👤 Jon Jonasson

Familial hypercholesterolemia (FH) and other disorders with similar features are common genetic disorders that remain underdiagnosed and undertreated, due in part to the cost of screening. The aim of this study was to design and implement a whole gene targeted NGS panel for the molecular diagnosis of FH and statin intolerance with an emphasis on high quality variant calling, including copy number analysis. A whole gene panel for hybridisation-based short read NGS was designed for the dominant FH-genes low density lipoprotein receptor ( The panel sequencing resulted in high coverage and confident variant calling of included genes. Known causal variants were found in common dominant FH-genes in 43 % of the cohort. Copy number variants were found in This new tool can be used for a comprehensive high-quality molecular genetic analysis according to guidelines for the diagnosis and treatment of FH. Show less

Sudden cardiac death (SCD) and early onset cardiomyopathy (CM) in the young will always lead to suspicion of an underlying genetic disorder. Incited by the rapid advances in genetic testing for disease we have revisited families, which previously tested "gene-negative" for familial predominantly pediatric CM, in hopes of finding a causative gene variant. 10 different families with non-syndromic pediatric CM or hypertrophic cardiomyopathy (HCM) with severe disease progression and/or heredity for HCM/CM related SCD with "gene-negative" results were included. The index patient underwent genetic testing with a recently updated gene panel for CM and SCD. In case of failure to detect a pathogenic variant in a relevant gene, the index patient and both parents underwent clinical (i.e., partial) exome sequencing (trio-exome) in order to catch pathogenic variants linked to the disease in genes that were not included in the CM panel. The mean age at clinical presentation of the 10 index cases was 12.5 years (boys 13.4 years, Our results show the importance of renewed thorough clinical assessment and the necessity to challenge previous genetic test results with more comprehensive updated gene panels or exome sequencing if the initial test failed to identify a causative gene for early onset CM or SCD in children. In pediatric cardiomyopathy cases when the gene panel still fails to detect a causative variant, a trio exome sequencing strategy might resolve some unexplained cases, especially if a multisystemic condition is clinically missed. Show less

Hypertrophic cardiomyopathy (HCM) is a primary autosomal-dominant disorder of the myocardium with variable expressivity and penetrance. Occasionally, homozygous sarcomere genetic variants emerge while genotyping HCM patients. In these cases, a more severe HCM phenotype is generally seen. Here, we report a case of HCM that was diagnosed clinically at 39 years of age. Initial symptoms were shortness of breath during exertion. Successively, he developed a wide array of severe clinical manifestations, which progressed to an ominous end-stage heart failure that resulted in heart transplantation. Genotype analysis revealed a missense MYBPC3 variant NM₀₀₀₂₅₆.3:c.2618C>A,p.(Pro873His) that presented in the homozygous form. Conflicting interpretations of pathogenicity have been reported for the Pro873His MYBPC3 variant described here. Our patient, presenting with two copies of the variant and devoid of a normal allele, progressed to end-stage heart failure, which supports the notion of a deleterious effect of this variant in the homozygous form. Show less

Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88×10(-204)) and 10 loci for sphingolipids (smallest P-value = 3.10×10(-57)). After a correction for multiple comparisons (P-value<2.2×10(-9)), we observed four novel loci significantly associated with phospholipids (PAQR9, AGPAT1, PKD2L1, PDXDC1) and two with sphingolipids (PLD2 and APOE) explaining up to 3.1% of the variance. Further analysis of the top findings with respect to within class molar proportions uncovered three additional loci for phospholipids (PNLIPRP2, PCDH20, and ABDH3) suggesting their involvement in either fatty acid elongation/saturation processes or fatty acid specific turnover mechanisms. Among those, 14 loci (KCNH7, AGPAT1, PNLIPRP2, SYT9, FADS1-2-3, DLG2, APOA1, ELOVL2, CDK17, LIPC, PDXDC1, PLD2, LASS4, and APOE) mapped into the glycerophospholipid and 12 loci (ILKAP, ITGA9, AGPAT1, FADS1-2-3, APOA1, PCDH20, LIPC, PDXDC1, SGPP1, APOE, LASS4, and PLD2) to the sphingolipid pathways. In large meta-analyses, associations between FADS1-2-3 and carotid intima media thickness, AGPAT1 and type 2 diabetes, and APOA1 and coronary artery disease were observed. In conclusion, our study identified nine novel phospho- and sphingolipid loci, substantially increasing our knowledge of the genetic basis for these traits. Show less

Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic beta-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08x10(-66). The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1-3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p = 10(-4) or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested for a role in the development of common cardiovascular, metabolic, neurological, and psychiatric diseases. Show less

Recent genome-wide association (GWA) studies of lipids have been conducted in samples ascertained for other phenotypes, particularly diabetes. Here we report the first GWA analysis of loci affecting total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. Our study included a total of 17,797-22,562 persons, aged 18-104 years and from geographic regions spanning from the Nordic countries to Southern Europe. We established 22 loci associated with serum lipid levels at a genome-wide significance level (P < 5 x 10(-8)), including 16 loci that were identified by previous GWA studies. The six newly identified loci in our cohort samples are ABCG5 (TC, P = 1.5 x 10(-11); LDL, P = 2.6 x 10(-10)), TMEM57 (TC, P = 5.4 x 10(-10)), CTCF-PRMT8 region (HDL, P = 8.3 x 10(-16)), DNAH11 (LDL, P = 6.1 x 10(-9)), FADS3-FADS2 (TC, P = 1.5 x 10(-10); LDL, P = 4.4 x 10(-13)) and MADD-FOLH1 region (HDL, P = 6 x 10(-11)). For three loci, effect sizes differed significantly by sex. Genetic risk scores based on lipid loci explain up to 4.8% of variation in lipids and were also associated with increased intima media thickness (P = 0.001) and coronary heart disease incidence (P = 0.04). The genetic risk score improves the screening of high-risk groups of dyslipidemia over classical risk factors. Show less