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Molecular Genetics of Neurodevelopmental Disorders
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Molecular Genetics of 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 (15 December 2024) | Viewed by 22079

Special Issue Editors

Prof. Dr. Richard Eugene Frye

E-Mail Website
Guest Editor
Autism Discovery and Treatment Foundation and Rossignol Medical Center, Phoenix, AZ, USA
Interests: neurodevelopmental disorders; metabolic disorders; genetic symptoms; epigenetics; gene regulation
Special Issues, Collections and Topics in MDPI journals
Dr. Richard G. Boles

E-Mail Website
Guest Editor
The Center for Neurological and Neurodevelopmental Health, Vorhees, NJ, USA
Interests: neurodevelopmental disorders; functional disorders; mitochondrial genetics; channelopathies; DNA sequencing
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Stephen G. Kahler

E-Mail Website
Guest Editor
UK Healthcare, University of Kentucky, Lexington, KY, USA
Interests: autism spectrum disorder

Special Issue Information

Dear Colleagues,

Neurodevelopmental disorders affect a significant number of children during vulnerable periods of their lives and can have a substantial lifelong impact on them and their families. Despite intensive research, we have much to learn regarding the etiology of these disorders. In particular, although the genetic component is large and many genetic variants have been identified, the mechanism through which they predispose towards the autism phenotype and how treatments can mitigate the development process, remain unclear. The genetic component is highly complex, not only in terms of the number of genes known to be involved, but also in terms of multiple pathways, low penetrance/high prevalence variants versus the opposite, de novo versus inherited variants, polygenetic interaction, and microRNA gene regulation. In many cases, the severity appears to be triggered by physiological stressors, and thus environmental factors, epigenetic changes, and gene–environmental interactions must also be considered.

Our goal is to publish high-impact, cutting-edge articles focusing on the emerging understanding of how complex genetic processes and/or gene–environmental interactions can provide insight into the pathophysiological processes that underlie the etiology or pathophysiology of neurodevelopmental disorders.

We encourage the submission of manuscripts describing any of the above-listed factors that provide insight into the etiological or pathophysiological processes underlying neurodevelopmental disorders. We also encourage submissions improving the description of genetic variants or conditions that help elucidate underlying biological mechanisms. Concepts that translate into novel treatments are encouraged but not required.

We encourage the submission of manuscripts describing any genetic processes or genetic syndromes involved in the development of neurodevelopmental disorders.

Prof. Dr. Richard Eugene Frye
Dr. Richard G. Boles
Prof. Dr. Stephen G. Kahler
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 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. 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 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

  • neurodevelopmental disorders
  • attention deficit hyperactivity disorder
  • intellectual disabilities
  • autism spectrum disorder
  • mitochondria
  • neuroinflammation
  • epigenetics
  • transcriptomics
  • genetic syndromes
  • polygenetic interactions

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Published Papers (8 papers)

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Research

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23 pages, 2374 KiB  
Article
Molecular and Functional Assessment of TSC1 and TSC2 in Individuals with Tuberous Sclerosis Complex
by Luiz Gustavo Dufner-Almeida, Laís F. M. Cardozo, Mariana R. Schwind, Danielly Carvalho, Juliana Paula G. Almeida, Andrea Maria Cappellano, Thiago G. P. Alegria, Santoesha Nanhoe, Mark Nellist, Maria Rita Passos-Bueno, Silvana Chiavegatto, Nasjla S. Silva, Sérgio Rosemberg, Ana Paula A. Pereira, Sérgio Antônio Antoniuk and Luciana A. Haddad
Genes 2024, 15(11), 1432; https://doi.org/10.3390/genes15111432 - 3 Nov 2024
Viewed by 2319
Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant neurodevelopmental disorder and multisystem disease caused by pathogenic DNA alterations in the TSC1 and TSC2 tumor suppressor genes. A molecular genetic diagnosis of TSC confirms the clinical diagnosis, facilitating the implementation of appropriate care and [...] Read more.
Tuberous sclerosis complex (TSC) is an autosomal dominant neurodevelopmental disorder and multisystem disease caused by pathogenic DNA alterations in the TSC1 and TSC2 tumor suppressor genes. A molecular genetic diagnosis of TSC confirms the clinical diagnosis, facilitating the implementation of appropriate care and surveillance. TSC1 and TSC2 encode the core components of the TSC1/2 complex (TSC1/2), a negative regulator of the mechanistic target of rapamycin (MTOR) complex 1 (TORC1). Functional analysis of the effects of TSC1 and TSC2 variants on TORC1 activity can help establish variant pathogenicity. We searched for pathogenic alterations to TSC1 and TSC2 in DNA isolated from 116 individuals with a definite clinical diagnosis of TSC. Missense variants and in-frame deletions were functionally assessed. Pathogenic DNA alterations were identified in 106 cases (91%); 18 (17%) in TSC1 and 88 (83%) in TSC2. Of these, 35 were novel. Disruption of TSC1/2 activity was demonstrated for seven TSC2 variants. Molecular diagnostics confirms the clinical diagnosis of TSC in a large proportion of cases. Functional assessment can help establish variant pathogenicity and is a useful adjunct to DNA analysis. Full article
(This article belongs to the Special Issue Molecular Genetics of Neurodevelopmental Disorders)
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9 pages, 459 KiB  
Article
Chromosome 15q11-q13 Duplication Syndrome: A Review of the Literature and 14 New Cases
by Maria Bisba, Christina Malamaki, Pantelis Constantoulakis and Spiros Vittas
Genes 2024, 15(10), 1304; https://doi.org/10.3390/genes15101304 - 8 Oct 2024
Cited by 3 | Viewed by 2837
Abstract
The 15q11.2q13 chromosomal region is particularly susceptible to chromosomal rearrangements due to low-copy repeats (LCRs) located inside this area. Specific breakpoints (BP1-BP5) that lead to deletions and duplications of variable size have been identified. Additionally, this specific region contains several imprinted genes, giving [...] Read more.
The 15q11.2q13 chromosomal region is particularly susceptible to chromosomal rearrangements due to low-copy repeats (LCRs) located inside this area. Specific breakpoints (BP1-BP5) that lead to deletions and duplications of variable size have been identified. Additionally, this specific region contains several imprinted genes, giving rise to complex syndromes (Prader–Willi, Angelman and 15q11-q13 duplication syndromes). 15q11.2-q13 duplication syndrome has been associated with neurodevelopmental disorders (hypotonia, developmental delay, speech delay and seizures) and ASD but is characterized by variable expressivity and reduced penetrance, features that make genetic counseling a complex procedure especially in prenatal cases. In the present study, a total of 14 pre- and postnatal cases were diagnosed as 15q11.2q13 duplication carriers using Affymetrix CytoScan 750 K array-CGH, and our analysis combined these with 120 cases existing in the literature. The inheritance pattern of the cases of this study is unknown, but as a review of the literature revealed, 62.96% of the affected carriers inherited the duplicated area from their mother. The combined results of this analysis (the present study and the literature) show that in the majority of the cases, the phenotype is a compound phenotype, with clinical characteristics that include ASD, intellectual disability, developmental delay and an absence of speech. The aim of this paper is to deliver new possibilities to genetic counseling that can be provided in prenatal and postnatal cases as the phenotype of 15q11.2q13 microduplication carriers cannot be fully predicted; so, clinical diagnoses should be a combination of molecular findings and clinical manifestations that are present. Full article
(This article belongs to the Special Issue Molecular Genetics of Neurodevelopmental Disorders)
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13 pages, 946 KiB  
Article
A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants
by Maria Carla Borroto, Coralie Michaud, Chloé Hudon, Pankaj B. Agrawal, Katherine Agre, Carolyn D. Applegate, Alan H. Beggs, Hans T. Bjornsson, Bert Callewaert, Mei-Jan Chen, Cynthia Curry, Orrin Devinsky, Tracy Dudding-Byth, Kelly Fagan, Candice R. Finnila, Ralitza Gavrilova, Casie A. Genetti, Susan M. Hiatt, Friedhelm Hildebrandt, Monica H. Wojcik, Tjitske Kleefstra, Caroline M. Kolvenbach, Bruce R. Korf, Paul Kruszka, Hong Li, Jessica Litwin, Julien Marcadier, Konrad Platzer, Patrick R. Blackburn, Margot R. F. Reijnders, Heiko Reutter, Ina Schanze, Joseph T. Shieh, Cathy A. Stevens, Zaheer Valivullah, Marie-José van den Boogaard, Eric W. Klee and Philippe M. Campeauadd Show full author list remove Hide full author list
Genes 2024, 15(8), 1033; https://doi.org/10.3390/genes15081033 - 6 Aug 2024
Cited by 2 | Viewed by 2743
Abstract
Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65. In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some [...] Read more.
Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65. In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some of them have been found in unaffected controls or relatives. Here, we describe individuals with likely pathogenic variants in KDM5B, including eight individuals with dominant missense variants. This study is a retrospective case series of 21 individuals with variants in KDM5B. We performed deep phenotyping and collected the clinical information and molecular data of these individuals’ family members. We compared the phenotypes according to variant type and to those previously described in the literature. The most common features were developmental delay, impaired intellectual development, behavioral problems, autistic behaviors, sleep disorders, facial dysmorphism, and overgrowth. DD, ASD behaviors, and sleep disorders were more common in individuals with dominant disruptive KDM5B variants, while individuals with dominant missense variants presented more frequently with renal and skin anomalies. This study extends our understanding of the KDM5B-related neurodevelopmental disorder and suggests the pathogenicity of certain dominant KDM5B missense variants. Full article
(This article belongs to the Special Issue Molecular Genetics of Neurodevelopmental Disorders)
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11 pages, 1117 KiB  
Article
Intellectual Disabilities and Neurocognitive Impairment in Adult Patients with Inherited Metabolic Diseases: A UK Single Centre Experience
by John Warner-Levy, Adrian H. Heald, Daniel Hand, Reena Sharma, Rachel Thomasson and Karolina M. Stepien
Genes 2024, 15(7), 923; https://doi.org/10.3390/genes15070923 - 15 Jul 2024
Viewed by 1458
Abstract
Inherited metabolic diseases (IMDs) are a group of heterogeneous genetic disorders resulting in substrate accumulation, energy deficiency, or complex molecular defects due to the failure of specific molecules to act as enzymes, cofactors, transporters, or receptors in specific metabolic pathways. The pathophysiological changes [...] Read more.
Inherited metabolic diseases (IMDs) are a group of heterogeneous genetic disorders resulting in substrate accumulation, energy deficiency, or complex molecular defects due to the failure of specific molecules to act as enzymes, cofactors, transporters, or receptors in specific metabolic pathways. The pathophysiological changes seen in IMDs are sometimes associated with intellectual disability (ID) or neurocognitive decline, necessitating multidisciplinary input. We here describe our experience at one tertiary metabolic centre in the UK. We reviewed the case prevalence and existing service provision in one adult IMD service covering a multi-ethnic population of 10 million in North England. In our cohort of 2268 IMD patients, 1598 patients had general metabolic conditions (70.5%), and 670 had lysosomal storage disease/disorders (LSD)s (29.5%). The overall prevalence of ID and neurocognitive decline was found to be 15.7% (n = 357), with patients with LSDs accounting for 23.5% (n = 84) of affected patients. Given the prevalence of ID in adults with IMDs, access to multidisciplinary input from neuropsychology and neuropsychiatry services is important. Education of healthcare professionals to diagnose IMDs in patients with ID, in addition to neurocognitive and neuropsychiatric presentations, will avoid missed diagnoses of IMD and will have a positive effect on patient outcomes. Full article
(This article belongs to the Special Issue Molecular Genetics of Neurodevelopmental Disorders)
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23 pages, 3682 KiB  
Article
Early Chronic Fluoxetine Treatment of Ts65Dn Mice Rescues Synaptic Vesicular Deficits and Prevents Aberrant Proteomic Alterations
by S. Hossein Fatemi, Elysabeth D. Otte, Timothy D. Folsom, Arthur C. Eschenlauer, Randall J. Roper, Justin W. Aman and Paul D. Thuras
Genes 2024, 15(4), 452; https://doi.org/10.3390/genes15040452 - 3 Apr 2024
Viewed by 2380
Abstract
Down syndrome (DS) is the most common form of inherited intellectual disability caused by trisomy of chromosome 21, presenting with intellectual impairment, craniofacial abnormalities, cardiac defects, and gastrointestinal disorders. The Ts65Dn mouse model replicates many abnormalities of DS. We hypothesized that investigation of [...] Read more.
Down syndrome (DS) is the most common form of inherited intellectual disability caused by trisomy of chromosome 21, presenting with intellectual impairment, craniofacial abnormalities, cardiac defects, and gastrointestinal disorders. The Ts65Dn mouse model replicates many abnormalities of DS. We hypothesized that investigation of the cerebral cortex of fluoxetine-treated trisomic mice may provide proteomic signatures that identify therapeutic targets for DS. Subcellular fractionation of synaptosomes from cerebral cortices of age- and brain-area-matched samples from fluoxetine-treated vs. water-treated trisomic and euploid male mice were subjected to HPLC-tandem mass spectrometry. Analysis of the data revealed enrichment of trisomic risk genes that participate in regulation of synaptic vesicular traffic, pre-synaptic and post-synaptic development, and mitochondrial energy pathways during early brain development. Proteomic analysis of trisomic synaptic fractions revealed significant downregulation of proteins involved in synaptic vesicular traffic, including vesicular endocytosis (CLTA, CLTB, CLTC), synaptic assembly and maturation (EXOC1, EXOC3, EXOC8), anterograde axonal transport (EXOC1), neurotransmitter transport to PSD (SACM1L), endosomal-lysosomal acidification (ROGDI, DMXL2), and synaptic signaling (NRXN1, HIP1, ITSN1, YWHAG). Additionally, trisomic proteomes revealed upregulation of several trafficking proteins, involved in vesicular exocytosis (Rab5B), synapse elimination (UBE3A), scission of endocytosis (DBN1), transport of ER in dendritic spines (MYO5A), presynaptic activity-dependent bulk endocytosis (FMR1), and NMDA receptor activity (GRIN2A). Chronic fluoxetine treatment of Ts65Dn mice rescued synaptic vesicular abnormalities and prevented abnormal proteomic changes in adult Ts65Dn mice, pointing to therapeutic targets for potential treatment of DS. Full article
(This article belongs to the Special Issue Molecular Genetics of Neurodevelopmental Disorders)
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22 pages, 6945 KiB  
Article
Variation of FMRP Expression in Peripheral Blood Mononuclear Cells from Individuals with Fragile X Syndrome
by Jamie L. Randol, Kyoungmi Kim, Matthew D. Ponzini, Flora Tassone, Alexandria K. Falcon, Randi J. Hagerman and Paul J. Hagerman
Genes 2024, 15(3), 356; https://doi.org/10.3390/genes15030356 - 13 Mar 2024
Cited by 3 | Viewed by 1834
Abstract
Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and autism spectrum disorder. The syndrome is often caused by greatly reduced or absent protein expression from the fragile X messenger ribonucleoprotein 1 (FMR1) gene due to expansion [...] Read more.
Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and autism spectrum disorder. The syndrome is often caused by greatly reduced or absent protein expression from the fragile X messenger ribonucleoprotein 1 (FMR1) gene due to expansion of a 5′-non-coding trinucleotide (CGG) element beyond 200 repeats (full mutation). To better understand the complex relationships among FMR1 allelotype, methylation status, mRNA expression, and FMR1 protein (FMRP) levels, FMRP was quantified in peripheral blood mononuclear cells for a large cohort of FXS (n = 154) and control (n = 139) individuals using time-resolved fluorescence resonance energy transfer. Considerable size and methylation mosaicism were observed among individuals with FXS, with FMRP detected only in the presence of such mosaicism. No sample with a minimum allele size greater than 273 CGG repeats had significant levels of FMRP. Additionally, an association was observed between FMR1 mRNA and FMRP levels in FXS samples, predominantly driven by those with the lowest FMRP values. This study underscores the complexity of FMR1 allelotypes and FMRP expression and prompts a reevaluation of FXS therapies aimed at reactivating large full mutation alleles that are likely not capable of producing sufficient FMRP to improve cognitive function. Full article
(This article belongs to the Special Issue Molecular Genetics of Neurodevelopmental Disorders)
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13 pages, 2044 KiB  
Article
KMT2D Deficiency Causes Sensorineural Hearing Loss in Mice and Humans
by Allison J. Kalinousky, Teresa R. Luperchio, Katrina M. Schrode, Jacqueline R. Harris, Li Zhang, Valerie B. DeLeon, Jill A. Fahrner, Amanda M. Lauer and Hans T. Bjornsson
Genes 2024, 15(1), 48; https://doi.org/10.3390/genes15010048 - 28 Dec 2023
Viewed by 2495
Abstract
Individuals with Kabuki syndrome type 1 (KS1) often have hearing loss recognized in middle childhood. Current clinical dogma suggests that this phenotype is caused by frequent infections due to the immune deficiency in KS1 and/or secondary to structural abnormalities of the ear. To [...] Read more.
Individuals with Kabuki syndrome type 1 (KS1) often have hearing loss recognized in middle childhood. Current clinical dogma suggests that this phenotype is caused by frequent infections due to the immune deficiency in KS1 and/or secondary to structural abnormalities of the ear. To clarify some aspects of hearing loss, we collected information on hearing status from 21 individuals with KS1 and found that individuals have both sensorineural and conductive hearing loss, with the average age of presentation being 7 years. Our data suggest that while ear infections and structural abnormalities contribute to the observed hearing loss, these factors do not explain all loss. Using a KS1 mouse model, we found hearing abnormalities from hearing onset, as indicated by auditory brainstem response measurements. In contrast to mouse and human data for CHARGE syndrome, a disorder possessing overlapping clinical features with KS and a well-known cause of hearing loss and structural inner ear abnormalities, there are no apparent structural abnormalities of the cochlea in KS1 mice. The KS1 mice also display diminished distortion product otoacoustic emission levels, which suggests outer hair cell dysfunction. Combining these findings, our data suggests that KMT2D dysfunction causes sensorineural hearing loss compounded with external factors, such as infection. Full article
(This article belongs to the Special Issue Molecular Genetics of Neurodevelopmental Disorders)
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Review

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21 pages, 355 KiB  
Review
Genetic Advancements in Infantile Epileptic Spasms Syndrome and Opportunities for Precision Medicine
by Hannah E. Snyder, Puneet Jain, Rajesh RamachandranNair, Kevin C. Jones and Robyn Whitney
Genes 2024, 15(3), 266; https://doi.org/10.3390/genes15030266 - 21 Feb 2024
Cited by 5 | Viewed by 4628
Abstract
Infantile epileptic spasms syndrome (IESS) is a devastating developmental epileptic encephalopathy (DEE) consisting of epileptic spasms, as well as one or both of developmental regression or stagnation and hypsarrhythmia on EEG. A myriad of aetiologies are associated with the development of IESS; broadly, [...] Read more.
Infantile epileptic spasms syndrome (IESS) is a devastating developmental epileptic encephalopathy (DEE) consisting of epileptic spasms, as well as one or both of developmental regression or stagnation and hypsarrhythmia on EEG. A myriad of aetiologies are associated with the development of IESS; broadly, 60% of cases are thought to be structural, metabolic or infectious in nature, with the remainder genetic or of unknown cause. Epilepsy genetics is a growing field, and over 28 copy number variants and 70 single gene pathogenic variants related to IESS have been discovered to date. While not exhaustive, some of the most commonly reported genetic aetiologies include trisomy 21 and pathogenic variants in genes such as TSC1, TSC2, CDKL5, ARX, KCNQ2, STXBP1 and SCN2A. Understanding the genetic mechanisms of IESS may provide the opportunity to better discern IESS pathophysiology and improve treatments for this condition. This narrative review presents an overview of our current understanding of IESS genetics, with an emphasis on animal models of IESS pathogenesis, the spectrum of genetic aetiologies of IESS (i.e., chromosomal disorders, single-gene disorders, trinucleotide repeat disorders and mitochondrial disorders), as well as available genetic testing methods and their respective diagnostic yields. Future opportunities as they relate to precision medicine and epilepsy genetics in the treatment of IESS are also explored. Full article
(This article belongs to the Special Issue Molecular Genetics of Neurodevelopmental Disorders)
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