INCREASING DIAGNOSTIC YIELD FOR INHERITED LIPIDEMIAS: NEXT-GENERATION SEQUENCING OF AN EXPANDED PANEL TAP TO RETURN Gregory Kellogg, Alex Bisignano, and Malgorzata Jaremko TO KIOSK MENU Phosphorus Diagnostics, New York, NY Introduction: Yield of Expanded Panel In Disease Causing Variants in Indication for Testing in Patients The diagnosis of inherited lipid disorders is Patients Undergoing Inherited Non-Familial with Mutations in Non-Familial complicated by clinical overlap between syndromes, Lipid Testing Hypercholesterolemia Related Hypercholesterolemia Related contributions of lifestyle and environment, and a Genes Genes spectrum of genetic risk, ranging from monogenic LDLR Not FH Gene Variant Disease Mendelian disease to polygenic risk. Targeted genetic 13% Related testing based only on clinical and biochemical 7% c.1336C>T phenotype can therefore be difficult due to these ABCG5 Sitosterolemia (p.Arg446Ter) confounding variables. Multi-gene panel testing has been demonstrated to be an effective method of c.1166G>A ABCG5 Sitosterolemia increasing diagnostic yield in inherited cancers and (p.Arg389His) other clinical specialties, and could therefore be c.547delC useful in inherited lipidemia testing. ABCG8 Images Sitosterolemia (p.Gln183fs) No Object/Purpose: Pathogenic Exon 19-20 Hypobetalip- APOB Familial Hypercholesterolemia Other Variant del oproteinemia We sought to determine the yield of testing of a 80% In 5/6 patients in whom a mutation in a non-familial c.1214C>T hypercholesterolemia gene mutations was identified, the multi-gene panel associated with a spectrum of Hepatic lipase LIPC (p.Thr405Met indication for testing was familial hypercholesterolemia. inherited lipidemias in a consecutive series of deficiency ) patients referred for clinical testing. Conclusions: c.953A>G Results: Hypertriglyceridemia/lipop LPL (p.Asn318Ser The inheritance pattern of familial lipidemia is a Methods: rotein lipase deficiency ) spectrum, ranging from monogenic disease to • Pathogenic/Likely Pathogenic polygenic risk. Three patients were heterozygous Next-generation sequencing (NGS) analyzing a 21 carriers for autosomal recessive disease and a gene panel was performed on 91 consecutive variants were identified in 18 • Heterozygous ABCG5 variants fourth was compound heterozygous for variants patients referred for inherited lipidemia testing. patients. were identified in 2 patients. associated with two different recessive diseases, • LDLR variants associated with • One patient was compound indicating that carrier status may contribute to familial hypercholesterolemia (FH) the phenotype in this patients. In two others, a heterozygous for an APOB Genes Assayed were identified in 12/91 (13.2%) variant in a gene not related to the primary variant and an ABCG8 variant. indication for testing was identified, further patients. ABCA1, ABCG5, ABCG8, ANGPTL3, APOA1, • Two patients carried the same indicating that variants in other genes may APOA5, APOB, APOC2, APOC3, CYP27A1, • Pathogenic/Likely Pathogenic contribute to the phenotype of patients clinically LPL variant. GPD1, GPIHBP1, LCAT, LDLR, LDLRAP1, LIPA, variants in genes not related to diagnosed with FH. In summary, NGS for an • One patient was heterozygous LIPC, LMF1, LPL, PCSK9, SAR1B familial hypercholesterolemia were expanded panel of lipid disorders can identify for a variant in LIPC. variants that contribute to patient phenotype and identified in 6 patients. and is a cost-effective method of increasing diagnostic yield.