Download Full Text (827 KB)
Current standard of practice for most children with suspected genetic disease is to undergo clinical molecular sequencing on germline-derived DNA taken from a blood draw. While there are exceptions for known somatic genetic diseases (ex. Sturge-Weber syndrome, McCune-Albright syndrome), somatic sources of DNA are not routinely clinically tested due to the invasive nature of a skin punch biopsy and lack of existing structures in some hospital systems for obtaining surgical tissue that might otherwise be discarded1,2. Germline whole-exome sequencing (WES) currently has a diagnostic yield of between 20-30% in pediatric cohorts, with germline whole-genome sequencing (WGS) increasing this yield by 10-20%3,4– at least a small percentage of non-diagnostic cases in these cohorts can be attributed to unidentified somatic variation/mosaicism 5,6.
There are several uses for DNA and RNA derived from tissue as opposed to germline specimens including:
- Identification of causative somatic genetic variants
- Identification of somatic mosaicism in selected tissues
- Functional validation of variants of interest
- Improved variant annotation
- Delineation of germline vs. acquired genetic variation in individuals with hematological cancers
Our study seeks to develop a systematic method of routine tissue collection for genetic studies as well as to provide broader evidence for the utility of these specimens in clarifying genetic diagnosis.
Zion, Tricia N.; Louiselle, Daniel A.; Puckett, Laura M B; Posey, Nyshele L.; Neal, Shelby H.; Elfrink, Mary M.; McDonald, Brittany D.; Greathouse, Alexandra; Belden, Bradley; Herd, Suzanne; Walter, Adam; Gibson, Margaret; Cheung, Warren A.; Johnston, Jeffrey J.; Cohen, Ana S A; Thiffault, Isabelle; Farrow, Emily; Miller, Neil; Pastinen, Tomi; and Grundberg, Elin, "Exploration Of Genetic Variation Beyond Leukocyte-Derived Germline DNA In A Pediatric Rare Disease Cohort" (2021). Research at Children's Mercy Month 2021. 18.