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

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...

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Published in:European journal of human genetics : EJHG 2019-08, Vol.27 (8), p.1254-1259
Main Authors: Scala, Marcello, Torella, Annalaura, Severino, Mariasavina, Morana, Giovanni, Castello, Raffaele, Accogli, Andrea, Verrico, Antonio, Vari, Maria Stella, Cappuccio, Gerarda, Pinelli, Michele, Vitiello, Giuseppina, Terrone, Gaetano, D'Amico, Alessandra, Nigro, Vincenzo, Capra, Valeria
Format: Article
Language:English
Subjects:
Astrocytoma
Basal ganglia
Brain cancer
Brain Neoplasms - genetics
Brain tumors
Child
Child, Preschool
Cortex
DEAD-box RNA Helicases - genetics
Female
Females
Genetic Predisposition to Disease - genetics
Hindbrain
Humans
Intellectual Disability - genetics
Male
Medulloblastoma
Mesencephalon
Mutation, Missense
Nervous System Malformations - genetics
Whole Exome Sequencing
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Summary: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.
ISSN:1018-4813
1476-5438
DOI:10.1038/s41431-019-0392-7