Abstract #1402734: Next Generation Sequencing Testing for Genetic Causes of Refractory Hypertriglyceridemia in an Outpatient Endocrine Clinic: A Case Series

Abstract

Endocrinologists often diagnose and treat patients with Hypertriglyceridemia (HTG), but genetic causes like Familial Chylomicronemia Syndrome (FCS) and Multifactorial Chylomicronemia Syndrome (MCS) can be missed in everyday practice. These are caused by mutations in the Lipoprotein Lipase (LPL) gene or genes required for the LPL activity and present with treatment-refractory elevated fasting Triglycerides (TRGs) and recurrent episodes of abdominal pain and/or acute pancreatitis (AP). By testing patients with refractory HTG for genetic variations linked to these syndromes we aimed to offer timely diagnosis and create more personalized treatment plans. Here, we strive to raise awareness over the importance of genetic testing in preventing HTG-related complications. Using Next Generation Sequencing we tested 7 patients presenting in an outpatient endocrine clinic with fasting TRGs above 500 mg/dl for mutations of 7 genes linked to HTG. None of the patients responded to treatment with at least 3 lipid-lowering drug classes and all reported recurrent abdominal pain, while 3 had history of at least 1 episode of AP. Genetic variants of MCS or FCS were found in 5 patients. Three patients had genotypes consistent with MCS, one being heterozygous for a risk mutation (C.-3A >G) of the Apolipoprotein A-V (APOA5) gene, and 2 heterozygous for a likely pathogenic allele (c.888delA and c.823C >T) of the same gene. Two patients had genotypes consistent with FCS, one compound heterozygous for 2 risk mutations of the APOA5 gene, and the other homozygous for a pathogenic variant (c.111delC) of the same gene. Interestingly, all the discovered mutations affected the APOA5 gene, responsible for enhancing the LPL activity, and none the LPL gene, the most common gene linked to FCS. Regarding treatment, strict low-fat diet lowered TRGs more than escalation of medical therapy in 4 patients. In outpatient endocrine clinics, patients with HTG often have a complicated comorbidity profile, which may lead providers to underestimate the potential genetic cause of HTG. A definitive diagnosis could relieve patients from the psychological burden of uncertainty. The diagnosis of genetic HTG makes a personalized treatment plan focusing on strict low-fat diet imperative in preventing complications. This can also help avoid unnecessary polypharmacy. Moreover, the need for more effective medications for FCS and MCS becomes clear. With new genetic treatments under development, the APOA5 gene could be a potential target. Hence, testing for genetic HTG can qualify patients to participate in relevant clinical trials and can direct the treatment towards these medications once they become available.