A neurodevelopmental disorder caused by a novel de novo SVA insertion in exon 13 of the SRCAP gene

Pathogenic variants in the SRCAP (SNF2-related CREBBP activator protein) gene, which encodes a chromatin-remodeling ATPase, cause neurodevelopmental disorders including Floating Harbor syndrome (FLHS). Here, we report the discovery of a de novo transposon insertion in SRCAP exon 13 from trio genome sequencing in a 28-year-old female with failure to thrive, developmental delay, mood disorder and seizure disorder. The insertion was a full-length (similar to 2.8 kb), antisense-oriented SVA insertion relative to the SRCAP transcript, bearing a 5' transduction and hallmarks of target-primed reverse transcription. The 20-bp 5' transduction allowed us to trace the source SVA element to an intron of a long non-coding RNA on chromosome 12, which is highly expressed in testis. RNA sequencing and qRT-PCR confirmed significant depletion of SRCAP expression and low-level exon skipping in the proband. This case highlights a novel disease-causing structural variant and the importance of transposon analysis in a clinical diagnostic setting.

Automated summary

This study reports the discovery of a de novo transposon insertion in the SRCAP gene, which causes neurodevelopmental disorders in a 28-year-old female. The insertion is a full-length antisense-oriented SVA insertion and originates from an intron of a highly expressed long non-coding RNA in testis. The insertion results in significant depletion of SRCAP expression and exon skipping.