Research Explained: Improvement of variant reclassification in genetic neurodevelopmental conditions

Authors: Michelle Kowanda, Rebecca Sheedy Smith, Jamie Lundy, Catherine Kentros,

Elisheva Kleinman, Lauren Kasparson Walsh, Gerhard Schratt, Cora M. Taylor, Wendy K. Chung

Publication Date: April 8, 2024

Research Explained By: Gabrielle Rushing, PhD, Science Program Director

Research Simplified Summary:

This research paper focuses on the reclassification of genetic variants in neurodevelopmental conditions. Variants are changes in the letters of our DNA that can affect our health – you can think of a variant like a misspelled work in the ‘DNA instruction book’. In some cases, the classification of these variants as either harmful (e.g., pathogenic/likely pathogenic) or benign can change over time as new evidence emerges. Sometimes variants are classified as ‘variants of uncertain significance’ or ‘VUS’ meaning that scientists need more information to decide how to classify them.

This study looked at the reclassification of VUS in a large group of rare diseases that affect brain development enrolled in Simons Searchlight, including OCNDS. The researchers found that about 20% of the variants were reclassified, with some being upgraded to a more harmful classification and others being downgraded to a less harmful classification. They interpreted classification using existing published research, analyzing DNA from family members, and used the variant reinterpretation guidelines tool from the American College of Medical Genetics and Genomics. The study found that certain genes, such as SCN2A, SLC6A1, and STXBP1, were more likely to have their variants reclassified.

For the CSNK2A1 gene, the authors found 13 individuals with a VUS in Simons Searchlight. Out of these 13, 6 were reclassified as pathogenic or likely pathogenic. Regular reevaluation of genetic variants is important because it can affect clinical care and help researchers better understand these conditions. The study also highlighted the need for more diverse representation in genetic databases to ensure equitable healthcare for all populations.