The Genetic Spectrum of Familial Hypertriglyceridemia in Oman

Abstract

Familial hypertriglyceridemia (F-HTG) is an autosomal disorder that causes severe elevation of serum triglyceride levels. It is caused by genetic alterations in LPL, APOC2, APOA5, LMF1, and GPIHBP1 genes. The mutation spectrum of F-HTG in Arabic populations is limited. Here, we report the genetic spectrum of six families of F-HTG of Arab ancestry in Oman. Methods: six Omani families affected with triglyceride levels >11.2 mmol/L were included in this study. Ampli-Seq sequencing of the selected gene panels was performed. Whole-exome sequencing and copy number variant analysis were also performed in cases with negative exome results. Three novel pathogenic missense variants in the LPL gene were identified, p.M328T, p.H229L, and p.S286G, along with a novel splice variant c.1322+15T > G. The LPL p.H229L variant existed in double heterozygous mutation with the APOA5 gene p.V153M variant. One family had a homozygous mutation in the LMF1 gene (c.G107A; p.G36D) and a heterozygous mutation in the LPL gene (c.G106A; p.D36N). All affected subjects did not have a serum deficiency of LPL protein. Genetic analysis in one family did not show any pathogenic variants even after whole-exome sequencing. These novel LPL and APOA5 mutations are not reported in other ethnic groups. This suggests that patients with F-HTG in Oman have a founder effect and are genetically unique. This warrants further analysis of patients of F-HTG in the Middle East for preventative and counseling purposes to limit the spread of the disease in a population of high consanguinity.

Current Understanding on the Genetic Basis of Key Metabolic Disorders: A Review

“…More than 200 mutations have been documented within the 30 kb LPL gene, which consists of 10 exons and encodes a protein of 475 amino acids with a 27 amino acid signal peptide, with only a limited number having been evaluated for pathogenesis [ 122 ]. A study conducted in Oman in a consanguine population revealed an association between F-HTG and alteration in multiple genes, which included LPL as well as APOC2, APOA5, GPIHPB1, and LMF1, implying that the genetic disorder is polygenic [ 123 ]; this finding has been supported by evidence from China, which indicates that the severity of F-HTG is digenic [ 124 ] and is likely to involve several molecular mechanisms, including splice-site variation [ 125 ]. The treatment of F-HTG focuses on the reduction of low-density lipoprotein (LDL) cholesterol levels, followed by management of non–high-density lipoprotein cholesterol levels; this can be achieved by changes in lifestyle and dietary modifications [ 126 ] or by the administration of statins such as Atorvastatin, Lovastatin, Fluvastatin, Pravastatin Rosuvastatin and Simvastatin [ 127 ].…”