Familial LCAT Deficiency and Low HDL-C Levels: In silico Characterization of Two Rare LCAT Missense Mutations

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TL;DR

This paper reports the first genetically confirmed case of familial LCAT deficiency (FLD) in Colombia, a 46-year-old woman with corneal opacity, low HDL-C (as low as 2.8 mg/dL), and two compound heterozygous LCAT mutations (Arg123Pro and Arg268His). In silico analyses predicted both mutations are deleterious, destabilizing the protein and impairing enzyme function. The case highlights the clinical heterogeneity of FLD, as the patient lacked renal failure or splenomegaly, and underscores the need for cardiovascular risk monitoring.

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**Background:** Familial LCAT deficiency (FLD) and Fish Eye Disease (FED) are rare autosomal recessive disorders caused by mutations in the LCAT gene, which encodes lecithin-cholesterol acyltransferase. This enzyme esterifies unesterified cholesterol in plasma, enabling HDL maturation and reverse cholesterol transport. FLD results from complete loss of both alpha and beta LCAT activity, leading to corneal opacities, very low HDL-C, anemia, proteinuria, and progressive renal failure. FED retains some beta activity, causing milder symptoms. The prevalence of LCAT mutations is below 1/1,000,000, and 2–9% of individuals with extremely low HDL-C have some LCAT deficiency. This study describes the first clinically and genetically confirmed FLD case in Colombia, a 46-year-old woman with two compound heterozygous LCAT missense variants.

**Methods:** Blood samples were collected from the proband and family members. Genomic DNA was extracted using the QIAamp DNA Mini Kit. Long PCR amplified a 6336 bp fragment covering all LCAT exons, followed by Sanger sequencing of all six exons. Two missense variants were identified: c.368G>C (p.Arg123Pro) and c.803G>A (p.Arg268His). In silico prediction tools (SIFT, PolyPhen-2, I-mutant 2.0, CADD, and HOPE) assessed the impact of these mutations on protein structure and function. Variant classification followed ACMG guidelines.

**Key Results:** The proband, a 46-year-old Colombian woman, presented with bilateral corneal opacity since age 10, progressive night vision deterioration, and no visual acuity alteration. She had hypothyroidism (diagnosed at age 30, TSH 9.09 mUI/mL), chronic dyslipidemia with persistently low HDL-C (as low as 2.8 mg/dL), high triglycerides (216 mg/dL), low Apo-A1 (34.6 mg/dL), total cholesterol 95.0 mg/dL, non-HDL cholesterol 92.2 mg/dL, VLDL 30 mg/dL, and LDL-C 43 mg/dL. Lipoprotein electrophoresis showed hypoalphalipoproteinemia (14.4% of total band) and increased beta fraction (78.6%). Esterified cholesterol was only 6% of total cholesterol (reference 60–80%). She had episodes of anemia in 2018 and 2019, hypercalciuria (31.86 mg/dL), and hypercalcemia (10.30 mg/dL), but no proteinuria, splenomegaly, or renal failure. Coronary CT showed no calcified plaques (calcium score 0 Agatston units). Two of her three brothers had recurrent low HDL-C (15–16 mg/dL). Genetic analysis revealed two compound heterozygous LCAT mutations: c.368G>C (p.Arg123Pro) inherited from her mother, and c.803G>A (p.Arg268His) inherited from her father. Both variants were classified as pathogenic by ACMG criteria. In silico predictions: Arg123Pro – SIFT 0.018 (deleterious), PolyPhen-2 1.0, I-mutant ΔG = −1.60 (decreased stability), CADD 26.5; Arg268His – SIFT 0.0, PolyPhen-2 1.0, I-mutant ΔG = −1.05, CADD 28.5. HOPE predicted physicochemical changes and loss of interactions for both. Arg123Pro is in the membrane-binding region; Arg268His is in the cap domain/lid region (residues 257–271), which controls access to the catalytic site and interacts with Apo-AI.

**Clinical Implications:** This is the first FLD case reported in Colombia and the first compound heterozygote for Arg123Pro and Arg268His. The patient’s early-onset corneal opacity (age 10) and lack of renal failure or splenomegaly illustrate the clinical heterogeneity of LCAT deficiency. The Arg123Pro mutation was previously described in a homozygous Spanish woman with proteinuria and renal lesions, but our patient had no renal compromise, suggesting additional genetic or environmental modifiers. The Arg268His mutation is known to cause FLD in compound heterozygotes. Both mutations likely impair LCAT function by destabilizing the protein and disrupting interactions critical for enzyme activity and HDL binding. Despite very low HDL-C, the patient had no coronary atherosclerosis at age 46, but remains at risk (median age of cardiovascular disease in LCAT deficiency is 56 years). This case emphasizes the need for cardiovascular risk monitoring and potential statin therapy. It also highlights the diagnostic challenges in differentiating FLD from FED without specialized assays (alpha/beta LCAT activity, CE/TC ratio), which are unavailable in many clinical settings. The report expands the mutational spectrum of LCAT deficiency and underscores the importance of genetic testing in patients with unexplained corneal opacities and very low HDL-C, particularly in Latin America.