<scp>X‐Linked</scp> intellectual disability update 2022

Schwartz, Charles E.; Louie, Raymond J.; Toutain, Annick; Skinner, Cindy; Friez, Michael J.; Stevenson, Roger E.

doi:10.1002/ajmg.a.63008

Cited by 10 publications

(9 citation statements)

References 108 publications

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“…For instance, X-linked intellectual disability is a well-studied brain disorder and by 2022, 162 associated genes have been identified 21 . Remarkably, the concentration of genes on the X-chromosome is double that of intellectual disability-associated genes on the autosomes 21 . Chromosome mutations, such as sex chromosome aneuploidy, can have profound implications on brain structures 14,22 , cognitive capacities 23,24 , behaviors 24 , and both neurological 24,25 and psychiatric disorders 26,27 .…”

Section: Figurementioning

confidence: 99%

“…Mounting evidence has shown that the X-chromosome significantly impacts a myriad of neurological diseases and psychiatric disorders from both genetic and epigenetic viewpoints 5,[18][19][20] . For instance, X-linked intellectual disability is a well-studied brain disorder and by 2022, 162 associated genes have been identified 21 . Remarkably, the concentration of genes on the X-chromosome is double that of intellectual disability-associated genes on the autosomes 21 .…”

Section: Genetic Architecturementioning

confidence: 99%

Section: Genetic Architecturementioning

confidence: 99%

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The pivotal role of the X-chromosome in the genetic architecture of the human brain

Jiang,

Sullivan,

et al. 2023

Preprint

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Genes on the X-chromosome are extensively expressed in the human brain, resulting in substantial influences on brain development, intellectual disability, and other brain-related disorders. To comprehensively investigate the X-chromosome's impact on the cerebral cortex, white matter tract microstructures, and intrinsic and extrinsic brain functions, we examined 2,822 complex brain imaging traits obtained from n = 34,000 subjects in the UK Biobank. We unveiled potential autosome-X-chromosome interaction, while proposing an atlas of dosage compensation (DC) for each set of traits. We observed a pronounced X-chromosome impact on the corticospinal tract and the functional amplitude and connectivity of visual networks. In association studies, we identified 50 genome-wide significant trait-locus pairs enriched in Xq28, 22 of which replicated in independent datasets (n = 4,900). Notably, 13 newly identified pairs were in the X-chromosome's non-pseudo-autosomal regions (NPR). The volume of the right ventral diencephalon shared genetic architecture with schizophrenia and educational attainment in a locus indexed by rs2361468 (located ~3kb upstream of PJA1, a conserved and ubiquitously expressed gene implicated in multiple psychiatric disorders). No significant associations were identified in the pseudo-autosomal regions (PAR) or the Y-chromosome. Finally, we explored sex-specific associations on the X-chromosome and compared differing genetic effects between sexes. We found much more associations can be identified in males (33 versus 9) given a similar sample size. In conclusion, our research provides invaluable insights into the X-chromosome's role in the human brain, contributing to the observed sex differences in brain structure and function.

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Section: Figurementioning

confidence: 99%

Section: Genetic Architecturementioning

confidence: 99%

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The pivotal role of the X-chromosome in the genetic architecture of the human brain

Jiang,

Sullivan,

et al. 2023

Preprint

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“…This review focuses on X-linked forms of ID that result from disruption of genes carried on the X chromosome. Out of almost 1400 genes associated with IDs, over 140 are X-linked [ 5 , 7 , 8 ]. The research and treatment of these disorders are often hindered and limited by the additional complexity introduced by the unique biology of the X chromosome.…”

Section: Introductionmentioning

confidence: 99%

Overcoming genetic and cellular complexity to study the pathophysiology of X-linked intellectual disabilities

Martinez,

Jiang,

Zhou

2024

J Neurodevelop Disord

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X-linked genetic causes of intellectual disability (ID) account for a substantial proportion of cases and remain poorly understood, in part due to the heterogeneous expression of X-linked genes in females. This is because most genes on the X chromosome are subject to random X chromosome inactivation (XCI) during early embryonic development, which results in a mosaic pattern of gene expression for a given X-linked mutant allele. This mosaic expression produces substantial complexity, especially when attempting to study the already complicated neural circuits that underly behavior, thus impeding the understanding of disease-related pathophysiology and the development of therapeutics. Here, we review a few selected X-linked forms of ID that predominantly affect heterozygous females and the current obstacles for developing effective therapies for such disorders. We also propose a genetic strategy to overcome the complexity presented by mosaicism in heterozygous females and highlight specific tools for studying synaptic and circuit mechanisms, many of which could be shared across multiple forms of intellectual disability.

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“…To date, 164 X-linked genes have been associated with intellectual disability. 2 Deletions and sequence alterations in these genes produce a wide spectrum of phenotypes from intellectual disability without other distinguishing manifestations (nonsyndromal XLID, IDX) to intellectual disability accompanied by characteristic craniofacial features, structural anomalies, metabolic disturbances, neuromuscular findings or behavioral abnormalities (X-linked intellectual disability (XLID) syndromes). Complete duplications of all genes associated with XLID have now been identified.…”

Section: Introductionmentioning

confidence: 99%

Clinical findings in individuals with duplication of genes associated with X‐linked intellectual disability

Sahajpal,

Ziats,

Chaubey

et al. 2023

Clinical Genetics

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Duplication of all genes associated with X‐linked intellectual disability (XLID) have been reported but the majority of the duplications include more than one XLID gene. It is exceptional for whole XLID gene duplications to cause the same phenotype as sequence variants or deletions of the same gene. Duplication of PLP1, the gene associated with Pelizaeus‐Merzbacher syndrome, is the most notable duplication of this type. More commonly, duplication of XLID genes results in very different phenotypes than sequence alterations or deletions. Duplication of MECP2 is widely recognized as a duplication of this type, but a number of others exist. The phenotypes associated with gene duplications are often milder than those caused by deletions and sequence variants. Among some duplications that are clinically significant, marked skewing of X‐inactivation in female carriers has been observed. This report describes the phenotypic consequences of duplication of 22 individual XLID genes, of which 10 are described for the first time.

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X‐Linked intellectual disability update 2022

Cited by 10 publications

References 108 publications

The pivotal role of the X-chromosome in the genetic architecture of the human brain

The pivotal role of the X-chromosome in the genetic architecture of the human brain

Overcoming genetic and cellular complexity to study the pathophysiology of X-linked intellectual disabilities

Clinical findings in individuals with duplication of genes associated with X‐linked intellectual disability

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