Improvement of variant reclassification in genetic neurodevelopmental conditions

Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Autism; Genetic neurodevelopmental disorders; Variant interpretation; Variant pathogenicity; Variants of uncertain significance.

Figure 1

Simons Searchlight genetic laboratory reports reviewed and the resulting variant classifications upon revision. A. Genetic laboratory reports are reviewed and curated prior to approving research participation. Genetic conditions with fewer than 5 participants do not meet the data release threshold and are not included in data releases until they accumulate 5 or more participants. B. Breakdown of variant categories before reclassification within version 11 Simons Searchlight data release and (C) post-reclassification categories of current American College of Medical Genetics and Genomics (ACMG) classification. B, benign; CNV, copy-number variant; LB, likely benign; LP, likely pathogenic; P, pathogenic; VUS, variant of uncertain significance.

Figure 2

Analysis of Simons Searchlight VUS variants, pre- and post-variant interpretation. A. Date (by year only) on the submitted genetics laboratory report (right y-axis), and the percent of variants of uncertain significance (VUS) in that year (left y-axis). B. Type of variant among VUS (AA, amino acid). C. Only including genetic conditions with >3 VUS submitted to the registry, number of VUS upgraded of the VUS reassessed by gene. D. Inheritance status of VUS that were reclassified (upper panel) and not reclassified (lower panel), and (E) type of genetic testing for all variants that were (upper panel) and were not reclassified (lower panel). del, deletion; ES, exome sequencing; GS, genome sequencing; ins, insertion; LP, likely pathogenic; P, pathogenic.

Figure 3

Criteria applied to aid in VUS reclassification for the 89 variants that were upgraded to likely pathogenic or pathogenic. LP, likely pathogenic; P, pathogenic; VUS, variants of uncertain significance.

Figure 4

Frequency of participant ethnicity at the time a VUS is submitted and how often VUS was reclassified after review (shaded). LP, likely pathogenic; P, pathogenic; VUS, variants of uncertain significance.

Figure 5

Percent VUS reclassified within Simons Searchlight (Searchlight) compared with ClinVar. ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001, using a χ² test. VUS, variants of uncertain significance.