Pathogenicity analysis and functional prediction of a rare LDLR variant in familial hypercholesterolemia combined...

Wilson disease (WD) is a hereditary disorder characterized by abnormal copper metabolism. WD in the liver can result in dyslipidemia, typically manifesting as decreased lipid metabolism. Familial hypercholesterolemia (FH) is an inherited disorder with markedly elevated low-density lipoprotein cholesterol (LDL-C) levels and mainly attributed to disease-causing variants in the low-density lipoprotein receptor (LDLR) gene. LDLR c.599T > G (p.Phe200Cys) variant has neither been reported in WD with FH, nor has the pathogenicity study and function prediction of LDLR c.599T > G (p.Phe200Cys) variant been reported.

In this study, a pediatric patient with a body mass index (BMI) of 13.7, without fatty liver, presented with elevated transaminase and blood lipid levels (LDL-C 8.64 mmol/L). He was diagnosed with WD and probable FH. Despite treatment for WD, which reduced the patient's transaminase levels, blood lipid levels did not improve. We performed genetic testing, clinical surveys, pedigree analysis, and pathogenic identification to clarify the cause of the patient's dyslipidemia.

Clinical and biochemical data from the patient and seven family members were evaluated using the Dutch Lipid Clinic Network (DLCN) diagnostic criteria. Whole-exome and Sanger sequencing were used to explore dyslipidemia-related variants and validate candidate variants, respectively. Bioinformatics analysis was used to evaluate the pathogenicity of the candidate variant and its structure‒function relationship.

The patient was clinically diagnosed with definite FH, and his mother and eldest maternal uncle were clinically diagnosed with probable FH and possible FH, respectively. The three patients carried a rare LDLR c.599T > G (p.Phe200Cys) variant, which was classified according to the American College of Medical Genetics and Genomics guidelines as likely pathogenic. Bioinformatics analyses categorized this variant, located in the fifth LDL receptor type A (LA) modules of ligand-binding domain (LBD) and affecting the random coil structure of LDLR.

The LDLR c.599T > G (p.Phe200Cys) variant was associated with FH combined with WD, and the heterozygous variant site was considered likely pathogenic. The variant may affect the ligand-binding function of LDLR by altering the random coil structure.