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Difficulty: MediumGenetic and Molecular Mechanisms

A 32-year-old man comes to the clinic to review the results of his recent laboratory tests. He originally presented for a well-patient examination, during which firm, nodular masses were noted on his bilateral Achilles tendons. A fasting lipid panel at that time showed a low-density lipoprotein (LDL) cholesterol level of 315 mg/dL. Due to a strong family history of early-onset coronary artery disease, he was referred for targeted genetic testing. The results reveal a heterozygous gain-of-function mutation in the PCSK9 gene.

During the visit, the patient mentions that his maternal cousin, who is 35 years old, has the identical clinical phenotype consisting of tendon xanthomas and severely elevated LDL cholesterol levels. The cousin also recently underwent targeted genetic testing, but his results showed a heterozygous loss-of-function mutation in the LDLR gene.

Which of the following genetic principles best explains the presence of an identical clinical phenotype in these two relatives despite having mutations in entirely different genes?

  1. Locus heterogeneityAnswer
  2. B
    Allelic heterogeneity
  3. C
    Pleiotropy
  4. D
    Variable expressivity
  5. E
    Incomplete penetrance

Answer

Locus heterogeneity
The correct answer is locus heterogeneity. This genetic principle describes a scenario in which a single clinical disease (phenotype) is caused by genetic mutations occurring at completely different loci (i.e., distinct, separate genes). Familial Hypercholesterolemia is a classic example of locus heterogeneity; it can result from loss-of-function mutations in the LDLR gene (which normally clears LDL from the blood), loss-of-function mutations in the APOB gene (which prevents LDL from binding the receptor), or gain-of-function mutations in the PCSK9 gene (which abnormally increases the degradation of LDL receptors). Because the patient and his cousin have the identical clinical presentation resulting from mutations in two different genes, locus heterogeneity is the correct principle.

Step-by-Step Solution

1
Analyze the clinical presentation of the patient and his cousin.
Both individuals have tendon xanthomas, severely elevated LDL cholesterol, and a family history of early-onset coronary artery disease, which defines the clinical phenotype of Familial Hypercholesterolemia.
Establishing that both patients have the exact same clinical condition is the first step in comparing their genetic backgrounds.
2
Compare the specific genetic testing results of both individuals.
The patient has a mutation in the PCSK9 gene, while the cousin has a mutation in the LDLR gene.
Identifying that the mutations reside in two entirely distinct, separate genes is necessary to define the correct genetic principle.
3
Match the clinical and genetic findings to the defining characteristics of genetic principles.
The occurrence of an identical disease phenotype caused by mutations at completely different genetic loci defines locus heterogeneity.
This confirms the underlying genetic mechanism responsible for the familial presentation.

Key Concept

Locus heterogeneity occurs when a single clinical disorder can be caused by mutations in multiple, distinct genes.
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Topics

Genetic and Molecular Mechanisms

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