Genetic Diagnosis in Children with Developmental Delay

A special issue of Children (ISSN 2227-9067). This special issue belongs to the section "Pediatric Neurology & Neurodevelopmental Disorders".

Deadline for manuscript submissions: closed (5 September 2023) | Viewed by 22081

Special Issue Editor


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Guest Editor
1. School of Medicine, Fu-Jen Catholic University, New Taipei City 242, Taiwan
2. Department of Pediatrics, Fu-Jen Catholic University Hospital, New Taipei City 243, Taiwan
Interests: pediatric neurology; epilepsy; child development and developmental delay; neurological critical care; medical education

Special Issue Information

Dear Colleagues,

Developmental delays have major impacts on children in the developing stage, which cause various degrees of motor delay, intellectual disabilities, epilepsy, and other deficits. The diagnoses of developmental delay are dependent on traditional screening by questionnaire checklists followed by a group of specialists working on pediatric, neurological, psychiatric, and psychological evaluations. The clinical complexity and uncertainty make a definite clinical diagnosis difficult.

The introduction of recent advances in neurogenetic testing in the past two decades, such as target panel testing and whole-exome or whole-genome sequencing, can give a potential etiologic diagnosis of children with developmental delay. More and more genetic problems have been discovered from common clinical phenotypes of developmental delay, including global delay, attention deficient hyperactivity disorder, autistic spectrum disorder, intellectual disability, or specific genetic syndromes. Identification of genetic mutation can help to deliver appropriate genetic counseling and care plans for patients and their families.

This Special Issue is dedicated to compiling the most recent knowledge about genetic diagnosis in children with developmental delay.

Prof. Dr. Kun-Long Hung
Guest Editor

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Keywords

  • developmental delay

  • genetic diagnosis

  • polymerase chain reaction (PCR)

  • fluorescence in situ hybridization (FISH)

  • array comparative genomic hybridization (array CGH)

  • target panel testing

  • whole exome sequencing

  • whole genome sequencing

Published Papers (7 papers)

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Editorial

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4 pages, 172 KiB  
Editorial
Genetic Diagnosis in Children with Developmental Delay
by Kun-Long Hung
Children 2024, 11(6), 669; https://doi.org/10.3390/children11060669 - 30 May 2024
Viewed by 363
Abstract
Developmental delay (DD) has a great impact on children at the developmental stage, and is often manifested by varying degrees of motor delays, intellectual disabilities, and other defects [...] Full article
(This article belongs to the Special Issue Genetic Diagnosis in Children with Developmental Delay)

Research

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14 pages, 3286 KiB  
Article
Identification of Extremely Rare Pathogenic CNVs by Array CGH in Saudi Children with Developmental Delay, Congenital Malformations, and Intellectual Disability
by Sajjad Karim, Ibtessam Ramzi Hussein, Hans-Juergen Schulten, Saad Alsaedi, Zeenat Mirza, Mohammed Al-Qahtani and Adeel Chaudhary
Children 2023, 10(4), 662; https://doi.org/10.3390/children10040662 - 31 Mar 2023
Viewed by 1748
Abstract
Chromosomal imbalance is implicated in developmental delay (DD), congenital malformations (CM), and intellectual disability (ID), and, thus, precise identification of copy number variations (CNVs) is essential. We therefore aimed to investigate the genetic heterogeneity in Saudi children with DD/CM/ID. High-resolution array comparative genomic [...] Read more.
Chromosomal imbalance is implicated in developmental delay (DD), congenital malformations (CM), and intellectual disability (ID), and, thus, precise identification of copy number variations (CNVs) is essential. We therefore aimed to investigate the genetic heterogeneity in Saudi children with DD/CM/ID. High-resolution array comparative genomic hybridization (array CGH) was used to detect disease-associated CNVs in 63 patients. Quantitative PCR was done to confirm the detected CNVs. Giemsa banding-based karyotyping was also performed. Array CGH identified chromosomal abnormalities in 24 patients; distinct pathogenic and/or variants of uncertain significance CNVs were found in 19 patients, and aneuploidy was found in 5 patients including 47,XXY (n = 2), 45,X (n = 2) and a patient with trisomy 18 who carried a balanced Robertsonian translocation. CNVs including 9p24p13, 16p13p11, 18p11 had gains/duplications and CNVs, including 3p23p14, 10q26, 11p15, 11q24q25, 13q21.1q32.1, 16p13.3p11.2, and 20q11.1q13.2, had losses/deletions only, while CNVs including 8q24, 11q12, 15q25q26, 16q21q23, and 22q11q13 were found with both gains or losses in different individuals. In contrast, standard karyotyping detected chromosomal abnormalities in ten patients. The diagnosis rate of array CGH (28%, 18/63 patients) was around two-fold higher than that of conventional karyotyping (15.87%, 10/63 patients). We herein report, for the first time, the extremely rare pathogenic CNVs in Saudi children with DD/CM/ID. The reported prevalence of CNVs in Saudi Arabia adds value to clinical cytogenetics. Full article
(This article belongs to the Special Issue Genetic Diagnosis in Children with Developmental Delay)
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13 pages, 1958 KiB  
Article
Long-Term Outcome of Neonatal Seizure with PACS2 Mutation: Case Series and Literature Review
by I-Jun Chou, Ju-Yin Hou, Wen-Lang Fan, Meng-Han Tsai and Kuang-Lin Lin
Children 2023, 10(4), 621; https://doi.org/10.3390/children10040621 - 26 Mar 2023
Cited by 1 | Viewed by 2645
Abstract
Phosphofurin Acidic Cluster Sorting Protein 2 (PACS2)-related early infantile developmental and epileptic encephalopathy (EIDEE) is a rare neurodevelopmental disorder. EIDEE is characterized by seizures that begin during the first three months of life and are accompanied by developmental impairment over time. In [...] Read more.
Phosphofurin Acidic Cluster Sorting Protein 2 (PACS2)-related early infantile developmental and epileptic encephalopathy (EIDEE) is a rare neurodevelopmental disorder. EIDEE is characterized by seizures that begin during the first three months of life and are accompanied by developmental impairment over time. In this article, we present three patients with EIDEE who experienced neonatal-onset seizures that developed into intractable seizures during infancy. Whole exome sequencing revealed a de novo heterozygous missense variant in all three patients in the p.Glu209Lys variant of the PACS2 gene. We conducted a literature review and found 29 cases to characterize the seizure patterns, neuroimaging features, the usage of anticonvulsants, and the clinical neurodevelopmental outcomes of PACS2-related EIDEE. The seizures were characterized by brief, recurring tonic seizures in the upper limbs, sometimes accompanied by autonomic features. Neuroimaging abnormalities were observed in the posterior fossa region, including mega cisterna magna, cerebellar dysplasia, and vermian hypoplasia. The long-term prognosis ranges from low–average intelligence to severe developmental retardation, emphasizing the importance of early recognition and accurate diagnosis by pediatric neurologists to provide personalized patient management. Full article
(This article belongs to the Special Issue Genetic Diagnosis in Children with Developmental Delay)
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Review

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16 pages, 4361 KiB  
Review
Holoprosencephaly: Review of Embryology, Clinical Phenotypes, Etiology and Management
by Maísa Malta, Rowim AlMutiri, Christine Saint Martin and Myriam Srour
Children 2023, 10(4), 647; https://doi.org/10.3390/children10040647 - 30 Mar 2023
Cited by 5 | Viewed by 7141
Abstract
Holoprosencephaly (HPE) is the most common malformation of the prosencephalon in humans. It is characterized by a continuum of structural brain anomalies resulting from the failure of midline cleavage of the prosencephalon. The three classic subtypes of HPE are alobar, semilobar and lobar, [...] Read more.
Holoprosencephaly (HPE) is the most common malformation of the prosencephalon in humans. It is characterized by a continuum of structural brain anomalies resulting from the failure of midline cleavage of the prosencephalon. The three classic subtypes of HPE are alobar, semilobar and lobar, although a few additional categories have been added to this original classification. The severity of the clinical phenotype is broad and usually mirrors the radiologic and associated facial features. The etiology of HPE includes both environmental and genetic factors. Disruption of sonic hedgehog (SHH) signaling is the main pathophysiologic mechanism underlying HPE. Aneuploidies, chromosomal copy number variants and monogenic disorders are identified in a large proportion of HPE patients. Despite the high postnatal mortality and the invariable presence of developmental delay, recent advances in diagnostic methods and improvements in patient management over the years have helped to increase survival rates. In this review, we provide an overview of the current knowledge related to HPE, and discuss the classification, clinical features, genetic and environmental etiologies and management. Full article
(This article belongs to the Special Issue Genetic Diagnosis in Children with Developmental Delay)
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14 pages, 1219 KiB  
Review
Genetic Testing in Children with Developmental and Epileptic Encephalopathies: A Review of Advances in Epilepsy Genomics
by Yu-Tzu Chang, Syuan-Yu Hong, Wei-De Lin, Chien-Heng Lin, Sheng-Shing Lin, Fuu-Jen Tsai and I-Ching Chou
Children 2023, 10(3), 556; https://doi.org/10.3390/children10030556 - 15 Mar 2023
Cited by 6 | Viewed by 3476
Abstract
Advances in disease-related gene discovery have led to tremendous innovations in the field of epilepsy genetics. Identification of genetic mutations that cause epileptic encephalopathies has opened new avenues for the development of targeted therapies. Clinical testing using extensive gene panels, exomes, and genomes [...] Read more.
Advances in disease-related gene discovery have led to tremendous innovations in the field of epilepsy genetics. Identification of genetic mutations that cause epileptic encephalopathies has opened new avenues for the development of targeted therapies. Clinical testing using extensive gene panels, exomes, and genomes is currently accessible and has resulted in higher rates of diagnosis and better comprehension of the disease mechanisms underlying the condition. Children with developmental disabilities have a higher risk of developing epilepsy. As our understanding of the mechanisms underlying encephalopathies and epilepsies improves, there may be greater potential to develop innovative therapies tailored to an individual’s genotype. This article provides an overview of the significant progress in epilepsy genomics in recent years, with a focus on developmental and epileptic encephalopathies in children. The aim of this review is to enhance comprehension of the clinical utilization of genetic testing in this particular patient population. The development of effective and precise therapeutic strategies for epileptic encephalopathies may be facilitated by a comprehensive understanding of their molecular pathogenesis. Full article
(This article belongs to the Special Issue Genetic Diagnosis in Children with Developmental Delay)
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16 pages, 508 KiB  
Review
Genome-Wide Sequencing Modalities for Children with Unexplained Global Developmental Delay and Intellectual Disabilities—A Narrative Review
by Mary Hsin-Ju Ko and Hui-Ju Chen
Children 2023, 10(3), 501; https://doi.org/10.3390/children10030501 - 3 Mar 2023
Cited by 5 | Viewed by 2298
Abstract
Unexplained global developmental delay (GDD) and intellectual disabilities (ID) together affect nearly 2% of the pediatric population. Establishing an etiologic diagnosis is crucial for disease management, prognostic evaluation, and provision of physical and psychological support for both the patient and the family. Advancements [...] Read more.
Unexplained global developmental delay (GDD) and intellectual disabilities (ID) together affect nearly 2% of the pediatric population. Establishing an etiologic diagnosis is crucial for disease management, prognostic evaluation, and provision of physical and psychological support for both the patient and the family. Advancements in genome sequencing have allowed rapid accumulation of gene–disorder associations and have accelerated the search for an etiologic diagnosis for unexplained GDD/ID. We reviewed recent studies that utilized genome-wide analysis technologies, and we discussed their diagnostic yield, strengths, and limitations. Overall, exome sequencing (ES) and genome sequencing (GS) outperformed chromosomal microarrays and targeted panel sequencing. GS provides coverage for both ES and chromosomal microarray regions, providing the maximal diagnostic potential, and the cost of ES and reanalysis of ES-negative results is currently still lower than that of GS alone. Therefore, singleton or trio ES is the more cost-effective option for the initial investigation of individuals with GDD/ID in clinical practice compared to a staged approach or GS alone. Based on these updated evidence, we proposed an evaluation algorithm with ES as the first-tier evaluation for unexplained GDD/ID. Full article
(This article belongs to the Special Issue Genetic Diagnosis in Children with Developmental Delay)
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17 pages, 867 KiB  
Review
Evaluation of Individuals with Non-Syndromic Global Developmental Delay and Intellectual Disability
by Rowim AlMutiri, Maisa Malta, Michael I. Shevell and Myriam Srour
Children 2023, 10(3), 414; https://doi.org/10.3390/children10030414 - 21 Feb 2023
Cited by 2 | Viewed by 3580
Abstract
Global Developmental Delay (GDD) and Intellectual Disability (ID) are two of the most common presentations encountered by physicians taking care of children. GDD/ID is classified into non-syndromic GDD/ID, where GDD/ID is the sole evident clinical feature, or syndromic GDD/ID, where there are additional [...] Read more.
Global Developmental Delay (GDD) and Intellectual Disability (ID) are two of the most common presentations encountered by physicians taking care of children. GDD/ID is classified into non-syndromic GDD/ID, where GDD/ID is the sole evident clinical feature, or syndromic GDD/ID, where there are additional clinical features or co-morbidities present. Careful evaluation of children with GDD and ID, starting with detailed history followed by a thorough examination, remain the cornerstone for etiologic diagnosis. However, when initial history and examination fail to identify a probable underlying etiology, further genetic testing is warranted. In recent years, genetic testing has been shown to be the single most important diagnostic modality for clinicians evaluating children with non-syndromic GDD/ID. In this review, we discuss different genetic testing currently available, review common underlying copy-number variants and molecular pathways, explore the recent evidence and recommendations for genetic evaluation and discuss an approach to the diagnosis and management of children with non-syndromic GDD and ID. Full article
(This article belongs to the Special Issue Genetic Diagnosis in Children with Developmental Delay)
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