Fish-Eye Disease and Norum Disease via the LCAT Gene

Fish eye disease (FED) is due to the deficiency of plasma lecithin-cholesterol acyltransferase (alpha-LCAT deficiency) and is referred to as incomplete or partial LCAT deficiency. FED is characterized by severe corneal opacities due to abnormal corneal lipid deposition, causing impaired vision which eventually leads to blindness. Other symptoms include dyslipoproteinaemia, which is characterized by increased levels of very low and low density lipoproteins (VLDL and LDL) and a 90% reduction in the level of high-density lipoprotein (HDL) (Carlson 1982; Carlson and Philipson 1979).

Clinically, FED differs from other familial conditions with deficiency of HDL such as Tangier disease, Milano-AI-apoprotein disease, and familial LCAT-deficiency (FLD) (due to alpha- and beta-LCAT deficiency referred as complete LCAT deficiency, also known as Norum disease). FLD is a severe form of disease and apart from corneal opacification patients present with normochromic anemia and progressive renal failure (by 4th to 5th decade) (Carlson 1982).

FED and FLD are autosomal recessive disorders. Both are due to homozygous or compound heterozygous pathogenic variants in LCAT (Holleboom et al. 2011). Missense variants dispersed in different regions of the LCAT gene were reported in both FLD and FED cases, which suggests several functionally important structural domains (Funke et al. 1993). Looking at the documented pathogenic variants in the Human Gene Mutation Database, protein truncating variants were reported in only FLD cases (HGMD). No other genotype-pyhentype correlations have been reported. LCAT pathogenic variants were highly prevalent in patients with low HDL cholesterol levels in the Netherlands due to the founder mutation p.Thr147Ile (Holleboom et al. 2011). So far, over 100 pathogenic variants (missense, nonsense, splicing, small and gross deletions and duplications and small indels) have been reported in LCAT (HGMD).

LCAT encodes a highly conserved enzyme lecithin:cholesterol acyltransferase (LCAT) that catalyzes the formation of most plasma cholesterol ester and plays an important role in the reverse transport of cholesterol from peripheral tissue to the liver (Maeda et al. 1991).

A mutation screening in Netherlands patients with low HDL levels identified LCAT pathogenic variants in 29% (28 of the 98) of patients and 18 of them carried the same variant (p.Thr147Ile), suggesting that it is a founder mutation (Holleboom et al. 2011).

This test provides full coverage of all coding exons of the LCAT gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).