Original Article   

Panminerva Medica 2022 Mar 11

DOI: 10.23736/S0031-0808.22.04612-2

Copyright © 2022 EDIZIONI MINERVA MEDICA

lingua: Inglese

Identification and functional characterization of 2 Rare LDLR stop gain variants (p.C231* and p.R744*) in Saudi familial hypercholesterolemia patients

Zuhier AWAN ^{1, 2}, Alhanuf BATRAN ¹, Faisal A. AL-ALLAF ³, Raneem S. ALHARBI ², Gehan A. HEJAZY ¹, Bassam JAMALAIL ^{2, 4}, Majid AL MANSOURI ¹, Abdulhadi I. BIMA ¹, Haifa ALMUKADI ⁵, Hussam I. KUTBI ⁶, Ahmed EALTAYYAR ⁶, Babajan BANAGANAPALLI ^{4, 7}, Noor A. SHAIK ^{4, 7} ✉

¹ Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; ² Department of Genetics, Al Borg Medical Laboratories, Jeddah, Saudi Arabia; ³ Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia; ⁴ Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; ⁵ Department of Pharmacology & Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; ⁶ Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaiziz University, Jeddah, Saudi Arabia; ⁷ Princess Al-Jawhara Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia

BACKGROUND: Familial hypercholesterolemia (FH) is a globally underdiagnosed inherited metabolic disorder. Owing to limited published data from Arab world, this study was conducted with the aim of identifying the genetic and molecular basis of FH in highly consanguineous Saudi population.
METHODS: We performed clinical screening, biochemical profiling, whole exome sequencing and variant segregation analysis of two Saudi FH families. Additionally, 500 normolipic individuals were screened to ensure the absence of FH variant in general Saudi population. Functional characterization of FH variants on secondary structure characteristics of RNA and protein molecules was performed using different bioinformatics modelling approaches.
RESULTS: WES analysis identified two independent rare LDLR gene stop gain variants (p.C231* and p.R744*) consistent to the clinical presentation of FH patients from two different families. RNAfold analysis has shown that both variants were predicted to disturb the free energy dynamics of LDLR mRNA molecule and destabilize its folding pattern and function. PSIPRED based structural modelling analysis has suggested that both variants bring drastic changes disturbing the secondary structural elements of LDLR molecule. The p.C231* and p.R744* variants are responsible for partial or no protein product, thus they are class 1 variants causing loss of function (LoF) LDLR variants.
CONCLUSIONS: This study highlights the effectiveness of the WES, sanger sequencing, and computational analysis in expanding FH variant spectrum in culturally distinct populations like Saudi Arabia. Genetic testing of FH patients is very essential in better clinical diagnosis, screening, treatment, and management and prevention of cardiovascular disease burden in the society.

KEY WORDS: Familial hypercholesterolemia; Exome sequencing; LDLR; mRNA