Saudi Familial Hypercholesterolemia Patients With Rare LDLR Stop Gain Variant Showed Variable Clinical Phenotype and Resistance to Multiple Drug Regimen.

Zuhier Ahmed Awan,Robert A Hegele,Bandar Ali Al-Shehri,Babajan Banaganapalli,Kaiser Jamil,Jumana Y Al-Aama,Omran M Rashidi,Noor A Shaik,Ramu Elango

doi:10.3389/fmed.2021.694668

Zuhier Ahmed Awan, Robert A Hegele + Show 7 more

Open Access

https://doi.org/10.3389/fmed.2021.694668

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Abstract

Familial hypercholesterolemia (FH), a well-known lipid disease caused by inherited genetic defects in cholesterol uptake and metabolism is underdiagnosed in many countries including Saudi Arabia. The present study aims to identify the molecular basis of severe clinical manifestations of FH patients from unrelated Saudi consanguineous families. Two Saudi families with multiple FH patients fulfilling the combined FH diagnostic criteria of Simon Broome Register, and the Dutch Lipid Clinic Network (DLCN) were recruited. LipidSeq, a targeted resequencing panel for monogenic dyslipidemias, was used to identify causative pathogenic mutation in these two families and in 92 unrelated FH cases. Twelve FH patients from two unrelated families were sharing a very rare, pathogenic and founder LDLR stop gain mutation i.e., c.2027delG (p.Gly676Alafs*33) in both the homozygous or heterozygous states, but not in unrelated patients. Based on the variant zygosity, a marked phenotypic heterogeneity in terms of LDL-C levels, clinical presentations and resistance to anti-lipid treatment regimen (ACE inhibitors, β-blockers, ezetimibe, statins) of the FH patients was observed. This loss-of-function mutation is predicted to alter the free energy dynamics of the transcribed RNA, leading to its instability. Protein structural mapping has predicted that this non-sense mutation eliminates key functional domains in LDLR, which are essential for the receptor recycling and LDL particle binding. In conclusion, by combining genetics and structural bioinformatics approaches, this study identified and characterized a very rare FH causative LDLR pathogenic variant determining both clinical presentation and resistance to anti-lipid drug treatment.

Highlights

Familial hypercholesterolemia (FH) (OMIM 143890) is a relatively common metabolic disease in which patients demonstrate life-long elevation of plasma low-density lipoprotein (LDL) cholesterol [1]
We show that LipidSeq targeted resequencing panel for monogenic dyslipidemias, can effectively detect FH causative LDLR founder variant (c.2027delG) in genetically isolated populations like Saudi Arabians
All classical manifestations of FH were present including bilateral large Achilles tendon xanthomas, huge cholesterol depositions around both mid-thighs, severe bilateral eye xanthelasma and corneal arcus, and bilateral multiple extensor tendon xanthomas on hands. His biochemical profile revealed on an average high level of total cholesterol (15.18 ± 1.33 mmol/L), LDL-C (12.98 ± 2.08 mmol/L) and normal triglycerides (0.81 ± 0.16 mmol/L) (Table 1)

Summary

Introduction

FH (OMIM 143890) is a relatively common metabolic disease in which patients demonstrate life-long elevation of plasma low-density lipoprotein (LDL) cholesterol [1]. If left untreated, modified LDL particles enter arterial wall macrophages contributing to plaque formation, within coronary arteries leading to premature development of coronary heart disease (CHD) [2]. Cholesterol-laden macrophages lead to formation of atheromatous plaques, and extensor tendon xanthomas (e.g., Achilles and fingers), xanthelasmata (yellow deposit underneath the skin of upper and lower eyelids), and arcus cornealis (cholesterol ring accumulating at the edge of the cornea) [3]. Diagnosis rates of FH are quite high among individuals who have a positive family history of premature CHD or hypercholesterolemia [7]

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