DDX3X-RD is a rare monogenic disorder, with nearly 200 individuals reported in the literature.
In this study, we reported two different series of individuals expressing DDX3X-RD. We expanded the phenotype by describing 48 new individuals (5 without clinical data), thus providing novel clinical features to aid clinical management of newly diagnosed individuals. We analyzed 44 caregivers’ self-reported characteristics and quality of life data, providing crucial “everyday life” information.
For most clinical features in this series, the distribution was similar to that in the literature. One of the major symptoms is ADHD (14/32 individuals, 44%). This finding was confirmed by caregivers in series 2, who largely considered ADHD to be the major problem affecting their relatives’ everyday life. Lifelong assessment of ADHD seems crucial for all individuals with DDX3X-RD and could lead to treatment, with medication (methylphenidate) or cognitive behavioral therapies12, meta-cognitive therapies, dialectical behavioral therapies, mindfulness-based interventions and cognitive remediation13,14, which are efficacious for ADHD symptoms. It would be useful to evaluate if ADHD is more on the attentional or hyperactivity side.
Sleep disturbance was observed in 10/35 individuals from series 1 and 14/44 from series 2 (30%), also reported recently in 10/15 and 13/23 individuals with DDX3X-RD (60%)15,16. Sleep disturbance need to be evaluated before assessment for ADHD, and might interfere with ADHD evaluation. Here again, lifelong assessment of sleep disturbance is crucial for all DDX3X-RD individuals and might lead to melatonin treatment for instance.
Even if not reported in this manuscript, we know anxiety is frequent in individuals with DDX3X-RD16 and could interfere with ADHD and with sleep disturbance. We strongly suggest searching for and treating ADHD, anxiety and sleep disturbance in individuals with DDX3X-RD because the caregivers’ main complaint was ADHD.
For the first time, we report data on developmental milestones: the mean walking age was 27.5 months and the first word appeared at 26.5 months.
The diagnosis of DDX3X-RD is established when identifying a heterozygous PV or LPV in DDX3X by molecular testing, However, one of the remaining challenges for the diagnosis is the reclassification of variants of unknown significance, which can be complex and time-consuming. A growing number of genetic conditions have demonstrated evidence of genome-wide DNA methylation profiles detectible in peripheral blood. Many profiles have been developed as highly sensitive and specific biomarkers called episignatures. An important clinical utility of DNA methylation episignatures is the ability to reclassify genetic variants of unknown clinical significance to provide insights into the molecular pathophysiology of the “episignature disorders”11.
Our study shows preliminary evidence of a mild genome-wide DNA methylation profile in DDX3X-RD. Ongoing efforts are focused on expanding the reference patient cohort to increase the sensitivity and specificity and develop an episignature classifier for DDX3X.
In conclusion, our study emphasizes the similarities between the data reported by physicians and that reported by caregivers. The major problem affecting the everyday life of relatives of caregivers is not always what physicians thought.