Variant Analysis in LDLR Gene Uncovers Genetic Basis of Familial Hypercholesterolemia: A Case Report
Correspondence Address :
Dr. Pratiksha Rakesh Chheda,
Lead Molecular Biologist, Department of Genomics, Sir H.N. Reliance Foundation Hospital and Research Centre, Prarthana Samaj, Raja Ram Mohan Roy Road, Girgaon, Mumbai-400004, Maharashtra, India.
E-mail: pratiksha.chheda@rfhospital.org
Familial Hypercholesterolemia (FH) is a hereditary disorder characterised by elevated blood cholesterol levels, predominantly Low-density Lipoprotein Cholesterol (LDL-C). This condition poses a significant risk for early-onset atherosclerotic cardiovascular diseases. A critical step toward effective clinical management is the precise identification of pathogenic variants responsible for FH. The present study aimed to unravel the genetic cause of FH through comprehensive variant effect prediction and comparison with clinical manifestations in a nine-year-old girl with hyperlipidemia. Whole Exome Sequencing (WES) was performed on the proband, and a set of three key genes associated with hyperlipidemia {Apolipoprotein E (APOE), Low -density Lipoprotein Receptors (LDLR), Proprotein Convertase Subtilisin /Kexin type 9 (PCSK9)} were evaluated for the presence of pathogenic mutations. The data were meticulously analysed based on the American College of Medical Genetics (ACMG) guidelines for variant classification. The analysis revealed two pathogenic variations in the LDLR gene: c.1A>C (p.Met1Leu) in exon 1 and a splice site variant c.1187-10G>A in intron 8. Sanger sequencing of family members confirmed the presence of one mutation each in the father and mother, while a younger sibling also carried both pathogenic variants. Genetic testing confirmed Heterozygous FH (HeFH) in the parents and Homozygous FH (HoFH) in both siblings. Proper classification of genetic variants is crucial for informed clinical decision-making and patient management. The study provides valuable insights into the molecular basis of FH in an Indian patient and contributes to the growing knowledge of the LDLR gene mutation spectrum.
Coronary heart disease, Gene mutation, Low-density lipoprotein receptor, Whole exome sequencing
DOI: 10.7860/JCDR/2024/68636.19422
Date of Submission: Nov 17, 2023
Date of Peer Review: Dec 30, 2023
Date of Acceptance: Apr 05, 2024
Date of Publishing: May 01, 2024
AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. No
PLAGIARISM CHECKING METHODS:
• Plagiarism X-checker: Dec 21, 2023
• Manual Googling: Mar 30, 2024
• iThenticate Software: Apr 02, 2024 (180%)
ETYMOLOGY: Author Origin
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