Article Text

Download PDFPDF
Original research
Comparing the frequency of variants of uncertain significance (VUS) between ancestry groups in a paediatric epilepsy cohort
  1. Bree E Martin1,
  2. Tristan Sands2,3,
  3. Louise Bier4,
  4. Amanda Bergner5,6,
  5. Amelia K Boehme2,
  6. Natalie Lippa7
  1. 1 Department of General Pediatrics, Boston Children's Hospital, Boston, Massachusetts, USA
  2. 2 Department of Neurology, Columbia University, New York, New York, USA
  3. 3 Columbia University Irving Medical Center, New York, New York, USA
  4. 4 Icahn School of Medicine at Mount Sinai, New York, New York, USA
  5. 5 Genetic Counseling Graduate Program, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA
  6. 6 Department of Genetics and Development, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA
  7. 7 Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, New York, USA
  1. Correspondence to Bree E Martin, Department of General Pediatrics, Boston Children's Hospital, Boston, Massachusetts, USA; bree.martin{at}


Background Studies indicate that variants of uncertain significance are more common in non-European populations due to lack of a diversity in population databases. This difference has not been explored in epilepsy, which is increasingly found to be genetic in paediatric populations, and has precision medicine applications. This study examines the differences in the frequency of uncertain next-generation sequencing (NGS) results among a paediatric epilepsy cohort between ancestral groups historically under-represented in biomedical research (UBR) and represented in biomedical research (RBR).

Methods A retrospective chart review of patients with epilepsy seen at Columbia University Irving Medical Center (CUIMC). One hundred seventy-eight cases met the following criteria: (1) visited any provider within the Pediatric Neurology Clinic at CUIMC, (2) had an ICD code indicating a diagnosis of epilepsy, (3) underwent NGS testing after March 2015 and (4) had self-reported ancestry that fit into a single dichotomous category of either historically represented or under-represented in biomedical research.

Results UBR cases had significantly higher rates of uncertain results when compared with RBR cases (79.2% UBR, 20.8% RBR; p value=0.002). This finding remained true after controlling for potential confounding factors, including sex, intellectual disability or developmental delay, epilepsy type, age of onset, number of genes tested and year of testing.

Conclusion Our results add to the literature that individuals who are of ancestries historically under-represented in genetics research are more likely to receive uncertain genetic results than those of represented majority ancestral groups and establishes this finding in an epilepsy cohort.

  • Epilepsy
  • Genetic Variation
  • Genetics, Population
  • Ethics
  • Public Health

Data availability statement

No data are available.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.


  • X @BreeOnGenes

  • Contributors All authors contributed to conceptualisation. BEM performed data curation, formal analysis, methodology, writing original draft, reviewing and editing, and is the guarantor of the content. TS and LB contributed to methodology and reviewing and editing. ALB contributed through supervision and reviewing and editing. AKB aided in formal analysis. NL contributed through methodology, supervision, and reviewing and editing.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.