Presentation description

Whole genome sequencing (WGS) is the most comprehensive genetic test available. It can be used to identify many disease-causing variants in critically ill children. However, standard clinical genome analysis has its limitations and leaves more than half of all cases undiagnosed, contributing to prolonged and distressing diagnostic odysseys for affected families. The ReSeq Project includes a multidisciplinary team of clinicians, geneticists, and genomic bioinformaticians who take an in-depth second look at these undiagnosed cases through reanalysis of existing clinical data. Subsequent investigation includes long-read sequencing, RNA sequencing, targeted diagnostic testing, and additional reanalysis within 1-2 years. One illustrative case is that of a two-year-old child who presented with low muscular tone, cardiac changes, difficulty feeding, and dysmorphic features. Clinical WGS was undiagnostic, and despite further genetic testing, the underlying cause for this child's condition remained unidentified. However, research reanalysis of the WGS data revealed a de novo variant in KAT6A. Intrigued by this finding and guided by methylation profiling, RNA sequencing was performed, revealing a deep intronic variant within the KAT6A gene. This variant resulted in the formation of a mini exon that caused the introduction of multiple premature stop codons that halted translation and prevented expression of the remaining sequence. This disruption in gene expression was deemed pathogenic, leading to a diagnosis of KAT6A syndrome in the child, ending their diagnostic odyssey. This cryptic variant, undetectable by clinical WGS, highlights the utility of our ongoing research reanalysis and the critical role of RNA sequencing in resolving diagnostically challenging cases.