Fig. 1

a Dysmorphic facial features of the reported patients with de novo DDX3X variants: a Patient 1 presents with occipital plagiocephaly, frizzy hair, flat face with midface hypoplasia, and short neck. Dysmorphic facial features include: arched eyebrows, mild esotropia of the left eye, low-set wide and simplified ears, long smooth philtrum, thin lips and upper vermillion border, absent cupid bow, and retrognathia; b Dysmorphic features of Patient 2 include prominent metopic ridge with glabellar nevus simplex, arched eyebrows with synophrys, hypotelorism with epicanthal folds, strabismus, low-set posteriorly rotated ears, malar hypoplasia, and microretrognathia; c Clinical photographs of Patient 3 showing arched eyebrows, midface hypoplasia, large ears, long philtrum, and retrognathia. b Brain MRI findings: a, b Patient 1 at the age of 8 years; c, d Patient 2 at the age of 2.5 years; e, f Patient 3 at the age of 12 years. In all patients, axial images reveal malformations of cortical development, characterized by bilateral frontal polymicrogyria in Patient 1 (a) and Patient 3 (b). In Patient 2, axial T1-weighted sequences show an abnormal fronto-insular gyral pattern (c). The anterior limb of the internal capsule is very small with dysmorphic appearance of the basal ganglia (a, c, d, arrowheads). The periventricular white matter is reduced, especially in Patients 1 and 2, with consequent enlargement of the lateral ventricles, especially in frontal and anterior temporal regions. Sagittal T1-weighted images demonstrate severe callosal hypodysgenesis with prevalent involvement of the isthmus and splenium in Patient 1 (b, thick arrow) and 3 (d, thick arrow), and milder callosal hypoplasia in Patient 2 (f, thick arrow). Note the marked hypoplasia of the anterior commissure in patient 1 and 2, and anterior commissure agenesis in Patient 3. There is pontine hypoplasia in all patients (arrows) associated with hypoplasia and mild rotation of the inferior portion of the vermis (open arrows, Patients 2 and 3). In patient 1 sagittal T1-weighted image demonstrates a hypointense cerebellar mass lesion (detailed depiction available in online Supplementary Fig. 1). c DDX3X gene transcripts (top) and DDX3X protein (bottom): a UCSC genome browser map (GRCh37/hg19) shows multiple gene products of DDX3X, with alternative splicing resulting in multiple transcript variants. The gene has a 5′−3′ orientation. The main transcript (black rectangle) of 16,874 bp is encoded by 17 exons; b Schematic, not to scale, representation of the domains of the full-length DDX3X protein and localization of the variants identified in the reported patients. N- and C-terminus are variable regions. The consensus eIF4E-binding sequence is important for the interaction with the eukaryotic initiation factor 4E (eIF4E), a translation initiation factor modulated by DDX3X. The RecA-like domains 1 and 2 are essential for the helicase activity. Each of these catalytic domains is composed of different conserved functional motifs, involved in ATP and RNA binding. aa amino acid