A 38-year-old man presents with his first myocardial infarction. Clinical examination reveals tendon xanthomas over the Achilles tendons and extensor surfaces of the hands, and corneal arcus noted at age 30. Serum LDL cholesterol is 290 mg/dL despite no prior lipid-lowering therapy. His pedigree (shown in the diagram) demonstrates **A**: affected individuals in every generation, approximately 50% of offspring affected, male-to-male transmission, and equal involvement of both sexes. His 12-year-old daughter has LDL 260 mg/dL, and his 8-year-old son has LDL 240 mg/dL. Genetic testing confirms a heterozygous pathogenic mutation in the LDLR gene on chromosome 19p13.2. Which inheritance pattern does the pedigree marked **A** demonstrate?
A. Polygenic multifactorial inheritance with no clear Mendelian pattern and variable penetrance across generations
B. Autosomal dominant (co-dominant) inheritance with heterozygotes severely affected and homozygotes presenting with catastrophic childhood coronary artery disease
C. X-linked dominant inheritance with heterozygous females mildly affected and hemizygous males severely affected
D. Autosomal recessive inheritance where only homozygotes are affected and parents remain phenotypically normal
Explanation
Why Autosomal dominant (co-dominant) inheritance is correct
The pedigree marked A demonstrates classic autosomal dominant inheritance with co-dominant expression. The key diagnostic features are: (1) vertical transmission with affected individuals in every generation; (2) approximately 50% of offspring affected, consistent with a heterozygous parent transmitting the mutation; (3) male-to-male transmission (father to son), which excludes X-linked inheritance; (4) equal involvement of both sexes. The LDLR gene mutation is heterozygous in this patient and his children, causing severe hypercholesterolemia (LDL 240–290 mg/dL) with premature atherosclerosis, tendon xanthomas, and corneal arcus—hallmarks of heterozygous familial hypercholesterolemia (HeFH). Homozygous individuals (not present in this pedigree) would present with LDL >500 mg/dL and myocardial infarction in the first decade of life. This pattern is pathognomonic for autosomal dominant inheritance of LDLR mutations [Goldstein & Brown, Nobel Lecture; Harrison's Lipid Disorders].
Why each distractor is wrong
Autosomal recessive: Autosomal recessive disorders do not show vertical transmission; both parents would be asymptomatic carriers, and only homozygous offspring would be affected. This pedigree shows affected individuals in every generation and affected parents transmitting to ~50% of offspring, excluding recessive inheritance.
X-linked dominant: X-linked dominant inheritance would show affected heterozygous females with milder phenotype and affected hemizygous males with severe disease. Critically, there would be no male-to-male transmission (affected fathers cannot pass X-linked traits to sons). This pedigree demonstrates clear male-to-male transmission (father to son), definitively excluding X-linked inheritance.
Polygenic multifactorial: Polygenic inheritance shows no clear Mendelian pattern, variable penetrance, and clustering in families without vertical transmission in a predictable 50% ratio. The sharp 50% segregation ratio and male-to-male transmission in this pedigree are incompatible with polygenic inheritance.
High-YieldNEET PG
Autosomal dominant inheritance is recognized by vertical transmission, ~50% offspring affected, male-to-male transmission, and equal sex involvement; LDLR mutations cause heterozygous FH with LDL 190–400 mg/dL and premature CAD, and homozygous FH with LDL >500 mg/dL and childhood MI.
Goldstein & Brown, Nobel Lecture; Harrison's Lipid Disorders
Practice similar questions
Sign up free to access AI-powered MCQ practice with detailed explanations and adaptive learning.
