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Published on: September 15, 2018
Variable phenotype associated with compound LDLR gene mutations in familial hypercholesterolemia patients: Case
Noor Alicezah Mohd Kasim1,2, Yung-An Chua1,3, Siti Hamimah Sheikh Abdul Kadir1,3
1Cardiovascular Advancement and Research Excellence Institute (CARE Institute), Universiti Teknologi MARA, Selangor, Malaysia.
Insights
Homozygous familial hypercholesterolemia (HoFH) can present with variable symptoms due to compound LDL receptor (LDLR) mutations. Novel LDLR variants in exon 18 may lead to milder hypercholesterolemia and atypical clinical features in HoFH patients.
Area of Science:
- Genetics
- Cardiology
- Biochemistry
Background:
- Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extremely high LDL cholesterol (LDL-C) and premature cardiovascular disease.
- It is typically caused by mutations in the LDL receptor (LDLR) gene, leading to impaired LDL-C clearance.
- This report details two unrelated HoFH cases with compound LDLR mutations, presenting with atypical clinical manifestations.
Purpose of the Study:
- To report two rare cases of HoFH with compound LDLR mutations.
- To investigate the genotype-phenotype correlation in these patients.
- To highlight the importance of recognizing variability in HoFH presentation.
Main Methods:
- Case identification through family cascade and routine screening.
- Comprehensive lipid profiling.
- Next-generation sequencing of FH-related genes, including LDLR, APOB, PCSK9, ABCG5, and ABCG8.
- Classification of novel LDLR variants according to ACMG guidelines.
Main Results:
- Two novel compound LDLR variants in exon 18 were identified: c.2548-1_2548delGAinsTC (pathogenic) and c.2556_2557insTCAGTCTGG (p.Leu853Serfs*12; likely pathogenic).
- Case 1 was homozygous for both variants; Case 2 was homozygous for the splice-site variant and heterozygous for the frameshift variant.
- Despite biallelic LDLR variants, both patients exhibited relatively milder hypercholesterolemia and lacked classical HoFH stigmata like tendon xanthomas.
Conclusions:
- LDLR variants in exon 18, affecting the cytoplasmic tail, may be associated with attenuated clinical expression in HoFH.
- Genotype-phenotype variability in HoFH necessitates careful consideration for accurate diagnosis and management.
- Individualized risk stratification and treatment strategies are crucial for patients with HoFH.
Rationale:
Homozygous familial hypercholesterolemia (HoFH) is a rare inherited disorder with an extremely elevated level of low-density lipoprotein (LDL) cholesterol (LDL-C) and accelerated premature coronary artery disease (PCAD). It is primarily caused by a single pathogenic variant of the LDL receptor (LDLR) gene. This report presents 2 rare and unrelated cases of HoFH with compound LDLR mutations. These 2 individuals presented with atypical clinical features and demonstrated variable degrees of hypercholesterolemia.
Patient Concerns:
Case 1 is a 36-year-old Malay woman identified during family cascade screening with a pretreated LDL-C of 8.5 mmol/L and a strong family history of PCAD. Case 2 is a 58-year-old Indian woman discovered to have a pretreated LDL-C of 5.2 mmol/L during routine health screening, without a significant family history of hypercholesterolemia or PCAD. Neither patient demonstrated tendon xanthomas or other lipid stigmata.
Diagnoses:
Both patients underwent lipid profiling and targeted next-generation sequencing of FH-related genes (LDLR, APOB, PCSK9, ABCG5, and ABCG8). Two novel LDLR variants were identified in exon 18: c.2548-1_2548delGAinsTC (pathogenic) and c.2556_2557insTCAGTCTGG (p.Leu853Serfs*12; likely pathogenic) and classified according to American College of Medical Genetics and Genomics guidelines. Case 1 was homozygous for both variants, while Case 2 was homozygous for the splice-site variant and heterozygous for the frameshift variant.
Interventions:
Both patients received guideline-directed lipid-lowering therapy and ongoing cardiovascular risk management.
Outcomes:
Despite biallelic LDLR variants, both patients demonstrated relatively milder hypercholesterolemia and absence of classical HoFH stigmata.
Lessons:
The LDLR variants located in exon 18 affecting the cytoplasmic tail domain may be associated with attenuated clinical expression. Recognition of genotype-phenotype variability is crucial for accurate diagnosis, risk stratification, and individualized management of HoFH.
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