Intellectual disability genomics: current state, pitfalls and future challenges

Maia, Nuno; Sá, Maria João Nabais; Melo‐Pires, Manuel; Brouwer, Arjan P.M. de; Jorge, Paula

doi:10.1186/s12864-021-08227-4

Cited by 42 publications

(30 citation statements)

References 196 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ID and ASD have high genetic components in their etiology, and the genetic deficits of ID and ASD are highly heterogeneous, ranging from chromosomal abnormalities and copy number variations of genomic DNA (CNV) to small insertions and deletions (indel) and single nucleotide variants (SNV) [ 8 , 9 ]. More than 1000 genes are associated with ASD [ 10 ] and intellectual disability [ 11 ], and there are significant overlaps in pathogenic genes between ID and ASD, suggesting shared pathogenesis mechanisms between ID and ASD. Further, most pathogenic mutations associated with ID and ASD are individualized and personalized.…”

Section: Introductionmentioning

confidence: 99%

Two Genetic Mechanisms in Two Siblings with Intellectual Disability, Autism Spectrum Disorder, and Psychosis

Huang

Fang

Kung

et al. 2022

JPM

View full text Add to dashboard Cite

Intellectual disability (ID) and autism spectrum disorder (ASD) are complex neurodevelopmental disorders with high heritability. To search for the genetic deficits in two siblings affected with ID and ASD in a family, we first performed a genome-wide copy number variation (CNV) analysis using chromosomal microarray analysis (CMA). We found a 3.7 Mb microdeletion at 22q13.3 in the younger sister. This de novo microdeletion resulted in the haploinsufficiency of SHANK3 and several nearby genes involved in neurodevelopment disorders. Hence, she was diagnosed with Phelan–McDermid syndrome (PMS, OMIM#606232). We further performed whole-genome sequencing (WGS) analysis in this family. We did not detect pathogenic mutations with significant impacts on the phenotypes of the elder brother. Instead, we identified several rare, likely pathogenic variants in seven genes implicated in neurodevelopmental disorders: KLHL17, TDO2, TRRAP, EIF3F, ATP10A, DICER1, and CDH15. These variants were transmitted from his unaffected parents, indicating these variants have only moderate clinical effects. We propose that these variants worked together and led to the clinical phenotypes in the elder brother. We also suggest that the combination of multiple genes with moderate effects is part of the genetic mechanism of neurodevelopmental disorders.

show abstract

Section: Introductionmentioning

confidence: 99%

Two Genetic Mechanisms in Two Siblings with Intellectual Disability, Autism Spectrum Disorder, and Psychosis

Huang

Fang

Kung

et al. 2022

JPM

View full text Add to dashboard Cite

show abstract

“…DD/ID is a prevailing neurodevelopmental disorder [6,38,39]. Although the majority of severe DD/ID are prone to have a monogenetic origin, the cause of DD/ID remains unexplained in at least 50% of cases [40,41]. This phenotypic and genetic heterogeneity often result in a delay in diagnosis.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Novel Mutation in CTCF in a Family with MRD21

Qiao

Chen

Han

et al. 2022

Preprint

View full text Add to dashboard Cite

Background Developmental delay (DD) and intellectual disability (ID) represent one of the biggest medical and social challenges in our society with a prevalence of 1 ~ 3% worldwide. Currently, at least 50% of DD/ID cases remained unexplained. Mental retardation, autosomal dominant 21 (MRD21), caused by mutations in CTCF, is a rare DD/ID-related disease. The clinical phenotypes of MRD21 are highly variable but are not considered sufficiently distinct to be clinically recognizable. To date, only 37 pathogenic/likely pathogenic mutations in CTCF associated with MRD21 have been identified, and the pathogenesis of CTCF remains largely unknown. Methods Whole exon sequencing (WES) and bioinformatics analysis were used to identify the mutation as being responsible for an 18-month-old girl with unexplained DD, abnormality of the face and congenital heart disease. The origin of the mutation was analyzed by Sanger sequencing. The pathogenicity of the missense mutation was mainly analyzed by western blot (WB) and molecular dynamics (MD) simulations. Results We identified a novel missense mutation in CTCF (c.1115C > T, p. Ser372Phe) using WES, and Sanger sequencing indicated that the mutation was de novo. The expression levels of CTCF in 293T cells were unaltered by the missense mutation. However, MD simulations supported the pathogenicity of the p. Ser372Phe mutation, which resulted a decrease in the binding affinity of CTCF with DNA. Conclusions Our study broadens the mutational spectrum of CTCF and provides a better understanding of the pathogenicity of missense mutations in CTCF. This is the first time that MD simulations have been applied to evaluate the pathogenicity of missense mutations in CTCF.

show abstract

“…ID is influenced both by genetic as well as environmental factors that affect the development and functioning of the nervous system, prenatally, perinatally, or postnatally or a combination thereof. Conventional cytogenetics, such as karyotyping and fluorescence in situ hybridization (FISH), allow the identification of about 15% of ID causes [ 2 ]. The advent of chromosomal microarrays (CMA) and whole exome sequencing (WES), two clinical tests frequently applied in the diagnosis of ID, has increased the diagnostic yield of neurodevelopmental disorders (NDDs) to 15–20% and 30–43%, respectively [ 3 ].…”

Section: Intellectual Disabilitymentioning

confidence: 99%

Human Brain Models of Intellectual Disability: Experimental Advances and Novelties

Merckx

Esch

2022

IJMS

View full text Add to dashboard Cite

Intellectual disability (ID) is characterized by deficits in conceptual, social and practical domains. ID can be caused by both genetic defects and environmental factors and is extremely het-erogeneous, which complicates the diagnosis as well as the deciphering of the underlying pathways. Multiple scientific breakthroughs during the past decades have enabled the development of novel ID models. The advent of induced pluripotent stem cells (iPSCs) enables the study of patient-de-rived human neurons in 2D or in 3D organoids during development. Gene-editing tools, such as CRISPR/Cas9, provide isogenic controls and opportunities to design personalized gene therapies. In practice this has contributed significantly to the understanding of ID and opened doors to identify novel therapeutic targets. Despite these advances, a number of areas of improvement remain for which novel technologies might entail a solution in the near future. The purpose of this review is to provide an overview of the existing literature on scientific breakthroughs that have been advancing the way ID can be studied in the human brain. The here described human brain models for ID have the potential to accelerate the identification of underlying pathophysiological mechanisms and the development of therapies.

show abstract

Intellectual disability genomics: current state, pitfalls and future challenges

Cited by 42 publications

References 196 publications

Two Genetic Mechanisms in Two Siblings with Intellectual Disability, Autism Spectrum Disorder, and Psychosis

Two Genetic Mechanisms in Two Siblings with Intellectual Disability, Autism Spectrum Disorder, and Psychosis

Identification of a Novel Mutation in CTCF in a Family with MRD21

Human Brain Models of Intellectual Disability: Experimental Advances and Novelties

Contact Info

Product

Resources

About