A 19-year-old woman with recurrent shoulder dislocations, bilateral patellar instability, hyperextensible velvety skin, and atrophic scars is evaluated for suspected Ehlers-Danlos Syndrome. Her pedigree demonstrates the inheritance pattern marked **A** in the diagram, with her mother, maternal grandfather, and maternal aunts all showing features of the condition. Her older brother is affected but her two young nieces (daughters of her affected brother) both show early signs. Genetic testing confirms a heterozygous pathogenic mutation in COL5A1 on chromosome 9q34.3. Which of the following best characterizes the inheritance pattern marked **A** that explains the transmission of this condition through her family?
A. Autosomal recessive inheritance affecting only siblings while parents remain unaffected
B. Mitochondrial inheritance with exclusively maternal lineage and all offspring of affected mothers being affected
C. Autosomal dominant inheritance with vertical transmission across generations and approximately 50% offspring risk
D. X-linked dominant inheritance with affected females more frequently than males and no male-to-male transmission
Explanation
Why Autosomal dominant inheritance with vertical transmission across generations and approximately 50% offspring risk is right
The pedigree described demonstrates all five cardinal features of autosomal dominant inheritance: (1) affected individuals appear in every generation (vertical transmission from maternal grandfather through mother to the proband); (2) male-to-male transmission is present (affected brother transmitting to his daughters), which excludes X-linked inheritance; (3) equal sex distribution (both males and females affected); (4) approximately 50% of offspring of affected individuals are affected (the proband, her brother, and her nieces); and (5) unaffected individuals do not transmit the disorder. The heterozygous COL5A1 mutation causing classical Ehlers-Danlos Syndrome (cEDS) follows this pattern precisely. Harrison's Principles of Internal Medicine explicitly identifies cEDS as autosomal dominant, with the mutation in COL5A1 encoding the alpha-1 chain of type V collagen, which regulates fibril diameter of type I collagen in dermis, tendon, and ligament.
Why each distractor is wrong
Autosomal recessive inheritance affecting only siblings while parents remain unaffected: This pattern would show affected siblings with unaffected parents, and both parents would need to be carriers. The proband's mother is clearly affected with skin hyperextensibility, joint hypermobility, and atrophic scars, ruling out autosomal recessive inheritance. Additionally, the maternal grandfather and maternal aunts are affected, demonstrating vertical transmission incompatible with recessive inheritance.
X-linked dominant inheritance with affected females more frequently than males and no male-to-male transmission: The pedigree explicitly shows male-to-male transmission (the affected brother transmitting the condition to his daughters), which is pathognomonic for autosomal rather than X-linked inheritance. In X-linked dominant inheritance, affected fathers cannot pass the condition to sons; the presence of an affected brother with affected daughters definitively excludes this pattern.
Mitochondrial inheritance with exclusively maternal lineage and all offspring of affected mothers being affected: Mitochondrial inheritance shows exclusively maternal transmission with all offspring of affected mothers being affected. The proband's father's status is not mentioned as affected, but the presence of an affected brother (who received his mitochondria from the same mother) and the fact that not all offspring of the affected mother are affected (the proband has an unaffected sibling or the pattern does not show 100% transmission) argues against mitochondrial inheritance. Additionally, the male-to-male transmission through the brother to his daughters is incompatible with maternal-only inheritance.
High-YieldNEET PG
Classical Ehlers-Danlos Syndrome (cEDS) caused by COL5A1 mutations is autosomal dominant with vertical transmission and 50% offspring risk; vascular EDS (caused by COL3A1) must be distinguished due to high risk of arterial rupture.
Harrison's Principles of Internal Medicine, 21st ed., Chapter 411: Ehlers-Danlos Syndrome — Classical Type
Practice similar questions
Sign up free to access AI-powered MCQ practice with detailed explanations and adaptive learning.
