Pedigree With an Unaffected Sister
A family seeks genetic counseling. The proband, a 24-year-old woman, has progressive exercise intolerance with lactic acidosis and mild muscle weakness. Her mother and maternal grandmother have similar symptoms; her maternal grandfather does not. The proband has two siblings: a brother with mild symptoms and a sister with none. The proband's mother has two sisters: one is unaffected, and one is severely affected and has three children (two daughters and a son), all affected. The affected aunt's husband is unaffected and unrelated. The proband's father is unaffected, and his large family has no history of the condition. A student concludes that the pedigree shows mitochondrial inheritance with complete penetrance and predicts that the proband's unaffected sister will certainly have unaffected children. Another student argues for autosomal recessive inheritance because the affected aunt's husband could be a carrier.
1. Evaluate the two students' inheritance hypotheses. Which features of the pedigree support or contradict each, and which hypothesis is better supported by the pedigree alone?
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The mitochondrial hypothesis is supported by the maternal pattern: the affected grandmother has affected daughters, the affected mother has affected children, and no affected man transmits the condition. The affected aunt has three affected children, which is also consistent with maternal transmission. However, complete penetrance is contradicted twice: the proband's mother has an unaffected daughter, and the grandmother has an unaffected daughter. A mitochondrial variant with incomplete penetrance, heteroplasmy, or a threshold effect could explain those individuals, but the student's specific claim of complete penetrance is wrong.
The autosomal recessive hypothesis is possible but requires multiple carriers. For the proband and her affected brother to be affected, both unaffected parents would have to be carriers. For the affected aunt to have three affected children with an unrelated unaffected man, he would also have to be a carrier, and each child would independently have a 1/2 chance of inheriting two mutant alleles. That is possible but less parsimonious, especially if the condition is rare. The pedigree alone cannot prove either model. The maternal transmission pattern and the presence of unaffected females in the maternal line make mitochondrial inheritance with variable heteroplasmy the stronger working hypothesis, but molecular testing is needed.
2. What additional data would most efficiently distinguish mitochondrial from autosomal recessive inheritance, and how would you counsel the unaffected sister?
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The most efficient step is molecular testing of the affected proband, ideally with a tissue that is relevant to the phenotype. Mitochondrial DNA variants can be unevenly distributed, so blood may show low heteroplasmy while urine, saliva, or muscle shows more. If a pathogenic mtDNA variant is found in the proband, the mother and the unaffected sister can be tested for the same variant and for heteroplasmy level. That information would directly address whether the sister carries the variant and would replace pedigree guessing with a measured recurrence risk. If no mtDNA variant is found, sequence analysis of autosomal recessive genes associated with the phenotype and carrier testing of the parents would be appropriate.
Counseling should not promise that the unaffected sister will certainly have unaffected children. If she carries a mitochondrial variant at low heteroplasmy, her children could inherit a higher proportion of variant mitochondria and be affected, or could be unaffected. The risk is not a simple Mendelian fraction. If testing shows no variant in her relevant tissues, her risk is much lower, though not zero if heteroplasmy is below detection. She should be told that the prediction in the pedigree is a hypothesis, not a certainty.