<i>WDR45</i> variants as a major cause for a clinically variable intellectual disability syndrome from early infancy in females

Pathogenic variants of WD repeat domain 45 (<i>WDR45</i>) cause neurodegeneration with brain iron accumulation 5 (NBIA5), which is characterised by progressive neurological regression and brain iron accumulation in adulthood. Early diagnosis of NBIA5 patients is difficult because they often show only a non-specific developmental delay in childhood, but it is essential for lifelong medical management. We investigated 32 females with developmental delays for coding variants of <i>WDR45</i> using Sanger sequencing. Whole-genome sequencing (WGS) and X chromosome inactivation (XCI) analysis were also performed. We identified two disease-causing variants, one of which was a novel stop-loss variant, c.1051delG p.(Val351CysfsTer60), in a female with severe developmental delay from early infancy with epileptic spasms. The XCI analysis (which we originally developed) suggested a random pattern in white blood cells. WGS did not reveal any other pathogenic variants, including those in two iron transporter genes. Together with our previous findings in the WGS study, <i>WDR45</i> variants accounted for 12% (6/51) of the females with developmental delay, suggesting that <i>WDR45</i> is a major gene in females with developmental delay. Pathogenic variants of <i>WDR45</i> result in various phenotypes that do not necessarily correlate with variant types or XCI skewing patterns.