TY - JOUR
T1 - Identification of Novel and Known LDLR Variants Triggering Severe Familial Hypercholesterolemia in Saudi Families
AU - Alnouri, Fahad
AU - Al-Allaf, Faisal A
AU - Athar, Mohammad
AU - Al-Rasadi, Khalid
AU - Alammari, Dalal
AU - Alanazi, Menwar
AU - Abduljaleel, Zainularifeen
AU - Awan, Zuhier
AU - Bouazzaoui, Abdellatif
AU - Dairi, Ghida
AU - Elbjeirami, Wafa M
AU - Karra, Hussam
AU - Kinsara, Abdulhalim J
AU - Taher, Mohiuddin M
N1 - Publisher Copyright:
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
PY - 2022/7/1
Y1 - 2022/7/1
N2 - BACKGROUND: Familial hypercholesterolemia (FH) is a common illness mainly caused by variants occurring in the low-density lipoprotein receptor (LDLR) gene. FH is a leading cause of coronary artery disease. OBJECTIVE: This study aims to determine genetic defect(s) in homozygous and heterozygous FH index patients and their first-degree blood relatives and understand the genotype-phenotype correlation. METHODS: This study employed the genetic screening of FH-related genes by next-generation sequencing and cascade screening by capillary sequencing. RESULTS: We identified the presence of a novel frameshift variant [c.335_336insCGAG, p.(F114Rfs*17)] and three known missense variants [c.622G>A, p.(E208K)], [c.1474G>A, p.(D492N)], [c.1429G>A, p.(D477N)] in the LDLR gene of four unrelated Saudi families with FH. In proband 1, a nonsense variant c.1421C>G, p.(S474*) was also detected at exon 9 of the lipoprotein lipase gene. The segregation arrangement of the identified variants corresponded with the clinical characteristics. In this study, all the detected variants were confined in the ligand-binding domain and epidermal growth factor (EGF)-precursor homology domain of the LDLR protein, which portrayed severe clinical phenotypes of FH. Moreover, these LDLR variants were in a highly conserved residue of the proteins. CONCLUSION: In addition to the finding of the novel variant in the LDLR gene that extends the spectrum of variants causing FH, the results of this study also support the need for diagnostic screening and cascade genetic testing of this high-risk condition and to understand the genotype-phenotype correlation, which could lead to better prevention of coronary artery disease.
AB - BACKGROUND: Familial hypercholesterolemia (FH) is a common illness mainly caused by variants occurring in the low-density lipoprotein receptor (LDLR) gene. FH is a leading cause of coronary artery disease. OBJECTIVE: This study aims to determine genetic defect(s) in homozygous and heterozygous FH index patients and their first-degree blood relatives and understand the genotype-phenotype correlation. METHODS: This study employed the genetic screening of FH-related genes by next-generation sequencing and cascade screening by capillary sequencing. RESULTS: We identified the presence of a novel frameshift variant [c.335_336insCGAG, p.(F114Rfs*17)] and three known missense variants [c.622G>A, p.(E208K)], [c.1474G>A, p.(D492N)], [c.1429G>A, p.(D477N)] in the LDLR gene of four unrelated Saudi families with FH. In proband 1, a nonsense variant c.1421C>G, p.(S474*) was also detected at exon 9 of the lipoprotein lipase gene. The segregation arrangement of the identified variants corresponded with the clinical characteristics. In this study, all the detected variants were confined in the ligand-binding domain and epidermal growth factor (EGF)-precursor homology domain of the LDLR protein, which portrayed severe clinical phenotypes of FH. Moreover, these LDLR variants were in a highly conserved residue of the proteins. CONCLUSION: In addition to the finding of the novel variant in the LDLR gene that extends the spectrum of variants causing FH, the results of this study also support the need for diagnostic screening and cascade genetic testing of this high-risk condition and to understand the genotype-phenotype correlation, which could lead to better prevention of coronary artery disease.
KW - coronary artery disease
KW - low-density lipoprotein receptor
KW - next-generation sequencing
KW - variant
KW - cholesterol
KW - Familial hypercholesterolemia
KW - Hyperlipoproteinemia Type II/diagnosis
KW - Humans
KW - Saudi Arabia/epidemiology
KW - Coronary Artery Disease/diagnosis
KW - Homozygote
KW - Phenotype
KW - Mutation
KW - Receptors, LDL/genetics
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UR - https://www.mendeley.com/catalogue/21015fff-ec55-3f78-97e8-1ecb69f33b45/
U2 - 10.2174/1570161120666220304101606
DO - 10.2174/1570161120666220304101606
M3 - Article
C2 - 35249492
SN - 1570-1611
VL - 20
SP - 361
EP - 369
JO - Current Vascular Pharmacology
JF - Current Vascular Pharmacology
IS - 4
ER -