of effective drugs uncovered repression of de novo lipogenesis as the convergent molecular pathway. We present FatTracer, a CRISPR screening platform to identify steatosis modulators and putative targets using APOB−/− and MTTP−/− organoids. From a screen targeting 35 genes implicated in lipid metabolism and/or NAFLD risk, FADS2 (fatty acid desaturase 2) emerged as an important determinant of hepatic steatosis. Enhancement of FADS2 expression increases polyunsaturated fatty acid abundancy which, in turn, reduces de novo lipogenesis. These organoid models facilitate study of steatosis etiology and drug targets.

Case report of familial hypobetalipoproteinemia: a novel APOB mutation and literature review.

Familial hypobetalipoproteinemia is an autosomal dominantly inherited disorder of lipid metabolism characterized by a <5th percentile plasma levels of low-density lipoprotein cholesterol or total apolipoprotein B, caused by mutations in the APOB gene. Patients with heterozygous APOB-related familial hypobetalipoproteinemia are usually asymptomatic or manifest with mild liver dysfunction or hepatic steatosis. A 14-year-old Korean boy was referred to our clinic because of low low-density lipoprotein cholesterol and elevated aminotransferase levels. He did not complain specific symptoms of hypobetalipoproteinemia, but his laboratory and radiologic tests showed low low-density lipoprotein cholesterol, low apolipoprotein B, high aminotransferases, severe fatty liver, and hepatosplenomegaly. A multigene panel test identified a heterozygous mutation for p.Lys3846Ter (c.11536A>T) in the APOB gene, which has not been reported in previous studies and was not detected in his parents with normal lipid profiles. Limiting intake of saturated fat, increased physical activity, and vitamin E supplementation were performed. Subsequent laboratory tests revealed normalized aminotransferase levels.

Targeted sequencing of a gene panel in patients with familial hypercholesterolemia from Southern Poland.

Familial hypercholesterolemia (FH) is an autosomal dominant monogenic lipid metabolism disorder characterized by a significantly elevated level of low‑density lipoprotein (LDL) cholesterol and leading to premature ischemic heart disease. FH is caused by mutations in the LDLR, APOB, and PCSK9 genes; however, these mutations account for only about 40% of FH cases. In order to obtain a genetic diagnosis of FH, sequencing of other genes involved in the lipid metabolism might be useful. This study aimed to describe genetic variants in genes associated with FH in a group of patients from the Małopolska province in Southern Poland, using the targeted next generation sequencing (NGS) technology. The study involved 90 unrelated adults (age range, 18-70 years) with FH diagnosed clinically according to the Simon Broome Register criteria. A custom‑designed capture assay and the Illumina MiSeq platform were used. The panel included exons and exon / intron boundaries of known FH‑causing genes: LDLR, APOB, and PCSK9, as well as genes previously associated with high cholesterol levels: APOE, ABCG5, ABCG8, LPL, NPC1, LDLRAP1, LIPC, STAP1, and CELSR2. Genetic variants were classified based on in silico predictions and ClinVar reports. We detected 4 patients with variants in the LDLR and APOB genes that had not been previously linked to FH in ClinVar. We also found APOB mutations outside the common LDL receptor-binding region, in exons 26 and 29. Interestingly, we observed a high frequency of pathogenic variants in exon 4 of the APOE gene: rs7412, probably damaging (4 patients) and rs429358, benign (16 patients). NGS is a useful and reliable method to detect new variants in genes related to FH. In addition, the results enable the detection of FH phenocopies and introduction of appropriate treatment.

Real-World Evaluation of a Population Germline Genetic Screening Initiative for Family Medicine Patients.

Hereditary factors contribute to disease development and drug pharmacokinetics. The risk of hereditary disease development can be attenuated or eliminated by early screening or risk reducing interventions. The purpose of this study was to assess the clinical utility of germline medical exome sequencing in patients recruited from a family medicine clinic and compare the mutation frequency of hereditary predisposition genes to established general population frequencies. At the University of Kentucky, 205 family medicine patients underwent sequencing in a Clinical Laboratory Improvement Amendments of 1988-compliant laboratory to identify clinically actionable genomic findings. The study identified pathogenic or likely pathogenic genetic variants—classified according to the American College of Medical Genetics and Genomics variant classification guidelines—and actionable pharmacogenomic variants, as defined by the Clinical Pharmacogenetics Implementation Consortium. Test results for patients with pharmacogenomic variants and pathogenic or likely pathogenic variants were returned to the participant and enrolling physician. Hereditary disease predisposition gene mutations in APOB, BRCA2, MUTYH, CACNA1S, DSC2, KCNQ1, LDLR, SCN5A, or SDHB were identified in 6.3% (13/205) of the patients. Nine of 13 (69.2%) underwent subsequent clinical interventions. Pharmacogenomic variants were identified in 76.1% (156/205) of patients and included 4.9% (10/205) who were prescribed a medication that had pharmacogenomic implications. Family physicians changed medications for 1.5% (3/205) of patients to prevent toxicity. In this pilot study, we found that with systemic support, germline genetic screening initiatives were feasible and clinically beneficial in a primary care setting.

*Ketogenic Diets Exacerbating Hypercholesterolemia in APOE Variants and APOB Mutations-Potential Role for Measuring Intestinal Absorption of Lipids

Lead Author's Financial Disclosures Nothing to disclose. Study Funding None. Background/Synopsis Familial Hypercholesterolemia (FH) is caused primarily by mutations in either LDL receptor, APOB, or PCSK9 genes. There are other genetic causes of LDL elevation including APOE4 variants. Objective/Purpose We present two patients with markedly elevated LDL suspicious for FH who were subsequently diagnosed with APOE3/4 variants while on ketogenic diets. We also present a patient with a known APOB mutation who had a marked elevation of LDL on a ketogenic diet. Methods Case 1: 58-year-old male with no prior medical history was found to have elevated cholesterol of 600mg/dL and LDL>455mg/dL while on a ketogenic diet. Prior to initiating the diet, his cholesterol was 206mg/dL and LDL was 132mg/dL. Genetic testing revealed a ApoE3/4 variant. His most recent cholesterol increased to 706mg/dL and LDL to >500mg/dL. Case 2: 53-year-old male with hypertension cholesterol of 282mg/dL and LDL of 212mg/dL went on a ketogenic diet and lost 100lbs. Follow up lipid panel demonstrated a cholesterol of 400mg/dL and LDL of 317mg/dL. Genetic testing revealed a APOE3/4 variant. Case 3: 45-year-old female with FH and known APOB missense mutation went on a ketogenic diet for weight loss. Prior to initiating the diet, her total cholesterol was 311 mg/dL and LDL was 211 mg/dL. While on the ketogenic diet, her total cholesterol was 550 mg/dL and LDL was 454 mg/dL. Her LDL decreased to 276mg/dl on a less strict ketogenic diet. Results All three patients had a normal exercise stress test, normal carotid duplex ultrasound, and coronary calcium score of zero. They refused the initiation of a statin. All 3 patients had the Boston Heart Cholesterol Balance Test performed that directly measures the absorption markers (beta-sitosterol, campesterol and cholestanol) for circulating plasma cholesterol. Only the patient with the APOB mutation had increased intestinal absorption of cholesterol, suggesting a response to ezetimibe. She agreed to initiate ezetimibe, her LDL subsequently decreased by 52% to 132mg/dl. Conclusions We hypothesize patients with APOE variants and APOB mutations could have an exaggerated elevation of their LDL levels while on ketogenic diets. Although these 3 patients did not demonstrate progressive atherosclerosis, the long-term effect of this diet is unknown. We recommend that all patients on a ketogenic diet have their LDL monitored and if there is a significant increase, undergo genetic testing for FH, APOE and other genetic variants. Since this patient group is often reluctant to start statins, the Cholesterol Balance Test may be useful to identify patients who may respond well to ezetimibe. Nothing to disclose.

Identification of New Genetic Determinants in Pediatric Patients with Familial Hypercholesterolemia Using a Custom NGS Panel.

The most common form of inherited lipid disorders is familial hypercholesterolemia (FH). It is characterized primarily by high concentrations of the clinical triad of low-density lipoprotein cholesterol, tendon xanthomas and premature CVD. The well-known genetic background are mutations in LDLR, APOB and PCSK9 gene. Causative mutations can be found in 60–80% of definite FH patients and 20–30% of those with possible FH. Their occurrence could be attributed to the activity of minor candidate genes, whose causal mechanism has not been fully discovered. The aim of the conducted study was to identify disease-causing mutations in FH-related and candidate genes in pediatric patients from Poland using next generation sequencing (NGS). An NGS custom panel was designed to cover 21 causative and candidate genes linked to primary dyslipidemia. Recruitment was performed using Simon Broome diagnostic criteria. Targeted next generation sequencing was performed on a MiniSeq sequencer (Illumina, San Diego, CA, USA) using a 2 × 150 bp paired-end read module. Sequencing data analysis revealed pathogenic and possibly pathogenic variants in 33 out of 57 studied children. The affected genes were LDLR, APOB, ABCG5 and LPL. A novel pathogenic 7bp frameshift deletion c.373_379delCAGTTCG in the exon 4 of the LDLR gene was found. Our findings are the first to identify the c.373_379delCAGTTCG mutation in the LDLR gene. Furthermore, the double heterozygous carrier of frameshift insertion c.2416dupG in the LDLR gene and missense variant c.10708C>T in the APOB gene was identified. The c.2416dupG variant was defined as pathogenic, as confirmed by its cosegregation with hypercholesterolemia in the proband’s family. Although the APOB c.10708C>T variant was previously detected in hypercholesterolemic patients, our data seem to demonstrate no clinical impact. Two missense variants in the LPL gene associated with elevated triglyceride plasma level (c.106G>A and c.953A>G) were also identified. The custom NGS panel proved to be an effective research tool for identifying new causative aberrations in a genetically heterogeneous disease as familial hypercholesterolemia (FH). Our findings expand the spectrum of variants associated with the FH loci and will be of value in genetic counseling among patients with the disease.

APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia

Primary hypercholesterolemia is characterized by elevated LDL-cholesterol (LDL-C) levels isolated in autosomal dominant hypercholesterolemia (ADH) or associated with elevated triglyceride levels in familial combined hyperlipidemia (FCHL). Rare APOE variants are known in ADH and FCHL. We explored the APOE molecular spectrum in a French ADH/FCHL cohort of 5743 unrelated probands. The sequencing of LDLR, PCSK9, APOB, and APOE revealed 76 carriers of a rare APOE variant, with no mutation in LDLR, PCSK9, or APOB. Among the 31 APOE variants identified here, 15 are described in ADH, 10 in FCHL, and 6 in both probands. Five were previously reported with dyslipidemia and 26 are novel, including 12 missense, 5 synonymous, 2 intronic, and 7 variants in regulatory regions. Sixteen variants were predicted as pathogenic or likely pathogenic, and their carriers had significantly lower polygenic risk scores (wPRS) than carriers of predicted benign variants. We observed no correlation between LDL-C levels and wPRS, suggesting a major effect of APOE variants. Carriers of p.Leu167del were associated with a severe phenotype. The analysis of 11 probands suggests that carriers of an APOE variant respond better to statins than carriers of a LDLR mutation. Altogether, we show that the APOE variants account for a significant contribution to ADH and FCHL.

Comparison of two polygenic risk scores to identify non-monogenic primary hypocholesterolemias in a large cohort of Italian hypocholesterolemic subjects

Primary Hypobetalipoproteinemias (HBL) are a group of dominant and recessive monogenic genetic disorders caused by mutations in APOB, PCSK9, ANGPTL3, MTTP, Sar1b genes and characterized by plasma levels of total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (apoB) below the 5th percentile of the distribution in a given population. Mutations in the candidate genes account only for a small proportion of subjects with HBL suggesting a role for a polygenic contribution to the low cholesterol phenotype. To explore the complex genetic architecture of HBL we compared two polygenic risk scores in order to assess the role of the polygenic burden and the differences in the clinical phenotype between monogenic and polygenic HBL; we studied a cohort of 170 subjects with primary HBL referred over a 25-year period to 2 Italian reference centers have been studied. The genetic analyses have been based on: Sanger sequencing, in-house NGS customized panel and two scores, PRS1 and PRS2 for the polygenic burden. Sixty 60 (35%) and 63 (37%) subjects had a monogenic and polygenic HBL respectively. LDL-C plasma levels were significantly lower in monogenic HBL (30.87 ± 3.12 mg/dl) compared with the non-monogenic HBL (42.80 ± 2.18 mg/dl) (p<0.002) with no differences in the percentage of fatty liver. Only PRS1 is effective in detecting polygenic HBL while PRS2 does not improve the polygenic diagnosis.

Genomic and transcriptomic somatic alterations of hepatocellular carcinoma in non-cirrhotic livers

Genomic and transcriptomic somatic alterations of hepatocellular carcinoma in non-cirrhotic livers

LDL-C Concentrations and the 12-SNP LDL-C Score for Polygenic Hypercholesterolaemia in Self-Reported South Asian, Black and Caribbean Participants of the UK Biobank.

Background: Monogenic familial hypercholesterolaemia (FH) is an autosomal dominant disorder characterised by elevated low-density lipoprotein cholesterol (LDL-C) concentrations due to monogenic mutations in LDLR, APOB, PCSK9, and APOE. Some mutation-negative patients have a polygenic cause for elevated LDL-C due to a burden of common LDL-C-raising alleles, as demonstrated in people of White British (WB) ancestry using a 12-single nucleotide polymorphism (SNP) score. This score has yet to be evaluated in people of South Asian (SA), and Black and Caribbean (BC) ethnicities. Objectives: 1) Compare the LDL-C and 12-SNP score distributions across the three major ethnic groups in the United Kingdom: WB, SA, and BC individuals; 2) compare the association of the 12-SNP score with LDL-C in these groups; 3) evaluate ethnicity-specific and WB 12-SNP score decile cut-off values, applied to SA and BC ethnicities, in predicting LDL-C concentrations and hypercholesterolaemia (LDL-C>4.9 mmol/L). Methods: The United Kingdom Biobank cohort was used to analyse the LDL-C (adjusted for statin use) and 12-SNP score distributions in self-reported WB (n = 353,166), SA (n = 7,016), and BC (n = 7,082) participants. To evaluate WB and ethnicity-specific 12-SNP score deciles, the total dataset was split 50:50 into a training and testing dataset. Regression analyses (logistic and linear) were used to analyse hypercholesterolaemia (LDL-C>4.9 mmol/L) and LDL-C. Findings: The mean (±SD) measured LDL-C differed significantly between the ethnic groups and was highest in WB [3.73 (±0.85) mmol/L], followed by SA [3.57 (±0.86) mmol/L, p < 2.2 × 10−16], and BC [3.42 (±0.90) mmol/L] participants (p < 2.2 × 10−16). There were significant differences in the mean (±SD) 12-SNP score between WB [0.90 (±0.23)] and BC [0.72 (±0.25), p < 2.2 × 10−16], and WB and SA participants [0.86 (±0.19), p < 2.2 × 10−16]. In all three ethnic groups the 12-SNP score was associated with measured LDL-C [R 2 (95% CI): WB = 0.067 (0.065–0.069), BC = 0.080 (0.063–0.097), SA = 0.027 (0.016–0.038)]. The odds ratio and the area under the curve for hypercholesterolaemia were not statistically different when applying ethnicity-specific or WB deciles in all ethnic groups. Interpretation: We provide information on the differences in LDL-C and the 12-SNP score distributions in self-reported WB, SA, and BC individuals of the United Kingdom Biobank. We report the association between the 12-SNP score and LDL-C in these ethnic groups. We evaluate the performance of ethnicity-specific and WB 12-SNP score deciles in predicting LDL-C and hypercholesterolaemia.

Epilepsy Combined With Multiple Gene Heterozygous Mutation.

The fast pace of gene discovery has resulted in groundbreaking advances in the field of epilepsy genetics. Clinical testing using comprehensive gene panels, exomes, or genomes is now increasingly available and has significantly increased the diagnostic yield for early-onset epilepsies and enabled precision medicine approaches. In this paper, we report a case of epilepsy in a pedigree. The proband had heterozygous mutations in KCNC1 (NM_001112741.1:c.959G>A, p. Arg320His), CAPN3 (NM_000070.2:c.526G>A, p. Val176Met), and NEFH (NM_021076.3:c. 2595 delC, p. Lys866Argfs*51). Sanger sequencing verification was consistent with the results of whole-exome sequencing. The KCNC1 mutation was a de novo mutation, and the CAPN3 and NEFH mutations were inherited from their father and mother, respectively. Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, a heterozygous mutation was found for APOB (NM_000384.2: c.10579C > T, p. Arg3527Trp). The heterozygous mutation at this site was inherent in the pedigree. Coexpression analysis indicated that heterozygous mutations of KCNC1, CAPN3, NEFH, and APOB were closely related to the clinical phenotypes of the patient, and the clinical phenotypic heterogeneity of the disease may be the result of the interaction of multiple genes.

Whole Genome Sequencing Identifies a Recurrent Mutation in Complement Factor I (CFI) in Primary Myelofibrosis (PMF)

Whole Genome Sequencing Identifies a Recurrent Mutation in Complement Factor I (CFI) in Primary Myelofibrosis (PMF)