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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:

  1. Identification of causative somatic genetic variants
  2. Identification of somatic mosaicism in selected tissues
  3. Functional validation of variants of interest
  4. Improved variant annotation
  5. 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.

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Exploration Of Genetic Variation Beyond Leukocyte-Derived Germline DNA In A Pediatric Rare Disease Cohort