Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency



Lipoprotein lipase (LPL) deficiency is a serious lipid disorder of severe hypertriglyceridemia (SHTG) with chylomicronemia. A large number of variants in the LPL gene have been reported but their influence on LPL activity and SHTG has not been completely analyzed. Gaining insight into the deleterious effect of the mutations is clinically essential.


We used gene sequencing followed by in-vivo/in-vitro and in-silico tools for classification. We classified 125 rare LPL mutations in 33 subjects thought to have LPL deficiency and in 314 subjects selected for very SHTG.


Of the 33 patients thought to have LPL deficiency, only 13 were homozygous or compound heterozygous for deleterious mutations in the LPL gene. Among the 314 very SHTG patients, 3 were compound heterozygous for pathogenic mutants. In a third group of 51,467 subjects, from a general population, carriers of common variants, Asp9Asn and Asn291Ser, were associated with mild increase in triglyceride levels (11%-35%).


In total, 39% of patients clinically diagnosed as LPL deficient had 2 deleterious variants. Three patients selected for very SHTG had LPL deficiency. The deleterious mutations associated with LPL deficiency will assist in the diagnosis and selection of patients as candidates for the presently approved LPL gene therapy.


Rodrigues R1, Artieda M2, Tejedor D2, Martínez A2, Konstantinova P3, Petry H3, Meyer C3, Corzo D3, Sundgreen C3, Klor HU4, Gouni-Berthold I5, Westphal S6, Steinhagen-Thiessen E7, Julius U8, Winkler K9, Stroes E10, Vogt A11, Hardt P12, Prophet H13, Otte B14, Nordestgaard BG15, Deeb SS16, Brunzell JD17

  • 1. Progenika Biopharma, Bizkaia, Spain. Electronic address:
  • 2. Progenika Biopharma, Bizkaia, Spain.
  • 3. uniQure NV, Amsterdam, The Netherlands.
  • 4. Director of the German HITRIG, Third Medical Department and Policlinic, Giessen University Hospital, Justus-Liebig-University of Giessen, Giessen, Germany.
  • 5. Center for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany.
  • 6. Institute of Clinical Chemistry, Lipid Clinic, Magdeburg, Germany.
  • 7. Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • 8. Universitätsklinikum Carl Gustav Carus an der Technischen Universität, Medizinische Klinik III, Dresden, Germany.
  • 9. Institute of Clinical Chemistry and Laboratory Medicine and Lipid Outpatient Clinic, University Hospital Freiburg, Freiburg, Germany.
  • 10. Department of Vascular Medicine, Amsterdam Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
  • 11. LMU Klinikum der Universität München, Medizinische Klinik und Poliklinik 4, München, Germany.
  • 12. Gießen and Marburg University Hospital, Giessen, Germany.
  • 13. Lipidambulanz, Rostock, Germany.
  • 14. Universitätsklinikum Münster, Medizinische Klinik D, Med. Clinic, Münster, Münster, Germany.
  • 15. Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 16. Department of Medicine (Division of Medical Genetics), University of Washington, Seattle, WA, USA; Department of Genome Sciences, University of Washington, Seattle, WA, USA.
  • 17. Department of Medicine (Division of Metabolism, Endocrinology and Nutrition), University of Washington, Seattle, WA, USA.


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