Genes

Research

17 pages, 1338 KiB

Open AccessArticle

A Study of the Genomic Variations Associated with Autistic Spectrum Disorders in a Russian Cohort of Patients Using Whole-Exome Sequencing

by Ekaterina A. Gibitova, Pavel V. Dobrynin, Ekaterina A. Pomerantseva, Elizaveta V. Musatova, Anna Kostareva, Igor Evsyukov, Sergey Y. Rychkov, Olga V. Zhukova, Oxana Y. Naumova and Elena L. Grigorenko

Genes 2022, 13(5), 920; https://doi.org/10.3390/genes13050920 - 20 May 2022

Cited by 3 | Viewed by 2384

Abstract

This study provides new data on the whole-exome sequencing of a cohort of children with autistic spectrum disorders (ASD) from an underexplored Russian population. Using both a cross-sectional approach involving a control cohort of the same ancestry and an annotation-based approach involving relevant [...] Read more.

This study provides new data on the whole-exome sequencing of a cohort of children with autistic spectrum disorders (ASD) from an underexplored Russian population. Using both a cross-sectional approach involving a control cohort of the same ancestry and an annotation-based approach involving relevant public databases, we explored exonic single nucleotide variants and copy-number variation potentially involved in the manifestation of ASD. The study results reveal new potential ASD candidate-variants found in the studied Russian cohort and show a high prevalence of common ASD-associated genomic variants, especially those in the genes known to be associated with the manifestation of intellectual disabilities. Our screening of an ASD cohort from a previously understudied population allowed us to flag at least a few novel genes (IGLJ2, FAM21A, OR11H12, HIP1, PRAMEF10, and ZNF717) regarding their potential involvement in ASD. Full article

(This article belongs to the Special Issue Genetics of Neurodevelopmental Disorders)

► Show Figures

Figure 1

12 pages, 1084 KiB

Open AccessArticle

Identification of Novel Gene Variants for Autism Spectrum Disorders in the Lebanese Population Using Whole-Exome Sequencing

by Perla Gerges, Tania Bitar, Frederic Laumonnier, Sylviane Marouillat, Georges Nemer, Christian R. Andres and Walid Hleihel

Genes 2022, 13(2), 186; https://doi.org/10.3390/genes13020186 - 21 Jan 2022

Cited by 4 | Viewed by 3638

Abstract

In our previous study, in which array CGH was used on 19 Lebanese ASD subjects and their parents, we identified rare copy number variants (CNVs) in 14 subjects. The five remaining subjects did not show any CNVs related to autism spectrum disorders (ASD). [...] Read more.

In our previous study, in which array CGH was used on 19 Lebanese ASD subjects and their parents, we identified rare copy number variants (CNVs) in 14 subjects. The five remaining subjects did not show any CNVs related to autism spectrum disorders (ASD). In the present complementary study, we applied whole-exome sequencing (WES), which allows the identification of rare genetic variations such as single nucleotide variations and small insertions/deletions, to the five negative CNV subjects. After stringent filtering of initial data on the five families, three novel genes potentially related to neurodevelopment were identified, including a de novo mutation in the MIS18BP1 gene. In addition, genes already known to be related to ASD contained sequence variations. Our findings outline the potential involvement of the novel de novo mutation in the MIS18BP1 gene in the genetic etiology and pathophysiology of ASD and highlights the genetic complexity of these disorders. Further studies with larger cohorts of subjects are needed to confirm these observations, and functional analyses need to be performed to understand the precise pathophysiology in these cases. Full article

(This article belongs to the Special Issue Genetics of Neurodevelopmental Disorders)

► Show Figures

Figure 1

11 pages, 2715 KiB

Open AccessArticle

A Novel GEMIN4 Variant in a Consanguineous Family Leads to Neurodevelopmental Impairment with Severe Microcephaly, Spastic Quadriplegia, Epilepsy, and Cataracts

by Hesham Aldhalaan, Albandary AlBakheet, Sarah AlRuways, Nouf AlMutairi, Maha AlNakiyah, Reema AlGhofaili, Kelly J. Cardona-Londoño, Khalid Omar Alahmadi, Hanan AlQudairy, Maha M. AlRasheed, Dilek Colak, Stefan T. Arold and Namik Kaya

Genes 2022, 13(1), 92; https://doi.org/10.3390/genes13010092 - 30 Dec 2021

Cited by 6 | Viewed by 2566

Abstract

Pathogenic variants in GEMIN4 contribute to a hereditary disorder characterized by neurodevelopmental features, microcephaly, cataracts, and renal abnormalities (known as NEDMCR). To date, only two homoallelic variations have been linked to the disease. Moreover, clinical features associated with the variants have not been [...] Read more.

Pathogenic variants in GEMIN4 contribute to a hereditary disorder characterized by neurodevelopmental features, microcephaly, cataracts, and renal abnormalities (known as NEDMCR). To date, only two homoallelic variations have been linked to the disease. Moreover, clinical features associated with the variants have not been fully elucidated yet. Here, we identified a novel variant in GEMIN4 (NM_015721:exon2:c.440A>G:p.His147Arg) in two siblings from a consanguineous Saudi family by using whole exome sequencing followed by Sanger sequence verification. We comprehensively investigated the patients’ clinical features, including brain imaging and electroencephalogram findings, and compared their phenotypic characteristics with those of previously reported cases. In silico prediction and structural modeling support that the p.His147Arg variant is pathogenic. Full article

(This article belongs to the Special Issue Genetics of Neurodevelopmental Disorders)

► Show Figures

Graphical abstract

13 pages, 5681 KiB

Open AccessArticle

Can the Synergic Contribution of Multigenic Variants Explain the Clinical and Cellular Phenotypes of a Neurodevelopmental Disorder?

by Nuno Maia, Maria João Nabais Sá, Cláudia Oliveira, Flávia Santos, Célia Azevedo Soares, Catarina Prior, Nataliya Tkachenko, Rosário Santos, Arjan P. M. de Brouwer, Ariana Jacome, Beatriz Porto and Paula Jorge

Genes 2022, 13(1), 78; https://doi.org/10.3390/genes13010078 - 28 Dec 2021

Cited by 1 | Viewed by 2178

Abstract

We describe an infant female with a syndromic neurodevelopmental clinical phenotype and increased chromosome instability as cellular phenotype. Genotype characterization revealed heterozygous variants in genes directly or indirectly linked to DNA repair: a de novo X-linked HDAC8 pathogenic variant, a paternally inherited FANCG [...] Read more.

We describe an infant female with a syndromic neurodevelopmental clinical phenotype and increased chromosome instability as cellular phenotype. Genotype characterization revealed heterozygous variants in genes directly or indirectly linked to DNA repair: a de novo X-linked HDAC8 pathogenic variant, a paternally inherited FANCG pathogenic variant and a maternally inherited BRCA2 variant of uncertain significance. The full spectrum of the phenotype cannot be explained by any of the heterozygous variants on their own; thus, a synergic contribution is proposed. Complementation studies showed that the FANCG gene from the Fanconi Anaemia/BRCA (FA/BRCA) DNA repair pathway was impaired, indicating that the variant in FANCG contributes to the cellular phenotype. The patient’s chromosome instability represents the first report where heterozygous variant(s) in the FA/BRCA pathway are implicated in the cellular phenotype. We propose that a multigenic contribution of heterozygous variants in HDAC8 and the FA/BRCA pathway might have a role in the phenotype of this neurodevelopmental disorder. The importance of these findings may have repercussion in the clinical management of other cases with a similar synergic contribution of heterozygous variants, allowing the establishment of new genotype–phenotype correlations and motivating the biochemical study of the underlying mechanisms. Full article

(This article belongs to the Special Issue Genetics of Neurodevelopmental Disorders)

► Show Figures

Figure 1

10 pages, 762 KiB

Open AccessArticle

EWAS of Monozygotic Twins Implicate a Role of mTOR Pathway in Pathogenesis of Tic Spectrum Disorder

by Mathis Hildonen, Amanda M. Levy, Christine Søholm Hansen, Jonas Bybjerg-Grauholm, Axel Skytthe, Nanette M. Debes, Qihua Tan and Zeynep Tümer

Genes 2021, 12(10), 1510; https://doi.org/10.3390/genes12101510 - 26 Sep 2021

Cited by 5 | Viewed by 2111

Abstract

Tic spectrum disorder (TSD) is an umbrella term which includes Gilles de la Tourette syndrome (GTS) and chronic tic disorder (CTD). They are considered highly heritable, yet the genetic components remain largely unknown. In this study we aimed to investigate disease-associated DNA methylation [...] Read more.

Tic spectrum disorder (TSD) is an umbrella term which includes Gilles de la Tourette syndrome (GTS) and chronic tic disorder (CTD). They are considered highly heritable, yet the genetic components remain largely unknown. In this study we aimed to investigate disease-associated DNA methylation differences to identify genes and pathways which may be implicated in TSD aetiology. For this purpose, we performed an exploratory analysis of the genome-wide DNA methylation patterns in whole blood samples of 16 monozygotic twin pairs, of which eight were discordant and six concordant for TSD, while two pairs were asymptomatic. Although no sites reached genome-wide significance, we identified several sites and regions with a suggestive significance, which were located within or in the vicinity of genes with biological functions associated with neuropsychiatric disorders. The two top genes identified (TSC1 and CRYZ/TYW3) and the enriched pathways and components (phosphoinosides and PTEN pathways, and insulin receptor substrate binding) are related to, or have been associated with, the PI3K/AKT/mTOR pathway. Genes in this pathway have previously been associated with GTS, and mTOR signalling has been implicated in a range of neuropsychiatric disorders. It is thus possible that altered mTOR signalling plays a role in the complex pathogenesis of TSD. Full article

(This article belongs to the Special Issue Genetics of Neurodevelopmental Disorders)

► Show Figures

Figure 1

Review

Jump to: Research, Other

15 pages, 14979 KiB

Open AccessReview

Genetic Variability of the Functional Domains of Chromodomains Helicase DNA-Binding (CHD) Proteins

by Ana R. Cardoso, Mónica Lopes-Marques, Manuela Oliveira, António Amorim, Maria J. Prata and Luísa Azevedo

Genes 2021, 12(11), 1827; https://doi.org/10.3390/genes12111827 - 19 Nov 2021

Cited by 7 | Viewed by 2588

Abstract

In the past few years, there has been an increasing neuroscientific interest in understanding the function of mammalian chromodomains helicase DNA-binding (CHD) proteins due to their association with severe developmental syndromes. Mammalian CHDs include nine members (CHD1 to CHD9), grouped into subfamilies according [...] Read more.

In the past few years, there has been an increasing neuroscientific interest in understanding the function of mammalian chromodomains helicase DNA-binding (CHD) proteins due to their association with severe developmental syndromes. Mammalian CHDs include nine members (CHD1 to CHD9), grouped into subfamilies according to the presence of specific functional domains, generally highly conserved in evolutionary terms. Mutations affecting these domains hold great potential to disrupt protein function, leading to meaningful pathogenic scenarios, such as embryonic defects incompatible with life. Here, we analysed the evolution of CHD proteins by performing a comparative study of the functional domains of CHD proteins between orthologous and paralogous protein sequences. Our findings show that the highest degree of inter-species conservation was observed at Group II (CHD3, CHD4, and CHD5) and that most of the pathological variations documented in humans involve amino acid residues that are conserved not only between species but also between paralogs. The parallel analysis of both orthologous and paralogous proteins, in cases where gene duplications have occurred, provided extra information showing patterns of flexibility as well as interchangeability between amino acid positions. This added complexity needs to be considered when the impact of novel mutations is assessed in terms of evolutionary conservation. Full article

(This article belongs to the Special Issue Genetics of Neurodevelopmental Disorders)

► Show Figures

Figure 1

20 pages, 4447 KiB

Open AccessReview

Genetics and Epigenetics of One-Carbon Metabolism Pathway in Autism Spectrum Disorder: A Sex-Specific Brain Epigenome?

by Veronica Tisato, Juliana A. Silva, Giovanna Longo, Ines Gallo, Ajay V. Singh, Daniela Milani and Donato Gemmati

Genes 2021, 12(5), 782; https://doi.org/10.3390/genes12050782 - 20 May 2021

Cited by 22 | Viewed by 5595

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition affecting behavior and communication, presenting with extremely different clinical phenotypes and features. ASD etiology is composite and multifaceted with several causes and risk factors responsible for different individual disease pathophysiological processes and clinical phenotypes. [...] Read more.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition affecting behavior and communication, presenting with extremely different clinical phenotypes and features. ASD etiology is composite and multifaceted with several causes and risk factors responsible for different individual disease pathophysiological processes and clinical phenotypes. From a genetic and epigenetic side, several candidate genes have been reported as potentially linked to ASD, which can be detected in about 10–25% of patients. Folate gene polymorphisms have been previously associated with other psychiatric and neurodegenerative diseases, mainly focused on gene variants in the DHFR gene (5q14.1; rs70991108, 19bp ins/del), MTHFR gene (1p36.22; rs1801133, C677T and rs1801131, A1298C), and CBS gene (21q22.3; rs876657421, 844ins68). Of note, their roles have been scarcely investigated from a sex/gender viewpoint, though ASD is characterized by a strong sex gap in onset-risk and progression. The aim of the present review is to point out the molecular mechanisms related to intracellular folate recycling affecting in turn remethylation and transsulfuration pathways having potential effects on ASD. Brain epigenome during fetal life necessarily reflects the sex-dependent different imprint of the genome-environment interactions which effects are difficult to decrypt. We here will focus on the DHFR, MTHFR and CBS gene-triad by dissecting their roles in a sex-oriented view, primarily to bring new perspectives in ASD epigenetics. Full article

(This article belongs to the Special Issue Genetics of Neurodevelopmental Disorders)

► Show Figures

Graphical abstract

Other

Jump to: Research, Review

13 pages, 705 KiB

Open AccessCase Report

Helsmoortel–Van der Aa Syndrome—Cardiothoracic and Ectodermal Manifestations in Two Patients as Further Support of a Previous Observation on Phenotypic Overlap with RASopathies

by Tímea Margit Szabó, István Balogh, Anikó Ujfalusi, Zsuzsanna Szűcs, László Madar, Katalin Koczok, Beáta Bessenyei, Ildikó Csürke and Katalin Szakszon

Genes 2022, 13(12), 2367; https://doi.org/10.3390/genes13122367 - 15 Dec 2022

Cited by 1 | Viewed by 3166

Abstract

The ADNP-gene-related neurodevelopmental disorder Helsmoortel–Van der Aa syndrome is a rare syndromic-intellectual disability—an autism spectrum disorder first described by Helsmoortel and Van der Aa in 2014. Recently, a large cohort including 78 patients and their detailed phenotypes were presented by Van Dijck [...] Read more.

The ADNP-gene-related neurodevelopmental disorder Helsmoortel–Van der Aa syndrome is a rare syndromic-intellectual disability—an autism spectrum disorder first described by Helsmoortel and Van der Aa in 2014. Recently, a large cohort including 78 patients and their detailed phenotypes were presented by Van Dijck et al., 2019, who reported developmental delay, speech delay and autism spectrum disorder as nearly constant findings with or without variable cardiological, gastroenterological, urogenital, endocrine and neurological manifestations. Among cardiac malformations, atrial septal defect, patent ductus arteriosus, patent foramen ovale and mitral valve prolapse were the most common findings, but other unspecified defects, such as mild pulmonary valve stenosis, were also described. We present two patients with pathogenic ADNP variants and unusual cardiothoracic manifestations—Bland–White–Garland syndrome, pectus carinatum superiorly along the costochondral junctions and pectus excavatum inferiorly in one patient, and Kawasaki syndrome with pericardiac effusion, coronary artery dilatation and aneurysm in the other—who were successfully treated with intravenous immunoglobulin, corticosteroid and aspirin. Both patients had ectodermal and/or skeletal features overlapping those seen in RASopathies, supporting the observations of Alkhunaizi et al. 2018. on the clinical overlap between Helsmoortel–Van der Aa syndrome and Noonan syndrome. We observed a morphological overlap with the Noonan-like disorder with anagen hair in our patients. Full article

(This article belongs to the Special Issue Genetics of Neurodevelopmental Disorders)

► Show Figures

Figure 1

6 pages, 530 KiB

Open AccessCase Report

A TSHZ3 Frame-Shift Variant Causes Neurodevelopmental and Renal Disorder Consistent with Previously Described Proximal Chromosome 19q13.11 Deletion Syndrome

by René G. Feichtinger, Martin Preisel, Katja Steinbrücker, Karin Brugger, Alexandra Radda, Saskia B. Wortmann and Johannes A. Mayr

Genes 2022, 13(12), 2191; https://doi.org/10.3390/genes13122191 - 23 Nov 2022

Viewed by 1374

Abstract

Heterozygous deletions at 19q12–q13.11 affecting TSHZ3, the teashirt zinc finger homeobox 3, have been associated with intellectual disability and behavioural issues, congenital anomalies of the kidney and urinary tract (CAKUT), and postnatal growth retardation in humans and mice. TSHZ3 encodes a transcription factor [...] Read more.

Heterozygous deletions at 19q12–q13.11 affecting TSHZ3, the teashirt zinc finger homeobox 3, have been associated with intellectual disability and behavioural issues, congenital anomalies of the kidney and urinary tract (CAKUT), and postnatal growth retardation in humans and mice. TSHZ3 encodes a transcription factor regulating the development of neurons but is ubiquitously expressed. Using exome sequencing, we identified a heterozygous frameshift variant c.119_120dup p.Pro41SerfsTer79 in TSHZ3 in a 7-year-old girl with intellectual disability, behavioural issues, pyelocaliceal dilatation, and mild urethral stenosis. The variant was present on the paternal TSHZ3 allele. The DNA from the father was not available for testing. This is the first report of a heterozygous point mutation in TSHZ3 causing the same phenotype as reported for monoallelic deletions in the same region. This confirms TSHZ3 as a novel disease gene for neurodevelopmental disorder in combination with behavioural issues and CAKUT. Full article

(This article belongs to the Special Issue Genetics of Neurodevelopmental Disorders)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Genetics of Neurodevelopmental Disorders

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (9 papers)

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI