Three de novo DDX3X variants associated with distinctive brain developmental abnormalities and brain tumor in intellectually disabled females

Abstract

De novo DDX3X variants account for 1-3% of syndromic intellectual disability (ID) in females and have been occasionally reported in males. Furthermore, somatic DDX3X variants occur in several aggressive cancers, including medulloblastoma. We report three unrelated females with severe ID, dysmorphic features, and a common brain malformative pattern characterized by malformations of cortical development, callosal dysgenesis, basal ganglia anomalies, and midbrain-hindbrain malformations. A pilocytic astrocytoma was incidentally diagnosed in Patient 1 and trigonocephaly was found in Patient 2. With the use of family based whole exome sequencing (WES), we identified three distinct de novo variants in DDX3X. These findings expand the phenotypic spectrum of DDX3X-related disorders, demonstrating unique neuroradiological features resembling those of the tubulinopathies, and support a role for DDX3X in neuronal development. Our observations further suggest a possible link between germline DDX3X variants and cancer development.

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