Clinical and Neuropsychological Phenotyping of Individuals With Somatic Variants in Neurodevelopmental Disorders

Somatic variants in brain-related genes can cause neurodevelopmental disorders, but detailed characterizations of their clinical phenotypes, neurobehavioral profiles, and comparisons with individuals with germline variants are limited.

Using data from the Simons Searchlight natural history cohort, which uses standardized parent-report data collection methods, we identified individuals with neurodevelopmental disorders caused by pathogenic somatic variants and examined their phenotypic data. We further used results from standardized measurements of adaptive functioning, social behavior, and emotional and behavioral problems to compare individuals with somatic variants with those with germline variants.

We identified 15 probands with pathogenic or likely pathogenic somatic variants in the Simons Searchlight cohort. For 8 individuals with detailed phenotype information, symptoms included developmental delay or language delay (n = 8), hypotonia (n = 5), autism spectrum disorder (n = 4), and epilepsy (n = 3). Individuals with mosaic variants showed a range of severity in their scores on standardized measurements of adaptive functioning, social behavior, and emotional and behavioral problems. In particular, some individuals with mosaic variants showed impairments that were similar in severity or more severe compared with individuals with germline variants in the same gene.

This study improves our understanding of the clinical phenotypes and neuropsychological profiles of individuals with mosaic pathogenic variants in neurodevelopmental disorders.