Improvement of variant reclassification in genetic neurodevelopmental conditions

Limited knowledge about disease mechanisms, few published cases, and the lack of functional assessment of variants for neurodevelopmental genetic disorders challenge diagnostic classification for variants and increase the frequency of variants of uncertain significance (VUS). Because inheritance patterns aid in variant interpretation for neurodevelopmental conditions, genetic testing including only the proband leads to larger numbers of VUS than testing strategies that include the parents.

We reinterpreted genetic variants submitted to the Simons Searchlight research registry using American College of Medical Genetics and Genomics variant interpretation guidelines, familial cascade testing, and literature curation with annual VUS reevaluation.

Simons Searchlight has independently evaluated 2834 genetic laboratory reports; 20.4% of variants (1.7% copy-number variants and 18.7% monogenic variants) were reclassified with 230 upgrades and 173 downgrades in pathogenicity. Of 351 monogenic VUS on the original clinical test report, 25.4% were reclassified as likely pathogenic or pathogenic. VUS in SCN2A, SLC6A1, or STXBP1 were more likely to have VUS reclassified compared with variants in other genes.

Regular reevaluation of neurodevelopmental genetic variants can be helpful because relevant variant reclassifications occur frequently and may affect clinical care. Simons Searchlight contributes to the international neurodevelopmental community by systematically reviewing uncertain variants annually and providing reclassified variants to participants, researchers, and ClinVar.