DDX3X Syndrome: Clinical, Neuroimaging, AI-Assisted Facial Profiling and Genotype-Phenotype Correlations.

Background/

Objectives

DDX3X syndrome (MIM#300958) is a neurodevelopmental disorder associated with intellectual disability, language impairment, and a characteristic neurobehavioral phenotype that predominantly affects females. Although dysmorphic features have been reported, a consistent facial phenotype and clear genotype-phenotype correlations have not been established.

Methods

We conducted an observational, ambispective, descriptive study including patients aged 0-18 years with a molecular diagnosis of DDX3X. Clinical, standardized facial images, neurobehavioral, neuroimaging, and molecular data were collected. Automated facial analysis was performed using Face2Gene after algorithm training.

Results

Of 11 identified patients, 9 were included (8 females); 8 variants were de novo and 4 novel. Two variants of uncertain significance underwent in silico analysis. Frequent facial features included thin upper lip (9/9), tapered chin (8/9), long uniform eyebrows (8/9), short neck (8/9), and long face (6/9). After training, Face2Gene identified DDX3X syndrome in 92% of cases within the top 5 suggestions, supporting its utility as a diagnostic aid. All females had intellectual disability and language disorder; 66% presented sleep disturbances and aggressive behavior. Neuroimaging revealed ventricular dilatation (5/9) and corpus callosum hypoplasia (3/9). Loss-of-function variants were associated with greater clinical severity.

Conclusions

This series suggests a recognizable facial phenotype of DDX3X syndrome and supports a possible genotype-phenotype correlation. Further studies are needed to confirm these findings.