Special Issue "Selected Papers from the International Workshop on Fragile X and Other Neurodevelopmental Disorders"

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (28 February 2020).

Special Issue Editors

Dr. Pietro Chiurazzi
E-Mail Website
Guest Editor
Institute of Medical Genetics, Catholic University, 00118 Rome, Italy
Interests: genetic diseases; epigenetics; pharmacology
Prof. Dr. Giovanni Neri
E-Mail Website
Guest Editor
Sezione di Medicina Genomica, Dipartimento Scienze della Vita e Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
Interests: fragile X syndrome; X-linked intellectual disability; RASopathies; overgrowth syndromes
Special Issues, Collections and Topics in MDPI journals
Dr. Maria Giuseppina Miano
E-Mail Website
Guest Editor
Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council, Naples, Italy
Interests: intellectual disability and developmental epileptic encephalopathies; ARX-KDM5C; disease models; convergent transcriptional pathways
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The 19th International Workshop Fragile X and other Neurodevelopmental Disorders will be held on September 18-21, 2019 in Sorrento, Italy. The event webpage is: www.igb.cnr.it/19thxlid/

Traditionally, this Workshop has two main aims: (1) To foster interdisciplinary and multidisciplinary research on the genetic bases, molecular pathogenesis, clinical presentation of, and innovative therapies for, intellectual disability, including fragile X syndrome, other X-linked conditions, autism, and other neurodevelopmental disorders; and (2) to provide an informal setting where trainees and young investigators across a range of scientific disciplines can build a network among both established and junior investigators.

All accepted papers from the Workshop will be entitled a 15% discount. Feel free to join the Institutional Open Access Program (IOAP) of MDPI for further benefits.

The current Special Issue invites submissions of unpublished original work describing recent advances on all aspects related to the following topics:

  • Fragile X and FMR1-related diseases;
  • Other XLID and autosomal ID conditions;
  • Syndromes caused by multiple “single gene” defects;
  • Mechanisms of disease using human models;
  • Autism, the unending nightmare of the geneticist;
  • Epigenetic signatures and diagnostic biomarkers;
  • Therapeutic perspectives.
Dr. Pietro Chiurazzi
Prof. Dr. Giovanni Neri
Dr. Maria Giuseppina Miano
Guest Editors

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 papers will be 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. Genes is an international peer-reviewed open access monthly 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 2400 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

  • intellectual disability
  • fragile X syndrome
  • X-linked intellectual disability
  • autosomal intellectual disability
  • autism
  • innovative therapies for intellectual disability

Published Papers (8 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Research

Article
A Private 16q24.2q24.3 Microduplication in a Boy with Intellectual Disability, Speech Delay and Mild Dysmorphic Features
Genes 2020, 11(6), 707; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11060707 - 26 Jun 2020
Cited by 5 | Viewed by 875
Abstract
No data on interstitial microduplications of the 16q24.2q24.3 chromosome region are available in the medical literature and remain extraordinarily rare in public databases. Here, we describe a boy with a de novo 16q24.2q24.3 microduplication at the Single Nucleotide Polymorphism (SNP)-array analysis spanning ~2.2 [...] Read more.
No data on interstitial microduplications of the 16q24.2q24.3 chromosome region are available in the medical literature and remain extraordinarily rare in public databases. Here, we describe a boy with a de novo 16q24.2q24.3 microduplication at the Single Nucleotide Polymorphism (SNP)-array analysis spanning ~2.2 Mb and encompassing 38 genes. The patient showed mild-to-moderate intellectual disability, speech delay and mild dysmorphic features. In DECIPHER, we found six individuals carrying a “pure” overlapping microduplication. Although available data are very limited, genomic and phenotype comparison of our and previously annotated patients suggested a potential clinical relevance for 16q24.2q24.3 microduplication with a variable and not (yet) recognizable phenotype predominantly affecting cognition. Comparing the cytogenomic data of available individuals allowed us to delineate the smallest region of overlap involving 14 genes. Accordingly, we propose ANKRD11, CDH15, and CTU2 as candidate genes for explaining the related neurodevelopmental manifestations shared by these patients. To the best of our knowledge, this is the first time that a clinical and molecular comparison among patients with overlapping 16q24.2q24.3 microduplication has been done. This study broadens our knowledge of the phenotypic consequences of 16q24.2q24.3 microduplication, providing supporting evidence of an emerging syndrome. Full article
Show Figures

Figure 1

Article
Altered Expression of GABAergic Markers in the Forebrain of Young and Adult Engrailed-2 Knockout Mice
Genes 2020, 11(4), 384; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11040384 - 01 Apr 2020
Cited by 5 | Viewed by 1044
Abstract
Impaired function of GABAergic interneurons, and the subsequent alteration of excitation/inhibition balance, is thought to contribute to autism spectrum disorders (ASD). Altered numbers of GABAergic interneurons and reduced expression of GABA receptors has been detected in the brain of ASD subjects and mouse [...] Read more.
Impaired function of GABAergic interneurons, and the subsequent alteration of excitation/inhibition balance, is thought to contribute to autism spectrum disorders (ASD). Altered numbers of GABAergic interneurons and reduced expression of GABA receptors has been detected in the brain of ASD subjects and mouse models of ASD. We previously showed a reduced expression of GABAergic interneuron markers parvalbumin (PV) and somatostatin (SST) in the forebrain of adult mice lacking the Engrailed2 gene (En2-/- mice). Here, we extended this analysis to postnatal day (P) 30 by using in situ hybridization, immunohistochemistry, and quantitative RT-PCR to study the expression of GABAergic interneuron markers in the hippocampus and somatosensory cortex of En2-/- and wild type (WT) mice. In addition, GABA receptor subunit mRNA expression was investigated by quantitative RT-PCR in the same brain regions of P30 and adult En2-/- and WT mice. As observed in adult animals, PV and SST expression was decreased in En2-/- forebrain of P30 mice. The expression of GABA receptor subunits (including the ASD-relevant Gabrb3) was also altered in young and adult En2-/- forebrain. Our results suggest that GABAergic neurotransmission deficits are already evident at P30, confirming that neurodevelopmental defects of GABAergic interneurons occur in the En2 mouse model of ASD. Full article
Show Figures

Figure 1

Article
Compound Phenotype Due to Recessive Variants in LARP7 and OTOG Genes Disclosed by an Integrated Approach of SNP-Array and Whole Exome Sequencing
Genes 2020, 11(4), 379; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11040379 - 31 Mar 2020
Cited by 1 | Viewed by 844
Abstract
Neurodevelopmental disorders are a challenge in medical genetics due to genetic heterogeneity and complex genotype-phenotype correlations. For this reason, the resolution of single cases not belonging to well-defined syndromes often requires an integrated approach of multiple whole-genome technologies. Such an approach has also [...] Read more.
Neurodevelopmental disorders are a challenge in medical genetics due to genetic heterogeneity and complex genotype-phenotype correlations. For this reason, the resolution of single cases not belonging to well-defined syndromes often requires an integrated approach of multiple whole-genome technologies. Such an approach has also unexpectedly revealed a complex molecular basis in an increasing number of patients, for whom the original suspect of a pleiotropic syndrome has been resolved as the summation effect of multiple genes. We describe a 10-year-old boy, the third son of first-cousin parents, with global developmental delay, facial dysmorphism, and bilateral deafness. SNP-array analysis revealed regions of homozygosity (ROHs) in multiple chromosome regions. Whole-exome sequencing prioritized on gene-mapping into the ROHs showed homozygosity for the likely pathogenic c.1097_1098delAG p. (Arg366Thrfs*2) frameshift substitution in LARP7 and the likely pathogenic c.5743C>T p.(Arg1915*) nonsense variant in OTOG. Recessive variants in LARP7 cause Alazami syndrome, while variants in OTOG cause an extremely rare autosomal recessive form of neurosensorial deafness. Previously unreported features were acrocyanosis and palmoplantar hyperhidrosis. This case highlights the utility of encouraging technological updates in medical genetics laboratories involved in the study of neurodevelopmental disorders and integrating laboratory outputs with the competencies of next-generation clinicians. Full article
Show Figures

Figure 1

Article
Small Molecules Targeting H3K9 Methylation Prevent Silencing of Reactivated FMR1 Alleles in Fragile X Syndrome Patient Derived Cells
Genes 2020, 11(4), 356; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11040356 - 27 Mar 2020
Cited by 5 | Viewed by 1081
Abstract
In fragile X syndrome (FXS), expansion of a CGG repeat tract in the 5′-untranslated region of the FMR1 gene to >200 repeats causes transcriptional silencing by inducing heterochromatin formation. Understanding the mechanism of FMR1 silencing is important as gene reactivation is a potential [...] Read more.
In fragile X syndrome (FXS), expansion of a CGG repeat tract in the 5′-untranslated region of the FMR1 gene to >200 repeats causes transcriptional silencing by inducing heterochromatin formation. Understanding the mechanism of FMR1 silencing is important as gene reactivation is a potential treatment approach for FXS. To date, only the DNA demethylating drug 5-azadeoxycytidine (AZA) has proved effective at gene reactivation; however, this drug is toxic. The repressive H3K9 methylation mark is enriched on the FMR1 gene in FXS patient cells and is thus a potential druggable target. However, its contribution to the silencing process is unclear. Here, we studied the effect of small molecule inhibitors of H3K9 methylation on FMR1 expression in FXS patient cells. Chaetocin showed a small effect on FMR1 gene reactivation and a synergistic effect on FMR1 mRNA levels when used in combination with AZA. Additionally, chaetocin, BIX01294 and 3-Deazaneplanocin A (DZNep) were able to significantly delay the re-silencing of AZA-reactivated FMR1 alleles. These data are consistent with the idea that H3K9 methylation precedes DNA methylation and that removal of DNA methylation is necessary to see the optimal effect of histone methyl-transferase (HMT) inhibitors on FMR1 gene expression. Nonetheless, our data also show that drugs targeting repressive H3K9 methylation marks are able to produce sustained reactivation of the FMR1 gene after a single dose of AZA. Full article
Show Figures

Figure 1

Article
A Novel WAC Loss of Function Mutation in an Individual Presenting with Encephalopathy Related to Status Epilepticus during Sleep (ESES)
Genes 2020, 11(3), 344; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11030344 - 24 Mar 2020
Cited by 6 | Viewed by 1163
Abstract
WAC (WW Domain Containing Adaptor With Coiled-Coil) mutations have been reported in only 20 individuals presenting a neurodevelopmental disorder characterized by intellectual disability, neonatal hypotonia, behavioral problems, and mildly dysmorphic features. Using targeted deep sequencing, we screened a cohort of 630 individuals with [...] Read more.
WAC (WW Domain Containing Adaptor With Coiled-Coil) mutations have been reported in only 20 individuals presenting a neurodevelopmental disorder characterized by intellectual disability, neonatal hypotonia, behavioral problems, and mildly dysmorphic features. Using targeted deep sequencing, we screened a cohort of 630 individuals with variable degrees of intellectual disability and identified five WAC rare variants: two variants were inherited from healthy parents; two previously reported de novo mutations, c.1661_1664del (p.Ser554*) and c.374C>A (p.Ser125*); and a novel c.381+2T>C variant causing the skipping of exon 4 of the gene, inherited from a reportedly asymptomatic father with somatic mosaicism. A phenotypic evaluation of this individual evidenced areas of cognitive and behavioral deficits. The patient carrying the novel splicing mutation had a clinical history of encephalopathy related to status epilepticus during slow sleep (ESES), recently reported in another WAC individual. This first report of a WAC somatic mosaic remarks the contribution of mosaicism in the etiology of neurodevelopmental and neuropsychiatric disorders. We summarized the clinical data of reported individuals with WAC pathogenic mutations, which together with our findings, allowed for the expansion of the phenotypic spectrum of WAC-related disorders. Full article
Show Figures

Graphical abstract

Article
Reversion to Normal of FMR1 Expanded Alleles: A Rare Event in Two Independent Fragile X Syndrome Families
Genes 2020, 11(3), 248; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11030248 - 26 Feb 2020
Cited by 5 | Viewed by 968
Abstract
Fragile X syndrome (FXS) is mostly due to the expansion and subsequent methylation of a polymorphic CGG repeat in the 5’ UTR of the FMR1 gene. Full mutation alleles (FM) have more than 200 repeats and result in FMR1 gene silencing and FXS. [...] Read more.
Fragile X syndrome (FXS) is mostly due to the expansion and subsequent methylation of a polymorphic CGG repeat in the 5’ UTR of the FMR1 gene. Full mutation alleles (FM) have more than 200 repeats and result in FMR1 gene silencing and FXS. FMs arise from maternal premutations (PM) that have 56–200 CGGs; contractions of a maternal PM or FM are rare. Here, we describe two unaffected boys in two independent FXS families who inherited a non-mosaic allele in the normal and intermediate range, respectively, from their mothers who are carriers of an expanded CGG allele. The first boy inherited a 51 CGG allele (without AGG interruptions) from his mother, who carries a PM allele with 72 CGGs. The other boy inherited from his FM mother an unusual allele with 19 CGGs resulting from a deletion, removing 85 bp upstream of the CGG repeat. Given that transcription of the deleted allele was found to be preserved, we assume that the binding sites for FMR1 transcription factors are excluded from the deletion. Such unusual cases resulting in non-mosaic reduction of maternal CGG expansions may help to clarify the molecular mechanisms underlying the instability of the FMR1 gene. Full article
Show Figures

Figure 1

Article
Autism in Fragile X Syndrome; A Functional MRI Study of Facial Emotion-Processing
Genes 2019, 10(12), 1052; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10121052 - 17 Dec 2019
Cited by 4 | Viewed by 1253
Abstract
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorder, and among those with fragile X syndrome, approximately 1/3rd meet a threshold for an autism spectrum disorder (ASD) diagnosis. Previous functional imaging studies of fragile X [...] Read more.
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorder, and among those with fragile X syndrome, approximately 1/3rd meet a threshold for an autism spectrum disorder (ASD) diagnosis. Previous functional imaging studies of fragile X syndrome have typically focused on those with fragile X syndrome compared to either neurotypical or autism spectrum disorder control groups. Further, the majority of previous studies have tended to focus on those who are more intellectually able than is typical for fragile X syndrome. In this study, we examine the impact of autistic traits in individuals with fragile X syndrome on a paradigm looking at facial emotion processing. The study included 17 individuals with fragile X syndrome, of whom 10 met criteria for autism as measured by the Autism Diagnostic Observation Schedule (ADOS). Prior to the scan, participants rehearsed on a mock scanner to help acclimatize to the scanner environment and thus allow more severely affected individuals to participate. The task examined the blood-oxygen-level-dependent (BOLD) response to fearful and neutral faces taken from the Ekman faces series. Individuals in the autism group had a region of significantly reduced activity centered on the left superior temporal gyrus, compared to those with FXS alone, in response to the fearful faces. We suggest that autism in individuals with fragile X syndrome is associated with similar changes in the neurobiology of facial emotion processing as seen in idiopathic autism. Full article
Show Figures

Figure 1

Article
X-Linked Emery–Dreifuss Muscular Dystrophy: Study Of X-Chromosome Inactivation and Its Relation with Clinical Phenotypes in Female Carriers
Genes 2019, 10(11), 919; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10110919 - 11 Nov 2019
Cited by 3 | Viewed by 980
Abstract
X-linked Emery–Dreifuss muscular dystrophy (EDMD1) affects approximately 1:100,000 male births. Female carriers are usually asymptomatic but, in some cases, they may present clinical symptoms after age 50 at cardiac level, especially in the form of conduction tissue anomalies. The aim of this study [...] Read more.
X-linked Emery–Dreifuss muscular dystrophy (EDMD1) affects approximately 1:100,000 male births. Female carriers are usually asymptomatic but, in some cases, they may present clinical symptoms after age 50 at cardiac level, especially in the form of conduction tissue anomalies. The aim of this study was to evaluate the relation between heart involvement in symptomatic EDMD1 carriers and the X-chromosome inactivation (XCI) pattern. The XCI pattern was determined on the lymphocytes of 30 symptomatic and asymptomatic EDMD1 female carriers—25 familial and 5 sporadic cases—seeking genetic advice using the androgen receptor (AR) methylation-based assay. Carriers were subdivided according to whether they were above or below 50 years of age. A variance analysis was performed to compare the XCI pattern between symptomatic and asymptomatic carriers. The results show that 20% of EDMD1 carriers had cardiac symptoms, and that 50% of these were ≥50 years of age. The XCI pattern was similar in both symptomatic and asymptomatic carriers. Conclusions: Arrhythmias in EDMD1 carriers poorly correlate on lymphocytes to a skewed XCI, probably due to (a) the different embryological origin of cardiac conduction tissue compared to lymphocytes or (b) the preferential loss of atrial cells replaced by fibrous tissue. Full article
Show Figures

Figure 1

Back to TopTop