Familial Lipoprotein Lipase Deficiency via the LPL Gene

Familial lipoprotein lipase (LPL) deficiency (Hyperlipoproteinemia Type 1) is characterized by very severe hypertriglyceridemia with episodes of recurrent abdominal pain, acute pancreatitis, eruptive cutaneous xanthomata, failure to thrive in infancy and hepatosplenomegaly. It usually manifests in early childhood (Blackett et al. 2013). Lipoprotein lipase is a critical enzyme in hydrolysation of serum triglycerides (TG) in chylomicrons (CM) and very low –density lipoproteins (VLDL). Deficiency of lipoprotein lipase prevents affected individuals from properly digesting certain fats and results in massive accumulation of fatty droplets called chylomicrons (chylomicronemia). The prevalence of lipoprotein lipase (LPL) deficiency is one in a million in the general population, with a carrier frequency in the French-Canadian population of 2.5% due to a founder effect (Rahalkar et al. 2009; Gagné et al. 1989).

Familial Lipoprotein Lipase Deficiency is an autosomal recessive disorder caused by pathogenic variants in LPL. LPL contains 10 exons, encodes 475 amino acids, and spans over 30 kb in Chromosome 8p22 (Monsalve et al. 1990). LPL encodes Lipoprotein Lipase, which is expressed in adipose tissue, skeletal muscle, kidney, intestine and neonatal liver (Siafakas et al. 1999). Causative variants in LPL decrease lipoprotein lipase activity interrupting lipid metabolism. Although missense variants are most common, splicing, nonsense, deletion, duplication and large rearrangement variants have also been reported (Human Gene Mutation Database).

Clinical sensitivity is expected to be high as LPL is the only known causative gene for Familial Lipoprotein Lipase Deficiency (Brunzell 2011). In addition, sequencing analysis detects ~97% of pathogenic variants while deletion/duplication analysis detects ~3% of causative variants (Brunzell 2011).

This test provides full coverage of all coding exons of the LPL gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.