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Turner syndrome and sexual differentiation of the brain: implications for understanding male-biased neurodevelopmental disorders.

ABSTRACT: Turner syndrome (TS) is one of the most common sex chromosome abnormalities. Affected individuals often show a unique pattern of cognitive strengths and weaknesses and are at increased risk for a number of other neurodevelopmental conditions, many of which are more common in typical males than typical females (e.g., autism and attention-deficit hyperactivity disorder). This phenotype may reflect gonadal steroid deficiency, haploinsufficiency of X chromosome genes, failure to express parentally imprinted genes, and the uncovering of X chromosome mutations. Understanding the contribution of these different mechanisms to outcome has the potential to improve clinical care for individuals with TS and to better our understanding of the differential vulnerability to and expression of neurodevelopmental disorders in males and females. In this paper, we review what is currently known about cognition and brain development in individuals with TS, discuss underlying mechanisms and their relevance to understanding male-biased neurodevelopmental conditions, and suggest directions for future research.

SUBMITTER: Knickmeyer RC

PROVIDER: S-EPMC3261262 | biostudies-other | 2011 Dec

REPOSITORIES: biostudies-other

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Turner syndrome and sexual differentiation of the brain: implications for understanding male-biased neurodevelopmental disorders.

Knickmeyer Rebecca Christine RC Davenport Marsha M

Journal of neurodevelopmental disorders 20110805 4

Turner syndrome (TS) is one of the most common sex chromosome abnormalities. Affected individuals often show a unique pattern of cognitive strengths and weaknesses and are at increased risk for a number of other neurodevelopmental conditions, many of which are more common in typical males than typical females (e.g., autism and attention-deficit hyperactivity disorder). This phenotype may reflect gonadal steroid deficiency, haploinsufficiency of X chromosome genes, failure to express parentally i ...[more]

PMID: 21818630

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Project description:Copy number variants (CNVs) at chromosome 16p13.11 have been associated with a range of neurodevelopmental disorders including autism, ADHD, intellectual disability and schizophrenia. Significant sex differences in prevalence, course and severity have been described for a number of these conditions but the biological and environmental factors underlying such sex-specific features remain unclear. We tested the burden and the possible sex-biased effect of CNVs at 16p13.11 in a sample of 10,397 individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridisation (aCGH); cases were compared with 11,277 controls. In order to identify candidate phenotype-associated genes, we performed an interval-based analysis and investigated the presence of ohnologs at 16p13.11; finally, we searched the DECIPHER database for previously identified 16p13.11 copy number variants. In the clinical referral series, we identified 46 cases with CNVs of variable size at 16p13.11, including 28 duplications and 18 deletions. Patients were referred for various phenotypes, including developmental delay, autism, speech delay, learning difficulties, behavioural problems, epilepsy, microcephaly and physical dysmorphisms. CNVs at 16p13.11 were also present in 17 controls. Association analysis revealed an excess of CNVs in cases compared with controls (OR?=?2.59; p?=?0.0005), and a sex-biased effect, with a significant enrichment of CNVs only in the male subgroup of cases (OR?=?5.62; p?=?0.0002), but not in females (OR?=?1.19, p?=?0.673). The same pattern of results was also observed in the DECIPHER sample. Interval-based analysis showed a significant enrichment of case CNVs containing interval II (OR?=?2.59; p?=?0.0005), located in the 0.83 Mb genomic region between 15.49-16.32 Mb, and encompassing the four ohnologs NDE1, MYH11, ABCC1 and ABCC6. Our data confirm that duplications and deletions at 16p13.11 represent incompletely penetrant pathogenic mutations that predispose to a range of neurodevelopmental disorders, and suggest a sex-limited effect on the penetrance of the pathological phenotypes at the 16p13.11 locus.

Project description:Background: Loss or partial loss of one X chromosome induces Turner syndrome (TS) in females, causing major medical concerns, including otologic disorders. However, the underlying genetic pathophysiology of otologic disorders in TS is mostly unclear. Methods: Ear-related genes of TS (TSEs) were identified by analyzing differentially expressed genes (DEGs) in two Gene Expression Omnibus (GEO)-derived expression profiles and ear-genes in the Comparative Toxicogenomic Database (CTD). Subsequently, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Disease Ontology (DO) analyses; Gene Set Enrichment Analysis (GSEA); and Gene Set Variation Analysis (GSVA) were adopted to study biological functions. Moreover, hub genes within the TSEs were identified by assessing protein-protein interaction (PPI), gene-microRNA, and gene-transcription factor (TF) networks. Drug-Gene Interaction Database (DGIdb) analysis was performed to predict molecular drugs for TS. Furthermore, three machine-learning analysis outcomes were comprehensively compared to explore optimal biomarkers of otologic disorders in TS. Finally, immune cell infiltration was analyzed. Results: The TSEs included 30 significantly upregulated genes and 14 significantly downregulated genes. Enrichment analyses suggested that TSEs play crucial roles in inflammatory responses, phospholipid and glycerolipid metabolism, transcriptional processes, and epigenetic processes, such as histone acetylation, and their importance for inner ear development. Subsequently, we described three hub genes in the PPI network and confirmed their involvement in Wnt/β-catenin signaling pathway and immune cell regulation and roles in maintaining normal auditory function. We also constructed gene-microRNA and gene-TF networks. A novel biomarker (SLC25A6) of the pathogenesis of otologic disorders in TS was identified by comprehensive comparisons of three machine-learning analyses with the best predictive performance. Potential therapeutic agents in TS were predicted using the DGIdb. Immune cell infiltration analysis showed that TSEs are related to immune-infiltrating cells. Conclusion: Overall, our findings have deepened the understanding of the pathophysiology of otologic disorders in TS and made contributions to present a promising biomarker and treatment targets for in-depth research.

Dataset Information

Turner syndrome and sexual differentiation of the brain: implications for understanding male-biased neurodevelopmental disorders.

Publications

Turner syndrome and sexual differentiation of the brain: implications for understanding male-biased neurodevelopmental disorders.

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