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Genetics of Autism Spectrum Disorders
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Genetics of Autism Spectrum Disorders

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Mental Health".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 11904

Special Issue Editor

Dr. Elena Bacchelli

E-Mail Website
Guest Editor
Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
Interests: genetics; autism spectrum disorders; complex diseases; neurodevelopmental disorders

Special Issue Information

Dear Colleagues,

Considerable advances have been made, over the past two decades, in understanding the genetic architecture of autism spectrum disorders (ASD). The genetic risk appears to be shaped by a combination of rare and common variants: In some instances, a single genetic variant of large effect is sufficient to cause ASD, while most other cases are caused by a complex combination of genetic variants, mostly with small effect sizes, as well as other nongenetic contributors.

More than 100 genes have now been identified, but many candidate genes are still unknown, and genetic models implicated in symptom severity or familiarity are unclear and controversial. Moreover, even if advances in genome-wide testing continue to yield new data at an unprecedented rate, the interpretation of rare variants, including inherited and de novo mutations as well as copy number variations (CNVs), is still a critical issue, hampering the translation of these data into clinical care.

Accumulation of genotype–phenotype data, complete evaluation of the genetic background even of carriers of candidate disease-associated variants, characterization of the role of epigenetic variation in ASD risk, and functional investigation using model and cellular systems hold much promise in unravelling the molecular underpinnings of ASD.

This Special Issue aims to collect Reviews and primary research articles that will cover these exciting topics and, more in general, will provide a valuable update on the current knowledge of the genetic architecture of ASD.

Dr. Elena Bacchelli
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • autism spectrum disorders
  • copy number variants (CNVs)
  • rare variants
  • common variants
  • de novo mutations
  • next-generation sequencing (NGS)
  • comorbidities
  • precision medicine
  • epigenetics
  • induced pluripotent stem cells (iPSCs)

Published Papers (2 papers)

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Research

21 pages, 864 KiB  
Article
Involvement of the 14-3-3 Gene Family in Autism Spectrum Disorder and Schizophrenia: Genetics, Transcriptomics and Functional Analyses
by Bàrbara Torrico, Ester Antón-Galindo, Noèlia Fernàndez-Castillo, Eva Rojo-Francàs, Sadaf Ghorbani, Laura Pineda-Cirera, Amaia Hervás, Isabel Rueda, Estefanía Moreno, Janice M. Fullerton, Vicent Casadó, Jan K. Buitelaar, Nanda Rommelse, Barbara Franke, Andreas Reif, Andreas G. Chiocchetti, Christine Freitag, Rune Kleppe, Jan Haavik, Claudio Toma and Bru Cormandadd Show full author list remove Hide full author list
J. Clin. Med. 2020, 9(6), 1851; https://doi.org/10.3390/jcm9061851 - 13 Jun 2020
Cited by 11 | Viewed by 5292
Abstract
The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed YWHAZ (encoding 14-3-3ζ) as a candidate gene for autism spectrum disorder (ASD) through a whole-exome sequencing study, which identified a frameshift variant within the gene [...] Read more.
The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed YWHAZ (encoding 14-3-3ζ) as a candidate gene for autism spectrum disorder (ASD) through a whole-exome sequencing study, which identified a frameshift variant within the gene (c.659-660insT, p.L220Ffs*18). Here, we explored the contribution of the seven human 14-3-3 family members in ASD and other psychiatric disorders by investigating the: (i) functional impact of the 14-3-3ζ mutation p.L220Ffs*18 by assessing solubility, target binding and dimerization; (ii) contribution of common risk variants in 14-3-3 genes to ASD and additional psychiatric disorders; (iii) burden of rare variants in ASD and schizophrenia; and iv) 14-3-3 gene expression using ASD and schizophrenia transcriptomic data. We found that the mutant 14-3-3ζ protein had decreased solubility and lost its ability to form heterodimers and bind to its target tyrosine hydroxylase. Gene-based analyses using publicly available datasets revealed that common variants in YWHAE contribute to schizophrenia (p = 6.6 × 10−7), whereas ultra-rare variants were found enriched in ASD across the 14-3-3 genes (p = 0.017) and in schizophrenia for YWHAZ (meta-p = 0.017). Furthermore, expression of 14-3-3 genes was altered in post-mortem brains of ASD and schizophrenia patients. Our study supports a role for the 14-3-3 family in ASD and schizophrenia. Full article
(This article belongs to the Special Issue Genetics of Autism Spectrum Disorders)
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20 pages, 2287 KiB  
Article
Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31
by Jonathan D. J. Labonne, Terri M. Driessen, Marvin E. Harris, Il-Keun Kong, Soumia Brakta, John Theisen, Modibo Sangare, Lawrence C. Layman, Cheol-Hee Kim, Janghoo Lim and Hyung-Goo Kim
J. Clin. Med. 2020, 9(1), 274; https://doi.org/10.3390/jcm9010274 - 19 Jan 2020
Cited by 12 | Viewed by 6123
Abstract
We report a genomic and phenotypic delineation for two chromosome regions with candidate genes for syndromic intellectual disability at 12q12 and Xp22.31, segregating independently in one family with four affected members. Fine mapping of three affected members, along with six unreported small informative [...] Read more.
We report a genomic and phenotypic delineation for two chromosome regions with candidate genes for syndromic intellectual disability at 12q12 and Xp22.31, segregating independently in one family with four affected members. Fine mapping of three affected members, along with six unreported small informative CNVs, narrowed down the candidate chromosomal interval to one gene LRRK2 at 12q12. Expression studies revealed high levels of LRRK2 transcripts in the whole human brain, cerebral cortex and hippocampus. RT-qPCR assays revealed that LRRK2 transcripts were dramatically reduced in our microdeletion patient DGDP289A compared to his healthy grandfather with no deletion. The decreased expression of LRRK2 may affect protein–protein interactions between LRRK2 and its binding partners, of which eight have previously been linked to intellectual disability. These findings corroborate with a role for LRRK2 in cognitive development, and, thus, we propose that intellectual disability and autism, displayed in the 12q12 microdeletions, are likely caused by LRRK2. Using another affected member, DGDP289B, with a microdeletion at Xp22.31, in this family, we performed the genomic and clinical delineation with six published and nine unreported cases. We propose HDHD1 and PNPLA4 for X-linked intellectual disability in this region, since their high transcript levels in the human brain substantiate their role in intellectual functioning. Full article
(This article belongs to the Special Issue Genetics of Autism Spectrum Disorders)
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