Genetic Risk Assessment in a Family Quartet Using Whole-Genome Sequencing
Author Information
Author(s): Dewey Frederick E., Chen Rong, Cordero Sergio P., Ormond Kelly E., Caleshu Colleen, Karczewski Konrad J., Whirl-Carrillo Michelle, Wheeler Matthew T., Dudley Joel T., Byrnes Jake K., Cornejo Omar E., Knowles Joshua W., Woon Mark, Sangkuhl Katrin, Gong Li, Thorn Caroline F., Hebert Joan M., Capriotti Emidio, David Sean P., Pavlovic Aleksandra, West Anne, Thakuria Joseph V., Ball Madeleine P., Zaranek Alexander W., Rehm Heidi L., Church George M., West John S., Bustamante Carlos D., Snyder Michael, Altman Russ B., Klein Teri E., Butte Atul J., Ashley Euan A.
Primary Institution: Stanford University
Hypothesis
Can a major allele reference sequence improve the accuracy of genetic risk assessment in a family with a history of thrombophilia?
Conclusion
The use of a major allele reference sequence significantly improves genotype accuracy for disease-associated variants in a family with inherited thrombophilia.
Supporting Evidence
- The major allele reference sequence reduced genotyping error rates by approximately 40%.
- 85.6% of genotype calls made against the major allele reference were confirmed by orthogonal genotyping.
- Identified multigenic risk for thrombophilia in the family.
- Demonstrated nearly equal frequency of recombination events in male and female parents.
- Developed ethnicity-specific major allele references for improved variant detection.
- Provided a fine map of meiotic crossover sites to sub-kb resolution.
- Utilized phased variant data for HLA typing and clinical interpretation.
- Showed discordance of inherited disease risk within the family.
Takeaway
This study shows how looking at the DNA of a family can help find out why they might get sick and how to treat them better.
Methodology
Whole-genome sequencing was performed on a family quartet, and a major allele reference sequence was developed for improved variant detection.
Potential Biases
Potential biases in variant calling due to the reference sequence used.
Limitations
The study may not generalize to populations outside the specific ethnic backgrounds of the family.
Participant Demographics
The family members self-reported northern European ancestry.
Statistical Information
P-Value
p=2.0×10−73
Statistical Significance
p<0.05
Digital Object Identifier (DOI)
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