Dataset Information

Partial LPL deletions: rare copy-number variants contributing towards severe hypertriglyceridemia.

ABSTRACT: Severe hypertriglyceridemia (HTG) is a relatively common form of dyslipidemia with a complex pathophysiology and serious health complications. HTG can develop in the presence of rare genetic factors disrupting genes involved in the triglyceride (TG) metabolic pathway, including large-scale copy-number variants (CNVs). Improvements in next-generation sequencing technologies and bioinformatic analyses have better allowed assessment of CNVs as possible causes of or contributors to severe HTG. We screened targeted sequencing data of 632 patients with severe HTG and identified partial deletions of the LPL gene, encoding the central enzyme involved in the metabolism of TG-rich lipoproteins, in four individuals (0.63%). We confirmed the genomic breakpoints in each patient with Sanger sequencing. Three patients carried an identical heterozygous deletion spanning the 5' untranslated region (UTR) to LPL exon 2, and one patient carried a heterozygous deletion spanning the 5'UTR to LPL exon 1. All four heterozygous CNV carriers were determined to have multifactorial severe HTG. The predicted null nature of our identified LPL deletions may contribute to relatively higher TG levels and a more severe clinical phenotype than other forms of genetic variation associated with the disease, particularly in the polygenic state. The identification of novel CNVs in patients with severe HTG suggests that methods for CNV detection should be included in the diagnostic workup and molecular genetic evaluation of patients with high TG levels.

SUBMITTER: Dron JS

PROVIDER: S-EPMC6824486 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Partial <i>LPL</i> deletions: rare copy-number variants contributing towards severe hypertriglyceridemia.

Dron Jacqueline S JS Wang Jian J McIntyre Adam D AD Cao Henian H Robinson John F JF Duell P Barton PB Manjoo Priya P Feng James J Movsesyan Irina I Malloy Mary J MJ Pullinger Clive R CR Kane John P JP Hegele Robert A RA

Journal of lipid research 20190913 11

Severe hypertriglyceridemia (HTG) is a relatively common form of dyslipidemia with a complex pathophysiology and serious health complications. HTG can develop in the presence of rare genetic factors disrupting genes involved in the triglyceride (TG) metabolic pathway, including large-scale copy-number variants (CNVs). Improvements in next-generation sequencing technologies and bioinformatic analyses have better allowed assessment of CNVs as possible causes of or contributors to severe HTG. We sc ...[more]

PMID: 31519763

Similar Datasets

Project description:Obesity is a multifactorial disorder with high heritability (50-75%), which is probably higher in early-onset and severe cases. Although rare monogenic forms and several genes and regions of susceptibility, including copy number variants (CNVs), have been described, the genetic causes underlying the disease still remain largely unknown. We searched for rare CNVs (>100kb in size, altering genes and present in <1/2000 population controls) in 157 Spanish children with non-syndromic early-onset obesity (EOO: body mass index >3 standard deviations above the mean at <3 years of age) using SNP array molecular karyotypes. We then performed case control studies (480 EOO cases/480 non-obese controls) with the validated CNVs and rare sequence variants (RSVs) detected by targeted resequencing of selected CNV genes (n = 14), and also studied the inheritance patterns in available first-degree relatives. A higher burden of gain-type CNVs was detected in EOO cases versus controls (OR = 1.71, p-value = 0.0358). In addition to a gain of the NPY gene in a familial case with EOO and attention deficit hyperactivity disorder, likely pathogenic CNVs included gains of glutamate receptors (GRIK1, GRM7) and the X-linked gastrin-peptide receptor (GRPR), all inherited from obese parents. Putatively functional RSVs absent in controls were also identified in EOO cases at NPY, GRIK1 and GRPR. A patient with a heterozygous deletion disrupting two contiguous and related genes, SLCO4C1 and SLCO6A1, also had a missense RSV at SLCO4C1 on the other allele, suggestive of a recessive model. The genes identified showed a clear enrichment of shared co-expression partners with known genes strongly related to obesity, reinforcing their role in the pathophysiology of the disease. Our data reveal a higher burden of rare CNVs and RSVs in several related genes in patients with EOO compared to controls, and implicate NPY, GRPR, two glutamate receptors and SLCO4C1 in highly penetrant forms of familial obesity.

Project description:Endometriosis is a complex gynecological condition that affects 6-10% of women in their reproductive years and is defined by the presence of endometrial glands and stroma outside the uterus. Twin, family, and genome-wide association (GWA) studies have confirmed a genetic role, yet only a small part of the genetic risk can be explained by SNP variation. Copy number variants (CNVs) account for a greater portion of human genetic variation than SNPs and include more recent mutations of large effect. CNVs, likely to be prominent in conditions with decreased reproductive fitness, have not previously been examined as a genetic contributor to endometriosis. Here we employ a high-density genotyping microarray in a genome-wide survey of CNVs in a case-control population that includes 2,126 surgically confirmed endometriosis cases and 17,974 population controls of European ancestry. We apply stringent quality filters to reduce the false positive rate common to many CNV-detection algorithms from 77.7% to 7.3% without noticeable reduction in the true positive rate. We detected no differences in the CNV landscape between cases and controls on the global level which showed an average of 1.92 CNVs per individual with an average size of 142.3 kb. On the local level we identify 22 CNV-regions at the nominal significance threshold (P<0.05), which is greater than the 8.15 CNV-regions expected based on permutation analysis (P<0.001). Three CNV's passed a genome-wide P-value threshold of 9.3 × 10(-4); a deletion at SGCZ on 8p22 (P = 7.3 × 10(-4), OR = 8.5, Cl = 2.3-31.7), a deletion in MALRD1 on 10p12.31 (P = 5.6 × 10(-4), OR = 14.1, Cl = 2.7-90.9), and a deletion at 11q14.1 (P = 5.7 × 10(-4), OR = 33.8, Cl = 3.3-1651). Two SNPs within the 22 CNVRs show significant genotypic association with endometriosis after adjusting for multiple testing; rs758316 in DPP6 on 7q36.2 (P = 0.0045) and rs4837864 in ASTN2 on 9q33.1 (P = 0.0002). Together, the CNV-loci are detected in 6.9% of affected women compared to 2.1% in the general population.

Dataset Information

Partial LPL deletions: rare copy-number variants contributing towards severe hypertriglyceridemia.

Publications

Partial <i>LPL</i> deletions: rare copy-number variants contributing towards severe hypertriglyceridemia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets