Developmental delay (DD) and intellectual disability (ID) are characterized by cognitive impairment caused by brain damage or incomplete development, with a global prevalence of ~1-3%. They comprise a set of complex neurodevelopmental disorders with extensive phenotypic heterogeneity and diverse underpinnings. Genetic causes are estimated to be responsible for approximately one quarter to one half of identified cases. At present, more than 600 genes and 130 rare copy number variants (CNVs) have been reported to be associated with DD and ID. Germline single nucleotide variants (SNVs) or CNVs have been implicated in DD and ID with autosomal dominant, autosomal recessive and X-linked inheritance. De novo germline mutations are also a prevalent cause of DD and ID. Hence, identification of candidate causal genes would allow us to understand the molecular causes underlying the disease phenotype which in turn would enable clinicians to make easy, timely and accurate clinical diagnoses.
Chromosome microarray (CMA) is an established first-level diagnostic test to identify chromosomal abnormalities, microdeletions or microduplication among patients with DD and ID, but can be limited by reduced sensitivity in detecting small genomic lesions. The reduced cost and turnaround time for whole genome sequencing and whole exome sequencing have improved further our overall ability to study DD and ID cohorts, rapidly accelerating our knowledge of causal genes, molecular pathways, and comorbid features. For example, multidisciplinary approaches have revealed involvement of chromatin remodeling, cell cycle regulation, and synapse formation in the mutational basis of DD and ID. Moreover, detailed categorization of comorbid features such as seizures and craniofacial dysmorphisms serve as early harbingers of eventual ID/DD, offering utility as diagnostic and prognostic markers.
In this Research Topic, we aim to feature new causal genes; advances in the mechanistic understanding of previously reported DD and ID genes; and potential therapeutic applications. We invite research focusing on:
• New causal gene identification for DD and ID.
• New molecular methods for identifying mutations.
• New approaches to clinical diagnosis.
• Transcriptional underpinnings of DD and ID in relevant cell types.
• Systems biology approaches to characterize functional groups of genes and proteins that contribute to brain development.
• Model organisms to study candidate variants, genes, or CNVs contributing to DD and ID.
• Novel therapeutic development strategies to improve quality of life for individuals with DD and ID.
• Grouping of individually rare ID/DD syndromes by function, pathway, or organelle that is impaired to accelerate functional understanding of the disease.
Developmental delay (DD) and intellectual disability (ID) are characterized by cognitive impairment caused by brain damage or incomplete development, with a global prevalence of ~1-3%. They comprise a set of complex neurodevelopmental disorders with extensive phenotypic heterogeneity and diverse underpinnings. Genetic causes are estimated to be responsible for approximately one quarter to one half of identified cases. At present, more than 600 genes and 130 rare copy number variants (CNVs) have been reported to be associated with DD and ID. Germline single nucleotide variants (SNVs) or CNVs have been implicated in DD and ID with autosomal dominant, autosomal recessive and X-linked inheritance. De novo germline mutations are also a prevalent cause of DD and ID. Hence, identification of candidate causal genes would allow us to understand the molecular causes underlying the disease phenotype which in turn would enable clinicians to make easy, timely and accurate clinical diagnoses.
Chromosome microarray (CMA) is an established first-level diagnostic test to identify chromosomal abnormalities, microdeletions or microduplication among patients with DD and ID, but can be limited by reduced sensitivity in detecting small genomic lesions. The reduced cost and turnaround time for whole genome sequencing and whole exome sequencing have improved further our overall ability to study DD and ID cohorts, rapidly accelerating our knowledge of causal genes, molecular pathways, and comorbid features. For example, multidisciplinary approaches have revealed involvement of chromatin remodeling, cell cycle regulation, and synapse formation in the mutational basis of DD and ID. Moreover, detailed categorization of comorbid features such as seizures and craniofacial dysmorphisms serve as early harbingers of eventual ID/DD, offering utility as diagnostic and prognostic markers.
In this Research Topic, we aim to feature new causal genes; advances in the mechanistic understanding of previously reported DD and ID genes; and potential therapeutic applications. We invite research focusing on:
• New causal gene identification for DD and ID.
• New molecular methods for identifying mutations.
• New approaches to clinical diagnosis.
• Transcriptional underpinnings of DD and ID in relevant cell types.
• Systems biology approaches to characterize functional groups of genes and proteins that contribute to brain development.
• Model organisms to study candidate variants, genes, or CNVs contributing to DD and ID.
• Novel therapeutic development strategies to improve quality of life for individuals with DD and ID.
• Grouping of individually rare ID/DD syndromes by function, pathway, or organelle that is impaired to accelerate functional understanding of the disease.
