Neurodevelopmental disorders

  • Article |

    Genome-wide analysis of tandem DNA repeats in the genomes of individuals with autism spectrum disorder and control participants reveals a strong contribution of tandem repeat expansions to the genetic aetiology and phenotypic complexity of autism spectrum disorder.

    • Brett Trost
    • , Worrawat Engchuan
    •  & Ryan K. C. Yuen
  • Article |

    The chromatin protein MeCP2 is a component of dynamic, liquid-like heterochromatin condensates, and the ability of MeCP2 to form condensates is disrupted by mutations in the MECP2 gene that occur in the neurodevelopmental disorder Rett syndrome.

    • Charles H. Li
    • , Eliot L. Coffey
    •  & Richard A. Young
  • Letter |

    A genome-wide association study of approximately 7,000 patients with neurodevelopmental disorders demonstrates that overall risk and clinical presentation in putative monogenic disorders is also influenced by common genetic variants present in the general population.

    • Mari E. K. Niemi
    • , Hilary C. Martin
    •  & Jeffrey C. Barrett
  • Letter |

    Experimental evidence that global Kctd13 reduction leads to increased RhoA levels that reduce synaptic transmission, implicating RhoA as a potential therapeutic target for neuropsychiatric disorders associated with copy-number variants that include KCTD13.

    • Christine Ochoa Escamilla
    • , Irina Filonova
    •  & Craig M. Powell
  • Letter |

    Analysis of the minimal functional unit for MeCP2 protein shows that its function is to recruit the NCoR/SMRT co-repressor complex to methylated sites on chromatin, which may have use in designing strategies for gene therapy of Rett syndrome.

    • Rebekah Tillotson
    • , Jim Selfridge
    •  & Adrian Bird
  • Letter |

    A human neurodevelopmental model fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain.

    • Thanathom Chailangkarn
    • , Cleber A. Trujillo
    •  & Alysson R. Muotri
  • Letter |

    Deep brain stimulation (DBS) of the fimbria–fornix—a region that provides input to the hippocampus—is shown to restore hippocampus-dependent memory and hippocampal long-term potentiation and neurogenesis in a mouse model of Rett syndrome, suggesting that DBS, which is already used in the treatment of several neurological conditions, could be a viable approach to mitigating cognitive impairment in Rett syndrome and other disorders of childhood intellectual disability.

    • Shuang Hao
    • , Bin Tang
    •  & Jianrong Tang
  • Letter |

    Up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis; here, in a systematic and nationwide study of 1,133 children with severe, undiagnosed developmental disorders, and their parents, exome sequencing and array-based detection of chromosomal rearrangements reveals novel genes causing developmental disorders, increasing the proportion of children that can now be diagnosed to 31%.

    • T. W. Fitzgerald
    • , S. S. Gerety
    •  & M. E. Hurles
  • Letter |

    Angelman syndrome is a neurodevelopmental disorder caused by disrupted function of the maternal copy of the imprinted UBE3A gene; here, targeting a long non-coding RNA that is responsible for silencing the paternal copy of UBE3A with antisense oligonucleotides is shown to partially restore UBE3A expression in the central nervous system and correct some cognitive deficits in a mouse model of the disease.

    • Linyan Meng
    • , Amanda J. Ward
    •  & Frank Rigo
  • Article |

    Family-based exome sequencing in a large autism study has identified 27 high-confidence gene targets and accurately estimates the contribution of both de novo gene-disrupting and missense mutations to the incidence of simplex autism, with target genes in affected females overlapping those in males of lower but not higher IQ; targets also overlap known targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes.

    • Ivan Iossifov
    • , Brian J. O’Roak
    •  & Michael Wigler
  • Brief Communications Arising |

    • Mark J. Zylka
    • , Ben D. Philpot
    •  & Ian F. King
  • Letter |

    Whole-genome sequencing is used to identify genetic alterations in patients with severe intellectual disability for whom all other tests, including array and exome sequencing, returned negative results; de novo single-nucleotide and copy number variations affecting the coding region seem to be a major cause of this disorder.

    • Christian Gilissen
    • , Jayne Y. Hehir-Kwa
    •  & Joris A. Veltman
  • Letter |

    Exome sequencing has found an excess of de novo mutations in the 4,000 most intolerant genes in patients with two classical epileptic encephalopathies (infantile spasms and Lennox–Gastaut syndrome); among them are multiple de novo mutations in GABRB3 and ALG13.

    • Andrew S. Allen
    • , Samuel F. Berkovic
    •  & Melodie R. Winawer
  • Letter |

    Overexpression of all 29 human transcripts of a region of the 16p11.2 chromosome in zebrafish embryos identifies KCTD13 as the message inducing the microcephaly phenotype associated with 16p11.2 duplication, whereas its suppression yields the macrocephalic phenotype associated with the reciprocal deletion, suggesting that KCTD13 is a major driver for the neurodevelopmental phenotypes associated with the 16p11.2 copy number variants.

    • Christelle Golzio
    • , Jason Willer
    •  & Nicholas Katsanis
  • Letter |

    Long interspersed nuclear elements-1 (L1) retrotransposons affect gene expression and neuronal function throughout brain development. These authors show that the absence of methyl-CpG-binding protein 2, a modulator of DNA methylation implicated in several neurodevelopmental disorders, increases L1 retrotransposon activity in rodent models, with this increase in susceptibility duplicated in patients with Rett syndrome. These correlations suggest that disease-related genetic mutations may influence L1 retrotransposon activity.

    • Alysson R. Muotri
    • , Maria C. N. Marchetto
    •  & Fred H. Gage
  • Article |

    Mutations in the methyl-CpG-binding protein 2 (MeCP2) gene cause Rett syndrome, a neurodevelopmental disorder with features of autism. Multiple mouse models of MeCP2 have been generated, but show only a subset of the symptoms of Rett syndrome. These authors find that mice with selective deletion of MeCP2 in GABA-mediated neurons show not only impaired GABA-mediated function, but capitulate multiple key features of Rett, further suggesting a role of inhibitory function in neuropsychiatric disease.

    • Hsiao-Tuan Chao
    • , Hongmei Chen
    •  & Huda Y. Zoghbi
  • Letter |

    Anxious temperament in both humans and monkeys is an important early predictor of psychopathology and is known to be heritable. These authors characterize the neural circuitry associated with this trait and the extent to which its function is heritable. A scan of related monkeys after exposure to mild stress showed that activation in both the amygdala and hippocampus was predictive of anxious temperament, but that heritability of activity in hippocampus was greater than that in amygdala.

    • Jonathan A. Oler
    • , Andrew S. Fox
    •  & Ned H. Kalin