The phenotype observed in individuals with Down syndrome (DS) due to trisomy 21 can be highly variable in terms of severity and types of additional features beyond the classic hallmarks (congenital hypotonia, dysmorphic features and cognitive impairment). Various factors may lead to this variability (e.g., specific gene expression level differences on chromosome 21), but the possibility of a dual diagnosis should be considered. For the majority of patients with DS, however, genetic testing is concluded once the DS confirmatory result is obtained from chromosomal microarray analysis or karyotyping, and any potential phenotypic deviations are not investigated further. We describe four patients from the in-patient service with a cytogenetically-confirmed diagnosis of Down syndrome for whom additional (rapid) trio exome sequencing was performed due to the presence of more severe neurological features than expected to be associated with DS.
