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Genetics of Rare Monogenic Neurodevelopmental Syndromes
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Genetics of Rare Monogenic Neurodevelopmental Syndromes

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 (20 December 2024) | Viewed by 17557

Special Issue Editors

Dr. Maya Chopra

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Guest Editor
Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Boston, MA 02115, USA
Interests: rare genetic syndromes; neurodevelopmental presentation; molecular mechanism; genotype-phenotype correlation; clinical trial; gene-based therapies
Dr. Elizabeth Emma Palmer

E-Mail Website
Guest Editor
1. Centre of Clinical Genetics, Sydney Children’s Hospitals Network, Randwick 2031, Australia
2. Discipline of Paediatrics and Child Health, Faculty of Medicine and Health, University of New South Wales, Randwick 2031, Australia
Interests: genetics; genetics education; epilepsy; intellectual disability; autism spectrum disorder; inclusive research; genomics; targeted therapies; rare diseases

Special Issue Information

Dear Colleagues,

Although monogenic neurodevelopmental syndromes are individually rare, they collectively pose a significant challenge to families and the educational and healthcare systems supporting them. With advances in genomic sequencing technologies and better resources for variant interpretation, including population databases, there has been a rapid acceleration in gene discovery, with over 1000 genes now implicated in neurodevelopment. This field continues to make great strides in elucidating the molecular basis of such disorders and delineating genotype–phenotype correlations. These are the building blocks—together with the establishment of validated preclinical models, identification of natural history trajectories and biomarkers, and strong partnerships with the patient and family communities—for the development of therapeutic options for these disorders over the next decade.

For this Special Issue, we welcome reviews, original articles, and short communications covering all areas related to monogenic neurodevelopmental syndromes. We seek manuscripts that explore genotype–phenotype associations, molecular mechanisms, precise phenotype delineation/ expansion, and clinical trial readiness programs for such disorders. We also encourage submissions demonstrating partnerships with the patient and family community, and studies including populations that have previously been under-represented in genomics research.

We look forward to receiving your contributions. Please feel free to contact the Editorial Office if you have any questions about the guidelines or requirements for this Special Issue.

Dr. Maya Chopra
Dr. Elizabeth Emma Palmer
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

  • mendelian NDD
  • monogenic neurodevelopmental syndrome
  • rare genetic disease
  • brain disorders
  • intellectual disability
  • autism

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Published Papers (7 papers)

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Research

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12 pages, 1521 KiB  
Article
CIC-Related Neurodevelopmental Disorder: A Review of the Literature and an Expansion of Genotype and Phenotype
by Ivan Ruiz, Kimberly Wiltrout, Coral Stredny and Sonal Mahida
Genes 2024, 15(11), 1425; https://doi.org/10.3390/genes15111425 - 31 Oct 2024
Viewed by 1963
Abstract
Background: Genetic testing for neurodevelopmental disorders is now considered the standard of care for unexplained epilepsy as well as autism spectrum disorders, intellectual disability, and developmental delays with as many as 50% of individuals identified as having an underlying genetic etiology. Capicua ( [...] Read more.
Background: Genetic testing for neurodevelopmental disorders is now considered the standard of care for unexplained epilepsy as well as autism spectrum disorders, intellectual disability, and developmental delays with as many as 50% of individuals identified as having an underlying genetic etiology. Capicua (CIC) is a transcriptional repressor and is widely expressed among human brain tissue. Patients in the literature with pathogenic variants in CIC present with a broad spectrum of phenotypic abnormalities. Common features include epilepsy, developmental delay, intellectual disability, autism spectrum disorder, and MRI abnormalities amongst other neurodevelopmental symptoms. Variant type, age of onset, sex, and severity of manifestation also differ amongst probands. However, the full genotypic and phenotypic spectrum of CIC-related neurodevelopmental disorder has not been elucidated. Methods: Here we review patients reported in the literature with CIC variants and present two additional patients representing a novel genotype and phenotype. Results: Whole exome sequencing (WES) in this proband identified a novel paternally inherited likely pathogenic variant in CIC c.1526del p.(Pro509Hisfs*14). Both proband and father present with isolated epilepsy without other significant neurodevelopmental disorders. A review of the previous literature identified 20 individuals harboring CIC variants; the majority of these individuals present with a combination of neurodevelopmental features. Sixteen distinct variants were identified amongst these 20 patients. Conclusions: This family represents an expansion of the genotypic and phenotypic spectrum of CIC-related neurodevelopmental disorder. This information may lead to clinically actionable management changes for future patients identified with CIC variants considering standard anti-epileptic medication-weaning protocols. Full article
(This article belongs to the Special Issue Genetics of Rare Monogenic Neurodevelopmental Syndromes)
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11 pages, 2939 KiB  
Article
A Novel Pathogenic TUBA1A Variant in a Croatian Infant Is Linked to a Severe Tubulinopathy with Walker–Warburg-like Features
by Akzam Saidin, Anet Papazovska Cherepnalkovski, Zeeshan Shaukat, Todor Arsov, Rashid Hussain, Ben J. Roberts, Marija Bucat, Klara Cogelja, Michael G. Ricos and Leanne M. Dibbens
Genes 2024, 15(8), 1031; https://doi.org/10.3390/genes15081031 - 5 Aug 2024
Viewed by 1310
Abstract
Tubulinopathies are associated with malformations of cortical development but not Walker–Warburg Syndrome. Intensive monitoring of a Croatian infant presenting as Walker–Warburg Syndrome in utero began at 21 weeks due to increased growth of cerebral ventricles and foetal biparietal diameter. Monitoring continued until Caesarean [...] Read more.
Tubulinopathies are associated with malformations of cortical development but not Walker–Warburg Syndrome. Intensive monitoring of a Croatian infant presenting as Walker–Warburg Syndrome in utero began at 21 weeks due to increased growth of cerebral ventricles and foetal biparietal diameter. Monitoring continued until Caesarean delivery at 34 weeks where the infant was eutrophic. Clinical assessment of a progressive neurological disorder of unknown aetiology found a macrocephalic head and markedly hypoplastic genitalia with a micropenis. Neurological examination showed generalized hypotonia with very rare spontaneous movements, hypotonia-induced respiratory insufficiency and ventilator dependence, and generalized myoclonus intensifying during manipulation. With clinical features of hypotonia, lissencephaly, and brain malformations, Walker–Warburg Syndrome was suspected; however, eye anomalies were absent. Genetic trio analysis via whole-exome sequencing only identified a novel de novo mutation in the TUBA1A gene (NM_006009.4:c.848A>G; NP_006000.2:p.His283Arg) in the infant, who died at 2 months of age, as the likely cause. We report a previously unpublished, very rare heterozygous TUBA1A mutation with clinical features of macrocephaly and hypoplastic genitalia which have not previously been associated with the gene. The absence of eye phenotypes or mutations in Walker–Warburg-associated genes confirm this as not a new presentation of Walker–Warburg Syndrome but a novel TUBA1A tubulinopathy for neonatologists to be aware of. Full article
(This article belongs to the Special Issue Genetics of Rare Monogenic Neurodevelopmental Syndromes)
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8 pages, 210 KiB  
Article
Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental Disorder
by Ineke Cordova, Alyssa Blesson, Juliann M. Savatt, Abigail Sveden, Sonal Mahida, Heather Hazlett, Erin Rooney Riggs and Maya Chopra
Genes 2024, 15(4), 423; https://doi.org/10.3390/genes15040423 - 28 Mar 2024
Cited by 5 | Viewed by 2658
Abstract
Pathogenic ASH1L variants have been reported in probands with broad phenotypic presentations, including intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, seizures, congenital anomalies, and other skeletal, muscular, and sleep differences. Here, we review previously published individuals with pathogenic ASH1L variants and [...] Read more.
Pathogenic ASH1L variants have been reported in probands with broad phenotypic presentations, including intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, seizures, congenital anomalies, and other skeletal, muscular, and sleep differences. Here, we review previously published individuals with pathogenic ASH1L variants and report three further probands with novel ASH1L variants and previously unreported phenotypic features, including mixed receptive language disorder and gait disturbances. These novel data from the Brain Gene Registry, an accessible repository of clinically derived genotypic and phenotypic data, have allowed for the expansion of the phenotypic and genotypic spectrum of this condition. Full article
(This article belongs to the Special Issue Genetics of Rare Monogenic Neurodevelopmental Syndromes)
23 pages, 2653 KiB  
Article
Genome Sequencing of Consanguineous Family Implicates Ubiquitin-Specific Protease 53 (USP53) Variant in Psychosis/Schizophrenia: Wild-Type Expression in Murine Hippocampal CA 1–3 and Granular Dentate with AMPA Synapse Interactions
by Ambreen Kanwal, Sohail A. Sheikh, Faiza Aslam, Samina Yaseen, Zachary Beetham, Nathan Pankratz, Connie R. Clabots, Sadaf Naz and José V. Pardo
Genes 2023, 14(10), 1921; https://doi.org/10.3390/genes14101921 - 9 Oct 2023
Viewed by 2307
Abstract
Psychosis is a severe mental disorder characterized by abnormal thoughts and perceptions (e.g., hallucinations) occurring quintessentially in schizophrenia and in several other neuropsychiatric disorders. Schizophrenia is widely considered as a neurodevelopmental disorder that onsets during teenage/early adulthood. A multiplex consanguineous Pakistani family was [...] Read more.
Psychosis is a severe mental disorder characterized by abnormal thoughts and perceptions (e.g., hallucinations) occurring quintessentially in schizophrenia and in several other neuropsychiatric disorders. Schizophrenia is widely considered as a neurodevelopmental disorder that onsets during teenage/early adulthood. A multiplex consanguineous Pakistani family was afflicted with severe psychosis and apparent autosomal recessive transmission. The first-cousin parents and five children were healthy, whereas two teenage daughters were severely affected. Structured interviews confirmed the diagnosis of DSM-V schizophrenia. Probands and father underwent next-generation sequencing. All available relatives were subjected to confirmatory Sanger sequencing. Homozygosity mapping and directed a priori filtering identified only one rare variant [MAF < 5(10)−5] at a residue conserved across vertebrates. The variant was a non-catalytic deubiquitinase, USP53 (p.Cys228Arg), predicted in silico as damaging. Genome sequencing did not identify any other potentially pathogenic single nucleotide variant or structural variant. Since the literature on USP53 lacked relevance to mental illness or CNS expression, studies were conducted which revealed USP53 localization in regions of the hippocampus (CA 1–3) and granular dentate. The staining pattern was like that seen with GRIA2/GluA2 and GRIP2 antibodies. All three proteins coimmunoprecipitated. These findings support the glutamate hypothesis of schizophrenia as part of the AMPA-R interactome. If confirmed, USP53 appears to be one of the few Mendelian variants potentially causal to a common-appearing mental disorder that is a rare genetic form of schizophrenia. Full article
(This article belongs to the Special Issue Genetics of Rare Monogenic Neurodevelopmental Syndromes)
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12 pages, 909 KiB  
Article
Multidisciplinary Management of Rett Syndrome: Twenty Years’ Experience
by Sandra Vilvarajan, Madeleine McDonald, Lyndal Douglas, Jessica Newham, Robyn Kirkland, Gloria Tzannes, Diane Tay, John Christodoulou, Susan Thompson and Carolyn Ellaway
Genes 2023, 14(8), 1607; https://doi.org/10.3390/genes14081607 - 11 Aug 2023
Cited by 7 | Viewed by 4798
Abstract
Over the last 20 years, the understanding and natural history of Rett syndrome has advanced, but to date no cure has emerged, with multidisciplinary management being symptomatic and supportive. This study provides a comprehensive review of the clinical features, comorbidities and multidisciplinary management [...] Read more.
Over the last 20 years, the understanding and natural history of Rett syndrome has advanced, but to date no cure has emerged, with multidisciplinary management being symptomatic and supportive. This study provides a comprehensive review of the clinical features, comorbidities and multidisciplinary management of a well-characterized cohort of females with classical Rett syndrome. We aim to improve awareness and understanding of Rett syndrome amongst pediatricians, pediatric subspecialists and allied health professionals to enable early diagnosis and a streamlined enrolment approach for future clinical trials. Rett syndrome, a complex X-linked condition, affecting mainly females, is due to pathogenic variants of the MECP2 gene in most affected individuals. The Rett syndrome Multidisciplinary Management clinic at The Children’s Hospital at Westmead, Sydney, Australia, was established in 2000. This retrospective analysis of individuals who attended the clinic from 2000 to 2020 was performed to identify the incidence and predicted age of onset of Rett syndrome related comorbidities, disease progression and to review management principles. Data collected included age of Rett syndrome diagnosis, MECP2 genotype, clinical features and medical comorbidities, such as sleep disturbance, seizures, breathing irregularities, scoliosis, mobility, hand stereotypies, hand function, constipation, feeding ability, use of gastrostomy, communication skills, QTc prolongation, anthropometry, and bruxism. Analysis of 103 girls who fulfilled the clinical diagnostic criteria for classical Rett syndrome with a pathogenic variant of the MECP2 gene showed a median age of diagnosis of 3 years. The most frequent MECP2 variant was c.502 C>T. Full article
(This article belongs to the Special Issue Genetics of Rare Monogenic Neurodevelopmental Syndromes)
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Review

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11 pages, 1241 KiB  
Review
SYNGAP1 Syndrome and the Brain Gene Registry
by Melissa R. Greco, Maya Chatterjee, Alexa M. Taylor and Andrea L. Gropman
Genes 2025, 16(4), 405; https://doi.org/10.3390/genes16040405 - 30 Mar 2025
Viewed by 363
Abstract
Background: The human brain relies on complex synaptic communication regulated by key genes such as SYNGAP1. SYNGAP1 encodes the GTPase-Activating Protein (SYNGAP), a critical synaptic plasticity and neuronal excitability regulator. Impaired SYNGAP1 function leads to neurodevelopmental disorders (NDDs) characterized by intellectual disability [...] Read more.
Background: The human brain relies on complex synaptic communication regulated by key genes such as SYNGAP1. SYNGAP1 encodes the GTPase-Activating Protein (SYNGAP), a critical synaptic plasticity and neuronal excitability regulator. Impaired SYNGAP1 function leads to neurodevelopmental disorders (NDDs) characterized by intellectual disability (ID), epilepsy, and behavioral abnormalities. These variants disrupt Ras signaling, altering AMPA receptor transport and synaptic plasticity and contributing to cognitive and motor difficulties. Despite advancements, challenges remain in defining genotype–phenotype correlations and distinguishing SYNGAP1-related disorders from other NDDs, which could improve underdiagnosis and misdiagnosis. Brain Gene Registry: The Brain Gene Registry (BGR) was established as a collaborative initiative, consolidating genomic and phenotypic data across multiple research centers. This database allows for extensive analyses, facilitating improved diagnostic accuracy, earlier interventions, and targeted therapeutic strategies. The BGR enhances our understanding of rare genetic conditions and is critical for advancing research on SYNGAP1-related disorders. Conclusions: While no FDA-approved treatments exist for SYNGAP1-related disorders, several therapeutic approaches are being investigated. These include taurine supplementation, ketogenic diets, and molecular strategies such as antisense oligonucleotide therapy to restore SYNGAP1 expression. Behavioral and rehabilitative interventions remain key for managing developmental and cognitive symptoms. Advancing research through initiatives like the BGR is crucial for refining genotype–phenotype associations and developing precision medicine approaches. A comprehensive understanding of SYNGAP1-related disorders will improve clinical outcomes and patient care, underscoring the need for continued interdisciplinary collaboration in neurodevelopmental genetics. Full article
(This article belongs to the Special Issue Genetics of Rare Monogenic Neurodevelopmental Syndromes)
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Other

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9 pages, 617 KiB  
Case Report
Case Report—An Inherited Loss-of-Function NRXN3 Variant Potentially Causes a Neurodevelopmental Disorder with Autism Consistent with Previously Described 14q24.3-31.1 Deletions
by René G. Feichtinger, Martin Preisel, Karin Brugger, Saskia B. Wortmann and Johannes A. Mayr
Genes 2023, 14(6), 1217; https://doi.org/10.3390/genes14061217 - 2 Jun 2023
Cited by 4 | Viewed by 2736
Abstract
Background: Heterozygous, large-scale deletions at 14q24.3-31.1 affecting the neurexin-3 gene have been associated with neurodevelopmental disorders such as autism. Both “de novo” occurrences and inheritance from a healthy parent suggest incomplete penetrance and expressivity, especially in autism spectrum disorder. NRXN3 encodes neurexin-3, a [...] Read more.
Background: Heterozygous, large-scale deletions at 14q24.3-31.1 affecting the neurexin-3 gene have been associated with neurodevelopmental disorders such as autism. Both “de novo” occurrences and inheritance from a healthy parent suggest incomplete penetrance and expressivity, especially in autism spectrum disorder. NRXN3 encodes neurexin-3, a neuronal cell surface protein involved in cell recognition and adhesion, as well as mediating intracellular signaling. NRXN3 is expressed in two distinct isoforms (alpha and beta) generated by alternative promoters and splicing. MM/Results: Using exome sequencing, we identified a monoallelic frameshift variant c.159_160del (p.Gln54AlafsTer50) in the NRXN3 beta isoform (NM_001272020.2) in a 5-year-old girl with developmental delay, autism spectrum disorder, and behavioral issues. This variant was inherited from her mother, who did not have any medical complaints. Discussion: This is the first detailed report of a loss-of-function variant in NRXN3 causing an identical phenotype, as reported for heterozygous large-scale deletions in the same genomic region, thereby confirming NRXN3 as a novel gene for neurodevelopmental disorders with autism. Full article
(This article belongs to the Special Issue Genetics of Rare Monogenic Neurodevelopmental Syndromes)
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