Background: GPIHBP1 binds lipoprotein lipase (LPL) and transports it to the capillary lumen. Results: A GPIHBP1 missense mutation (S107C) leads to the formation of GPIHBP1 multimers that cannot bind LPL. Conclusion: An extra cysteine leads to GPIHBP1 multimerization, defective LPL binding, and hypertriglyceridemia. Significance: This study identifies a novel mechanism by which GPIHBP1 mutations interfere with LPL binding and cause hypertriglyceridemia.

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Hereditary thrombocytopenia comprises extremely diverse diseases that are difficult to diagnose by phenotypes alone. Definite diagnoses are helpful for patient (Pt) management. To evaluate the role of whole exome sequencing (WES) in these Pts. Cases with unexplained long-standing thrombocytopenia and/or suggestive features were enrolled to the observational study. Bleeding scores and blood smear were evaluated. The variant pathogenicity from WES was determined by bioinformatics combined with all other information including platelet aggregometry, flow cytometry, and electron microscopy (EM). Seven unrelated Pts were recruited. All were female with macrothrombocytopenia. Clinical bleeding was presented in four Pts; extra-hematological features were minimal and family history was negative in every Pt. WES successfully identified all the 11 responsible mutant alleles; of these, four have never been previously reported. Pt 1 with GNE-related thrombocytopenia showed reduced lectin binding by flow cytometry, increased glycogen granules by EM and a novel homozygous mutation in GNE. Pts 2 and 3 had phenotypic diagnoses of Bernard Soulier syndrome and novel homozygous mutations in GP1BB and GP1BA, respectively. Pt 4 had impaired microtubule structures, concomitant delta storage pool disease by EM and a novel heterozygous TUBB1 mutation. Pt 5 had sitosterolemia showing platelets with reduced ristocetin responses and a dilated membrane system on EM with compound heterozygous ABCG5 mutations. Pts 6 and 7 had MYH9 disorders with heterozygous mutations in MYH9. This study substantiates the benefits of WES in identifying underlying mutations of macrothrombocytopenia, expands mutational spectra of four genes, and provides detailed clinical features for further phenotype-genotype correlations.

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Background The presence of tendon xanthomas, defined as thickening or nodularities of tendons, is subjective and remains largely undetected in patients with familial hypercholesterolemia (FH) in clinical practice. This study aimed to determine Achilles tendon thickness cutoff values associated with the highest diagnostic accuracy for identifying FH among Thai patients. Methods 63 subjects with possible, probable or definite FH according to the Dutch Lipid Clinic Network criteria, 58 subjects with hypercholesterolemia not compatible with FH and 55 normolipidemia subjects were recruited. Achilles tendon thickness was measured on each side separately at the point of maximum thickness using Lange skinfold calipers, Slim Guide skinfold calipers, plain radiograph of lateral ankles and ultrasonography. Ultrasonographic characteristics of the tendons were also recorded. The diagnostic performance of the maximum Achilles tendon thickness (maximum value of either left or right Achilles tendon of each person) obtained by each method was determined by Receiver-Operating Characteristic curves and optimal cut-points determined by Youden's index. Spearman rank-order correlation coefficient assessed factors associated with Achilles tendon thickness. Results Of all subjects, the mean age was 47 (±13) years, and 45% were male. The study groups were comparable in baseline characteristics except for a higher LDL cholesterol burden, a longer duration of lipid lowering therapy and a higher percentage of subjects receiving high intensity statins and ezetimibe in the FH group. Both types of skinfold calipers demonstrated 61% accuracy for diagnosing FH. An anteroposterior (AP) diameter on plain radiographs ≥7.7 mm had an 80% accuracy with 75% sensitivity and 82% specificity, whereas ultrasonographic thickness ≥6.4 mm. showed a 76% accuracy with 46% sensitivity and 93% specificity. Tendon border irregularities, diffuse hypoechogenicity and calcification were reported in a higher percentage of patients with FH, compared with the other 2 groups. Factors showing a significant correlation with Achilles tendon thickness in the FH group were years since FH diagnosis, a higher Dutch Lipid Clinic Network score and a higher body mass index (BMI). In the overall cohort, factors showing a significant correlation were higher LDL cholesterol burden and higher BMI. Conclusion Achilles tendon thickness measured by calipers showed low accuracy for FH diagnosis. An AP diameter on plain radiographs demonstrated highest sensitivity, whereas ultrasonographic thickness and area of Achilles tendon showed high specificity. Tendon irregularities, diffuse hypoechogenicity and calcification might serve as supportive findings. Presentation: No date and time listed

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Background Hyperalphalipoprtoteinemia (HALP) is primarily caused by loss-of-function mutations in key genes in the reverse cholesterol transport pathway (RCT) such as cholesteryl ester transfer protein, hepatic lipase, and endothelial lipase. Angiopoietin-like protein 3 (ANGPTL3) is a natural inhibitor of hepatic lipase and endothelial lipase. We have previously shown that ANGPTL3 levels are higher in HALP subjects compared to those of control. Angiopoietin-like protein 8 (ANGPTL8) is known to promote ANGPTL3 function. We aimed to examine ANGPTL8 levels in Thai HALP subjects. Methods Ninety subjects with HDL-cholesterol at least 100 mg/dl without other secondary causes, defined as HALP group, and ninety age-matched healthy controls were recruited from our outpatient clinic of tertiary university hospital. Clinical characteristics and lipid profiles of each group were obtained. Plasma ANGPTL8 levels were measured by ELISA. Results The mean age of the HALP subjects (91% female) was 58 ± 11 years. The mean HDL-cholesterol level in HALP group was significantly higher than that of the healthy controls (99 ± 17 mg/dl vs. 51 ± 6 mg/dl, p<0.001). The mean triglyceride level and LDL-cholesterol level in the HALP group were significantly lower than those of the controls (73 ± 31 mg/dl vs. 123 ± 50 mg/dl, p<0.001 and 131 ± 35 mg/dl vs. 144 ± 34 mg/dl, p=0.018, respectively). The mean plasma ANGPTL8 level was significantly higher in the HALP group compared to that of the controls (30.30 ± 10.80 ng/ml vs. 19.68 ± 7.81 ng/ml, p<0.001). HDL-cholesterol level was significantly correlated with plasma ANGPTL8 level in both groups (r=0.461, p<0.001). Plasma ANGPTL3 was the better determinant of HDL-cholesterol level than ANGPTL8. There was no significant correlation between plasma ANGPTL3 and ANGPTL8 levels (r=0.068, p=0.361). Conclusion Plasma ANGPTL8 levels in the HALP group were significantly higher than those of the healthy control and were significantly correlated with HDL-cholesterol levels. ANGPTL8 may be a potential determinant of HDL-cholesterol levels in Thai HALP subjects.