Estimating the genetic burden: What really is deleterious in the human genome?

Thomas Markello, M.D., Ph.D.
Medical Geneticist, Clinical Staff Physician
Office of the Clinical Director, National Human Genome Research Institute
The problem of validating a candidate gene variant as the actual cause of a disease in a single human with a pathologic phenotype is the single most resource-intensive part of using a human genome sequence in medical diagnosis. Finding “multiple independent alleles” in a natural population survey is the current gold standard. Recently, we reported another perspective on answering this question: Using a cohort of patients with different rare highly penetrant diseases matched to currently unaffected biological siblings, we generated a very small candidate list of genetic burden variants for both individuals summed over each group. The assertion is that if the proband lists are generated identically as the siblings lists while the sum of the candidates for the group of probands statistically exceeds the sibling’s summed list, there will be a high probability that the cause of many of the proband’s phenotypes are within the proband’s list. If the individual probands lists are small enough, this may guide resourcing decisions surrounding biological validation work.

Last modified: Jan 08, 2020