期刊
CLINICAL GENETICS
卷 100, 期 5, 页码 529-541出版社
WILEY
DOI: 10.1111/cge.14036
关键词
genotype-phenotype correlation; homozygous familial hypercholesterolemia; null variant; pathogenic variant; pediatric FH; variant cluster
资金
- Amgen
This study conducted a retrospective analysis on 528 genetically screened patients, revealing a gradual increase in LDL-cholesterol levels with different genetic statuses. The results highlight the importance of genetic diagnosis in FH patients.
Familial hypercholesterolemia (FH) is the most common genetic disease caused by variants in LDLR, APOB, PCSK9 genes; it is characterized by high levels of LDL-cholesterol and premature cardiovascular disease. We aim to perform a retrospective analysis of a genetically screened population (528 unrelated patients-342 adults and 186 children) to evaluate the biochemical and clinical correlations with the different genetic statuses. Genetic screening was performed by traditional sequencing and some patients were re-analyzed by next-generation-sequencing. Pathogenic variants, mainly missense in the LDLR gene, were identified in 402/528 patients (76.1%), including 4 homozygotes, 17 compound heterozygotes and 1 double heterozygotes. A gradual increase of LDL-cholesterol was observed from patients without pathogenic variants to patients with a defective variant, to patients with a null variant and to patients with two variants. Six variants accounted for 51% of patients; a large variability of LDL-cholesterol was observed among patients carrying the same variant. The frequency of pathogenic variants gradually increased from unlikely FH to definite FH, according to the Dutch Lipid Clinic Network criteria. Genetic diagnosis can help prognostic evaluation of FH patients, discriminating between the different genetic statuses or variant types. Clinical suspicion of FH should be considered even if few symptoms are present or if LDL-cholesterol is only mildly increased.
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