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Molecular Basis and Genetics of Intellectual Disability
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Molecular Basis and Genetics of Intellectual Disability

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

Deadline for manuscript submissions: 15 November 2024 | Viewed by 4406

Special Issue Editors

Dr. Orazio Palumbo

E-Mail Website1 Website2 Website3
Guest Editor
Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, Poliambulatorio “Giovanni Paolo II”, Viale Padre Pio, snc, 71013 San Giovanni Rotondo, FG, Italy
Interests: neurodevelopmental disorders; autism; epilepsy; copy number variations; genomic syndromes; next-generation sequencing; genotype–phenotype correlations
Special Issues, Collections and Topics in MDPI journals
Dr. Massimo Carella

E-Mail Website
Guest Editor
Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, Poliambulatorio “Giovanni Paolo II” Viale Padre Pio, snc, 71013 San Giovanni Rotondo, FG, Italy
Interests: linkage analysis; candidate gene; genetic diseases; neurodevelopmental disorders; epilepsy; genomic syndromes; next-generation sequencing; genotype–phenotype correlations; iPSCs
Special Issues, Collections and Topics in MDPI journals
Dr. Pietro Palumbo

E-Mail Website
Guest Editor
Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, Poliambulatorio “Giovanni Paolo II” Viale Padre Pio, snc, 71013 San Giovanni Rotondo, FG, Italy
Interests: neurodevelopmental disorders; epilepsy; autism spectrum disorders; next-generation sequencing; copy number variations; genotype–phenotype correlations
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Intellectual disability (ID) is a common neurodevelopmental disorder characterized by an intelligent quotient (QI) lower than 70, which is associated with functional deficit in adaptive behavior. ID represents a major challenge in medicine, being the most frequent cause of disability in children (nearly 3 of 100 babies are affected) and the main reason for referral in clinical genetic centers. Although the identification of underlying genetic defects and risk factors has increased significantly with the help of diagnostic technologies in the last decade, the mechanisms underlying the pathophysiology for this disorder remain elusive and, consequently, effective treatments have not yet been established. Finding a specific cause for ID has the potential to lead to more effective early intervention, targeted treatments, anticipation of comorbidities, and counselling for parents about prognosis and recurrence risk.

We encourage submissions of unpublished original manuscripts (research articles, reviews, and communications) to have a strong genetic component describing recent advances in all aspects related, but not limited, to the following topics: functional studies for ID-related genes or variants, gene expression analyses, rare variant analyses, animal models, iPSCs, non-coding RNAs and ID, clinical and molecular descriptions of new syndromic and non-syndromic forms of ID, and genotype–phenotype correlations.

Dr. Orazio Palumbo
Dr. Massimo Carella
Dr. Pietro Palumbo
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at mdpi.longhoe.net 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

  • ID-related genes
  • new syndromic and non-syndromic forms of ID
  • neurodevelopmental disorders
  • genotype–phenotype correlations
  • non-coding RNAs and ID
  • next-generation sequencing
  • chromosome microarray analysis
  • animal models
  • iPSCs

Published Papers (4 papers)

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15 pages, 4195 KiB  
Article
De Novo Pathogenic Variant in FBRSL1, Non OMIM Gene Paralogue AUTS2, Causes a Novel Recognizable Syndromic Manifestation with Intellectual Disability; An Additional Patient and Review of the Literature
by Nenad Bukvic, Marta De Rinaldis, Massimiliano Chetta, Antonio Trabacca, Maria Teresa Bassi, René Massimiliano Marsano, Lenka Holoubkova, Maria Rivieccio, Maria Oro, Nicoletta Resta, Jennifer Kerkhof, Bekim Sadikovic and Luigi Viggiano
Genes 2024, 15(7), 826; https://doi.org/10.3390/genes15070826 - 22 Jun 2024
Viewed by 413
Abstract
FBRSL1, together with FBRS and AUTS2 (Activator of Transcription and Developmental Regulator; OMIM 607270), constitutes a tripartite AUTS2 gene family. AUTS2 and FBRSL1 are evolutionarily more closely related to each other than to FBRS (Fibrosin 1; OMIM 608601). [...] Read more.
FBRSL1, together with FBRS and AUTS2 (Activator of Transcription and Developmental Regulator; OMIM 607270), constitutes a tripartite AUTS2 gene family. AUTS2 and FBRSL1 are evolutionarily more closely related to each other than to FBRS (Fibrosin 1; OMIM 608601). Despite its paralogous relation to AUTS2, FBRSL1’s precise role remains unclear, though it likely shares functions in neurogenesis and transcriptional regulation. Herein, we report the clinical presentation with therapeutic approaches and the molecular etiology of a patient harboring a de novo truncating variant (c.371dupC) in FBRSL1, leading to a premature stop codon (p.Cys125Leufs*7). Our study extends previous knowledge by highlighting potential interactions and implications of this variant, alongside maternal and paternal duplications, for the patient’s phenotype. Using sequence conservation data and in silico analysis of the truncated protein, we generated a predicted domain structure. Furthermore, our in silico analysis was extended by taking into account SNP array results. The extension of in silico analysis was performed due to the possibility that the coexistence of FBRSL1 truncating variant contemporary with maternal and paternal duplication could be a modifier of proband’s phenotype and/or influence the novel syndrome clinical characteristics. FBRSL1 protein may be involved in neurodevelopment due to its homology with AUTS2, together with distinctive neuronal expression profiles, and thus should be considered as a potential modulation of clinical characteristics in a novel syndrome. Finally, considering that FBRSL1 is apparently involved in neurogenesis and in transcriptional regulatory networks that orchestrate gene expression, together with the observation that different genetic syndromes are associated with distinct genomic DNA methylation patterns, the specific episignature has been explored. Full article
(This article belongs to the Special Issue Molecular Basis and Genetics of Intellectual Disability)
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8 pages, 732 KiB  
Case Report
Phenotypic Description of A Patient with ODLURO Syndrome and Functional Characterization of the Pathogenetic Role of A Synonymous Variant c.186G>A in KMT2E Gene
by Mario Benvenuto, Sofia Cesarini, Giulia Severi, Enrico Ambrosini, Angelo Russo, Marco Seri, Pietro Palumbo, Orazio Palumbo, Marco Castori, Emanuele Panza and Massimo Carella
Genes 2024, 15(4), 430; https://doi.org/10.3390/genes15040430 - 29 Mar 2024
Viewed by 1088
Abstract
O’Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant disorder caused by mutations in the KMT2E gene. The clinical phonotype of the affected individuals is typically characterized by global developmental delay, autism, epilepsy, hypotonia, macrocephaly, and very mild dysmorphic facial features. In this report, we [...] Read more.
O’Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant disorder caused by mutations in the KMT2E gene. The clinical phonotype of the affected individuals is typically characterized by global developmental delay, autism, epilepsy, hypotonia, macrocephaly, and very mild dysmorphic facial features. In this report, we describe the case of a 6-year-old boy with ODLURO syndrome who is a carrier of the synonymous mutation c.186G>A (p.Ala62=) in the KMT2E gene, predicted to alter splicing by in silico tools. Given the lack of functional studies on the c.186G>A variant, in order to assess its potential functional effect, we sequenced the patient’s cDNA demonstrating its impact on the mechanism of splicing. To the best of our knowledge, our patient is the second to date reported carrying this synonymous mutation, but he is the first whose functional investigation has confirmed the deleterious consequence of the variant, resulting in exon 4 skip**. Additionally, we suggest a potential etiological mechanism that could be responsible for the aberrant splicing mechanism in KMT2E. Full article
(This article belongs to the Special Issue Molecular Basis and Genetics of Intellectual Disability)
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8 pages, 1440 KiB  
Case Report
Duplication at 19q13.32q13.33 Segregating with Neuropsychiatric Phenotype in a Three-Generation Family: Towards the Definition of a Critical Region
by Daniele Guadagnolo, Gioia Mastromoro, Barbara Torres, Enrica Marchionni, Francesca di Palma, Marina Goldoni, Dario Cocciadiferro, Antonio Novelli, Laura Bernardini and Antonio Pizzuti
Genes 2023, 14(12), 2157; https://doi.org/10.3390/genes14122157 - 29 Nov 2023
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Abstract
Chromosomal submicroscopic imbalances represent well-known causes of neurodevelopmental disorders. In some cases, these can cause specific autosomal dominant syndromes, with high-to-complete penetrance and de novo occurrence of the variant. In other cases, they result in non-syndromic neurodevelopmental disorders, often acting as moderate-penetrance risk [...] Read more.
Chromosomal submicroscopic imbalances represent well-known causes of neurodevelopmental disorders. In some cases, these can cause specific autosomal dominant syndromes, with high-to-complete penetrance and de novo occurrence of the variant. In other cases, they result in non-syndromic neurodevelopmental disorders, often acting as moderate-penetrance risk factors, possibly inherited from unaffected parents. We describe a three-generation family with non-syndromic neuropsychiatric features segregating with a novel 19q13.32q13.33 microduplication. The propositus was a 28-month-old male ascertained for psychomotor delay, with no dysmorphic features or malformations. His mother had Attention-Deficit/Hyperactivity Disorder and a learning disability. The maternal uncle had an intellectual disability. Chromosomal microarray analysis identified a 969 kb 19q13.32q13.33 microduplication in the proband. The variant segregated in the mother, the uncle, and the maternal grandmother of the proband, who also presented neuropsychiatric disorders. Fragile-X Syndrome testing was negative. Exome Sequencing did not identify Pathogenic/Likely Pathogenic variants. Imbalances involving 19q13.32 and 19q13.33 are associated with neurodevelopmental delay. A review of the reported microduplications allowed to propose BICRA (MIM *605690) and KPTN (MIM *615620) as candidates for the neurodevelopmental delay susceptibility in 19q13.32q13.33 copy number gains. The peculiarities of this case are the small extension of the duplication, the three-generation segregation, and the full penetrance of the phenotype. Full article
(This article belongs to the Special Issue Molecular Basis and Genetics of Intellectual Disability)
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8 pages, 707 KiB  
Case Report
Identification of a Novel FOXP1 Variant in a Patient with Hypotonia, Intellectual Disability, and Severe Speech Impairment
by Mario Benvenuto, Pietro Palumbo, Ester Di Muro, Concetta Simona Perrotta, Tommaso Mazza, Giuseppa Maria Luana Mandarà, Orazio Palumbo and Massimo Carella
Genes 2023, 14(10), 1958; https://doi.org/10.3390/genes14101958 - 18 Oct 2023
Cited by 1 | Viewed by 1220
Abstract
The FOXP subfamily includes four different transcription factors: FOXP1, FOXP2, FOXP3, and FOXP4, all with important roles in regulating gene expression from early development through adulthood. Haploinsufficiency of FOXP1, due to deleterious variants (point mutations, copy number variants) disrupting the gene, leads [...] Read more.
The FOXP subfamily includes four different transcription factors: FOXP1, FOXP2, FOXP3, and FOXP4, all with important roles in regulating gene expression from early development through adulthood. Haploinsufficiency of FOXP1, due to deleterious variants (point mutations, copy number variants) disrupting the gene, leads to an emerging disorder known as “FOXP1 syndrome”, mainly characterized by intellectual disability, language impairment, dysmorphic features, and multiple congenital abnormalities with or without autistic features in some affected individuals (MIM 613670). Here we describe a 10-year-old female patient, born to unrelated parents, showing hypotonia, intellectual disability, and severe language delay. Targeted resequencing analysis allowed us to identify a heterozygous de novo FOXP1 variant c.1030C>T, p.(Gln344Ter) classified as likely pathogenetic according to the American College of Medical Genetics and Genomics guidelines. To the best of our knowledge, our patient is the first to date to report carrying this stop mutation, which is, for this reason, useful for broadening the molecular spectrum of FOXP1 clinically relevant variants. In addition, our results highlight the utility of next-generation sequencing in establishing an etiological basis for heterogeneous conditions such as neurodevelopmental disorders and providing additional insight into the phenotypic features of FOXP1-related syndrome. Full article
(This article belongs to the Special Issue Molecular Basis and Genetics of Intellectual Disability)
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