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 midbrainhindbrain 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.

Proteomic Analysis of Brain Region and Sex-Specific Synaptic Protein Expression in the Adult Mouse Brain

“…ASD is a heterogeneous group of neurodevelopmental disorders, characterized by early-onset deficits in social interaction and communication skills, together with restricted, repetitive behavior. Defects in DDX3X function in humans is associated with brain and behavioral abnormalities, microcephaly, facial dysmorphism, hypotonia, aggression and movement disorders and/or spasticity in female and probably in male [59,[76][77][78][79][80][81][82][83][84][85]. The finding of a sexual dimorphic autism related protein specifically in the striatum is of particular interest because defects in striatal circuitry are known to cause autism-like phenotypes [86].…”

A de novo DDX3X Variant Is Associated With Syndromic Intellectual Disability: Case Report and Literature Review

“…In comparison to published data, our patient did not present hypotonia, which was a common feature in previous reports. Furthermore, hand stereotypies and temporal horn dilatation have been occasionally associated with the DDX3X spectrum (15,19), while sleep disturbance has been reported in only two female patients (21), and hippocampus atrophy has not been reported in patients with DDX3X-related ID to date.…”

“…Somatic variants of the DDX3X gene have also been identified in a variety of malignancies (19). In two studies, five variants (c.1600C>T/p.R534C, c.1703C>T/p.P568L, c.641T>C/p.I214T, c.931C>T/p.R311 * , c.1084C>T/p.R362C) were reported to occur somatically in association with malignant melanoma, medulloblastoma, and esophageal squamous cell carcinoma (10,18).…”

“…To characterize DDX3X variants in intellectual disability and to explore the likely association between the phenotype and DDX3X gene variants, we performed a systematic literature search in the PubMed database, the Human Gene Mutation Database (HGMD), the Online Mendelian Inheritance in Man (OMIM) and the China National Knowledge Infrastructure (CNKI) databases for publications using "intellectual disability" or "developmental delay" and "DDX3X" as the keywords (until January 9th, 2020). In addition to our patient, we identified 96 patients with DDX3X variants reported previously (10,(13)(14)(15)(16)(17)(18)(19). We excluded four patients reported in a single publication and one fetus from further analysis since all comprehensive clinical presentations were unavailable (17,18).…”

“…nl/name-checker). Finally, we summarized the clinical and genetic characteristics of the remaining 91 patients reported in 10 publications (10,(13)(14)(15)(16)(18)(19)(20)(21)(22); the proportion of females was ∼89% (81/91), and only 10 male patients have been described. The findings are presented in Table 1 and Supplementary Table 1.…”