Routine Diagnostics Confirm Novel Neurodevelopmental Disorders

Abstract

Routine diagnostics is biased towards genes and variants with satisfactory evidence, but rare disorders with only little confirmation of their pathogenicity might be missed. Many of these genes can, however, be considered relevant, although they may have less evidence because they lack OMIM entries or comprise only a small number of publicly available variants from one or a few studies. Here, we present 89 individuals harbouring variants in 77 genes for which only a small amount of public evidence on their clinical significance is available but which we still found to be relevant enough to be reported in routine diagnostics. For 21 genes, we present case reports that confirm the lack or provisionality of OMIM associations (ATP6V0A1, CNTN2, GABRD, NCKAP1, RHEB, TCF7L2), broaden the phenotypic spectrum (CC2D1A, KCTD17, YAP1) or substantially strengthen the confirmation of genes with limited evidence in the medical literature (ADARB1, AP2M1, BCKDK, BCORL1, CARS2, FBXO38, GABRB1, KAT8, PRKD1, RAB11B, RUSC2, ZNF142). Routine diagnostics can provide valuable information on disease associations and support for genes without requiring tremendous research efforts. Thus, our results validate and delineate gene-disorder associations with the aim of motivating clinicians and scientists in diagnostic departments to provide additional evidence via publicly available databases or by publishing short case reports.

Keywords: epilepsy; exome sequencing; gene–disorder association; neurodevelopmental disorder; routine diagnostics.

Figure 1

Sankey diagram representing the proportions of disease groups associated with the cases, the ACMG variant classification and the final conclusion about whether a case report on the variant is worthwhile. Most cases were associated with neurodevelopmental delay with or without seizures. Of these, most identified variants were classified with uncertain significance, where a report was often worthwhile based on the criteria mentioned at the right end of the flowchart. NDD: Neurodevelopmental delay. VUS: Variant of uncertain significance. GDA: Gene–disease association.

Figure 2

Genes with limited evidence on their pathogenicity reported in our routine diagnostics. Genes are plotted based on the number of pathogenic variants in ClinVar (x-axis), HGMD (y-axis) and OMIM (colour), as of December 2021. For details, see Table 2.