Molecular characteristics

This syndrome is caused by a variety of mutation types in the X chromosome ZDHHC9 gene (frameshifts, splice site variants, missense variants, interstitial deletion). No genotype-phenotype correlations have yet been discovered.

In the majority of cases, the variant follows X-linked familial inheritance. One sporadic de novo case has been reported. The syndrome is fully penetrant in males, with variable expressivity within families. It may be partially penetrant in carrier females (some carriers have experienced epilepsy and mild learning difficulties).

Loss of function is the presumed mechanism across the mutation spectrum. ZDHHC9 encodes a palmitoylation enzyme, involved in post-translational modification and trafficking of a repertoire of targets – the critical targets responsible for phenotype have yet to be identified, but candidates include PSD95, voltage-gated sodium channels, and HRAS. Functional studies have demonstrated impact on neuronal dendritic arborization and inhibitory interneuron development.

Diagnostic testing is via exome sequencing or whole genome sequencing, and depends on analysis incorporating X-linked inheritance as a potential mode. ZDHHC9 should also be included on gene panels for intellectual disability or epilepsy.