Lipoprotein lipase deficiency: heterozygotes match homozygotes in severity

Biallelic pathogenic variants in the LPL gene are associated with familial lipoprotein lipase (LPL) deficiency. Homozygotes exhibit very severe hypertriglyceridemia (HTG) already in childhood, with phenotypic features such as pancreatitis, abdominal pain and xanthomata. Recent studies showed that HTG levels varied greatly between monoallelic LPL pathogenic/likely pathogenic variant carriers. The aim of our study was to investigate whether heterozygotes for pathogenic variants in the LPL gene in the Polish population may have clinical symptoms and, if so, to what extent.

Genetic data were derived from a Polish cohort of 5623 whole exome sequenced patients. In 52 cases the indication for WES genetic testing was "hypertriglyceridemia '' and for 5571 there was another clinical indication, mainly autism spectrum disorder, dysmorphia and neurodegenerative diseases.

We present 22 heterozygous and 2 homozygous/compound heterozygous individuals for the pathogenic/likely pathogenic LPL variant and describe HTG levels, phenotypic manifestations and age of onset in the context of molecular findings where available. We report for the first time heterozygous LPL individuals with very severe HTG (TG ≥ 22.6 mmol/l; > 2000 mg/dl) and additional symptoms such as pancreatitis and recurrent abdominal pain.

We argue that although the individuals carrying the single LPL pathogenic/likely pathogenic variant display the whole disease spectrum, the severe phenotype of heterozygotes with dominantly inherited LPL-related HTG may also exist.