A 42-year-old man presents to the cardiac catheterization lab with acute anterior STEMI. Examination reveals bilateral tendon xanthomas on the Achilles tendons, tuberous xanthomas on the elbows, xanthelasma, and corneal arcus. Lipid panel shows total cholesterol 412 mg/dL and LDL-C 332 mg/dL. His father died of MI at age 38, and his 14-year-old son has LDL-C of 280 mg/dL. Genetic testing confirms a heterozygous pathogenic mutation in the LDLR gene.

The inheritance pattern shown in the pedigree, marked as **A** in the diagram, is characterized by which of the following features?

Question

A 42-year-old man presents to the cardiac catheterization lab with acute anterior STEMI. Examination reveals bilateral tendon xanthomas on the Achilles tendons, tuberous xanthomas on the elbows, xanthelasma, and corneal arcus. Lipid panel shows total cholesterol 412 mg/dL and LDL-C 332 mg/dL. His father died of MI at age 38, and his 14-year-old son has LDL-C of 280 mg/dL. Genetic testing confirms a heterozygous pathogenic mutation in the LDLR gene.

The inheritance pattern shown in the pedigree, marked as **A** in the diagram, is characterized by which of the following features?

Accepted Answer

A. Heterozygotes have LDL-C 200–400 mg/dL with premature CAD in the 4th–5th decade; homozygotes have LDL-C >500 mg/dL with childhood MI; 50% offspring risk; male-to-male transmission present. ## Why option 1 is correct

The inheritance pattern marked **A** in the diagram represents **autosomal dominant codominant inheritance** characteristic of heterozygous familial hypercholesterolemia (HeFH). The clinical anchor is that heterozygotes have LDL-C in the 200–400 mg/dL range with premature CAD typically manifesting in the 4th–5th decade (as seen in this 42-year-old with STEMI and his brother with MI at 45). Homozygotes have LDL-C >500 mg/dL and present with childhood MI. The pedigree demonstrates vertical transmission over four generations, male-to-male transmission (confirming autosomal, not X-linked), and 50% offspring risk. The patient's 14-year-old son with LDL-C 280 mg/dL exemplifies childhood-onset hyperlipidemia in heterozygous offspring. This pattern is caused by >90% of familial hypercholesterolemia cases due to LDLR mutations on chromosome 19p13.2, resulting in reduced hepatic LDL clearance and lifelong elevated LDL-C. (Harrison's Principles of Internal Medicine, 21st ed., Chapter 405)

## Why each distractor is wrong

- **Option 2**: This describes autosomal recessive inheritance (e.g., LDLRAP1 mutations causing autosomal recessive hypercholesterolemia, ARH), where only homozygotes are affected and heterozygotes are phenotypically normal. This patient is heterozygous and clinically symptomatic, ruling out recessive inheritance. The 25% offspring risk is also incorrect for this pedigree.

- **Option 3**: This describes X-linked dominant inheritance, which would predominantly affect females and show no male-to-male transmission. The pedigree clearly demonstrates male-to-male transmission (father to son to grandson), which is pathognomonic for autosomal inheritance and excludes X-linked patterns.

- **Option 4**: This describes mitochondrial maternal transmission, where all offspring of affected mothers are affected and paternal transmission does not occur. The presence of male-to-male transmission (father to son) definitively excludes mitochondrial inheritance.

**High-Yield:** Heterozygous FH (HeFH, ~1:250 prevalence) presents with LDL-C 200–400 mg/dL and premature CAD in the 4th–5th decade; homozygous FH (HoFH, ~1:1,000,000) presents with LDL-C >500 mg/dL and childhood MI—the inheritance pattern is autosomal dominant codominant.

[cite: Harrison's Principles of Internal Medicine, 21st ed., Chapter 405: Disorders of Lipoprotein Metabolism — Familial Hypercholesterolemia]

Answer

B. Maternal transmission exclusively; all offspring of affected mothers are affected; paternal transmission does not occur; mitochondrial DNA mutations

Answer

C. Only homozygous individuals are clinically affected; heterozygotes are phenotypically normal carriers; autosomal recessive inheritance with 25% offspring risk

Answer

D. Predominantly affects females more than males; affected males have milder disease; maternal transmission pattern with variable penetrance

Explanation

Why option 1 is correct

Why each distractor is wrong

Practice similar questions

Join our NEET PG community