Neurodevelopmental disorders (NDDs) involve a wide range of symptoms and severity. Individuals may present with multiple indications including epilepsy, autism, intellectual disability, developmental delay, dysmorphic features, and other congenital anomalies. The broad and nonspecific nature of NDDs can lead to significant diagnostic challenges.
Multi-gene panel testing can help to stratify NDDs and identify causative variants. Unfortunately, they can also result in numerous variants of unknown significance (VUS), which can be a confusing and discouraging result for both patients and clinicians. Ambry’s variant team utilizes an integrated and functional approach for variant classification, to reduce VUS rates and increase the frequency of clear results.
In this video, we describe the following approaches for variant assessment:
- Parental co-segregation studies: utilized to identify de novo and familial variants
- Protein structural analysis: leveraging state-of-the art tools for protein modeling, with internal clinical data, against the vast information available in the protein databank to better understand the impact of the variant on the protein, such as destabilizing vs. neutral variants
- mRNA functional splicing assays: completed in Ambry’s Translational Genomics (ATG) for splicing VUS to identify variants that result in abnormal vs. normal splicing
The addition of our in-house functional studies has allowed us to reclassify over 40% of neurology-related VUS investigated in our ATG lab. Ambry’s commitment is to find answers and clarify whether a variant is disease causing. Combining these three approaches with additional lines of evidence such as clinical data, in silico analysis, and population allele frequency, enables us to implement an integrated and effective approach to variant classification and provide a clearer path towards accurate patient care.
