Molecular characteristics

Truncating variants clustering within the last two exons of the SRCAP gene cause FLHS, whereas truncating variants proximal to the FLHS locus result in DEHMBA or a non-FLHS SRCAP-related NDD. These individuals demonstrate a specific DNAm signature that can be used to positively identify affected individuals and distinguish them from FLHS.

Truncating variants located distally to the known FLHS locus do not cause FLHS, and they seem to result in an NDD different from FLHS. The distal variant group clinically manifests NDD, similar to their proximal SRCAP counterparts. Further clinical and molecular studies are needed especially on the “distal SRCAP cases”.

There is currently no evidence that SRCAP missense variants can be pathogenic; however, more variants should be tested to reach a definitive conclusion.