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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.

SUBMITTER: Scala M

PROVIDER: S-EPMC6777618 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Scala Marcello M Torella Annalaura A Severino Mariasavina M Morana Giovanni G Castello Raffaele R Accogli Andrea A Verrico Antonio A Vari Maria Stella MS Cappuccio Gerarda G Pinelli Michele M Vitiello Giuseppina G Terrone Gaetano G D'Amico Alessandra A Nigro Vincenzo V Capra Valeria V

European journal of human genetics : EJHG 20190401 8

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 pilocyti ...[more]

PMID: 30936465

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Project description:BACKGROUND:Intellectual Disability (ID) is characterized by deficits in intellectual functions such as reasoning, problem-solving, planning, abstract thinking, judgment, and learning. As new avenues are emerging for treatment of genetically determined ID (such as Down's syndrome or Fragile X syndrome), it is necessary to identify objective reliable and sensitive outcome measures for use in clinical trials. OBJECTIVE:We developed a novel visual analogical reasoning paradigm, inspired by the Progressive Raven's Matrices, but appropriate for Intellectually Disabled patients. This new paradigm assesses reasoning and inhibition abilities in ID patients. METHODS:We performed behavioural analyses for this task (with a reaction time and error rate analysis, Study 1) in 96 healthy controls (adults and typically developed children older than 4) and 41 genetically determined ID patients (Fragile X syndrome, Down syndrome and ARX mutated patients). In order to establish and quantify the cognitive strategies used to solve the task, we also performed an eye-tracking analysis (Study 2). RESULTS:Down syndrome, ARX and Fragile X patients were significantly slower and made significantly more errors than chronological age-matched healthy controls. The effect of inhibition on error rate was greater than the matrix complexity effect in ID patients, opposite to findings in adult healthy controls. Interestingly, ID patients were more impaired by inhibition than mental age-matched healthy controls, but not by the matrix complexity. Eye-tracking analysis made it possible to identify the strategy used by the participants to solve the task. Adult healthy controls used a matrix-based strategy, whereas ID patients used a response-based strategy. Furthermore, etiologic-specific reasoning differences were evidenced between ID patients groups. CONCLUSION:We suggest that this paradigm, appropriate for ID patients and developmental populations as well as adult healthy controls, provides an objective and quantitative assessment of visual analogical reasoning and cognitive inhibition, enabling testing for the effect of pharmacological or behavioural intervention in these specific populations.

Project description:BackgroundPoor self-care skills and personal hygiene resulted from limitations in learning and understanding, put intellectually disabled individuals at greater risk for intestinal parasitic infections (IPIs). Despite several regional reports in Iran, the overall burden on IPIs among intellectually disabled individuals is poorly understood. Hence, the present study aimed to estimate the pooled prevalence of IPIs among intellectually disabled individuals in Iran.MethodsUsing the PRISMA guidelines, we conducted a systematic review and meta-analysis of data retrieved from seven electronic databases (PubMed, Web of Science, Scopus, Embase, and ProQuest for English articles, as well as SID and Magiran for Persian) from their inception up to December 2020. Pooled prevalence was estimated using a random-effects model with a 95% confidence interval (CI) and depicted as a forest plot, while heterogeneity was evaluated using Cochran's Q-test.ResultsExactly 1263 of the 3004 intellectually disabled individuals examined by 14 studies across 10 provinces of Iran were positive for IPIs. Overall pooled prevalence estimate was 41% (95% CI 29-53%) with a range of 21% (95% CI 10-32%) to 68% (95% CI 55-80%) across sub-groups. Entamoeba coli (16.2%; 95% CI 10.3-22%), Blastocystis spp. (12.2%; 95% CI 7.2-17.2%), and Giardia duodenalis (11.9%; 95% CI 7.4-16.3%) were the most prevalent protozoan species. In terms of helminthic agents, the most prevalent species were Enterobius vermicularis (11.3%; 95% CI 6.3-16.3%) followed by Strongyloides stercoralis (10.9%; 95% CI 5.0-16.9%) and Hymenolepis nana (2.8%; 95% CI 0.4-5.2%) CONCLUSION: IPIs are highly prevalent among intellectually disabled individuals in Iran. Improving the health status and implementing infectious disease prevention strategies in rehabilitation centers, health promotion interventions to improve personal hygiene of intellectually disabled individuals, as well as utilize sensitive diagnostic methods besides routine stool examination techniques, and treatment of infected individuals will help in the control of these infections among intellectually disabled individuals.

Dataset Information

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

Publications

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

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