scholarly journals Novel Hemizygous Missense Variation in AFF2 Gene Underlies Fragile XE Syndrome

2020 ◽  
Author(s):  
Iftikhar Ahmed ◽  
Gaurav V Harlalka ◽  
Muhammad Ilyas ◽  
Asif Mir
Keyword(s):  
Intellectual Disability ◽  
Autism Spectrum ◽  
Sequencing Analysis ◽  
Speech Delay ◽  
Pakistani Population ◽  
Neurodevelopmental Delay ◽  
Whole Exome ◽  
Novel Variant ◽  
Missense Variation ◽  
Recessive Disorders

Abstract Background: Fragile XE (FRAXE) is an X-linked recessive condition of intellectual disability affecting 1 in 50,000 new born male. FRAXE is characterized by mild ID, cognitive impairment, speech delay and some cases patients display Autism Spectrum disorder (ASD) like phenotypes. . Method: In this study, we investigated a family with two male siblings with neurodevelopmental delay Whole exome sequencing analysis (WES) was employed to identify the pathogenic variant. Co-segregation analysis was performed through Sanger sequencing in affected and normal family members.Results: Two affected Proband of family were diagnosed with intellectual disability. A novel hemizygous variant, c.3348G>T; p.Asp1150Tyr, in AFF2 gene was identified as the pathogenic cause in affected individuals. It is first novel variant report in AFF2 gene within Pakistani population. Conclusion: In this study, novel hemizygous variant, c.3348G>T; p.Asp1150Tyr, in AFF2 gene was identified. The findings broaden the clinical and genetic spectrum of rare X-linked recessive disorders causing ID.

scholarly journals Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size

Brain ◽  
2019 ◽  
Vol 142 (9) ◽  
pp. 2617-2630 ◽  
Author(s):  
Diana Le Duc ◽  
Cecilia Giulivi ◽  
Susan M Hiatt ◽  
Eleonora Napoli ◽  
Alexios Panoutsopoulos ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Wnt Pathway ◽  
De Novo ◽  
Autism Spectrum ◽  
Neural Progenitors ◽  
Scaffolding Protein ◽  
Published Data ◽  
Ph Domain ◽  
Human Phenotype ◽  
Neurodevelopmental Delay

Abstract The underpinnings of mild to moderate neurodevelopmental delay remain elusive, often leading to late diagnosis and interventions. Here, we present data on exome and genome sequencing as well as array analysis of 13 individuals that point to pathogenic, heterozygous, mostly de novo variants in WDFY3 (significant de novo enrichment P = 0.003) as a monogenic cause of mild and non-specific neurodevelopmental delay. Nine variants were protein-truncating and four missense. Overlapping symptoms included neurodevelopmental delay, intellectual disability, macrocephaly, and psychiatric disorders (autism spectrum disorders/attention deficit hyperactivity disorder). One proband presented with an opposing phenotype of microcephaly and the only missense-variant located in the PH-domain of WDFY3. Findings of this case are supported by previously published data, demonstrating that pathogenic PH-domain variants can lead to microcephaly via canonical Wnt-pathway upregulation. In a separate study, we reported that the autophagy scaffolding protein WDFY3 is required for cerebral cortical size regulation in mice, by controlling proper division of neural progenitors. Here, we show that proliferating cortical neural progenitors of human embryonic brains highly express WDFY3, further supporting a role for this molecule in the regulation of prenatal neurogenesis. We present data on Wnt-pathway dysregulation in Wdfy3-haploinsufficient mice, which display macrocephaly and deficits in motor coordination and associative learning, recapitulating the human phenotype. Consequently, we propose that in humans WDFY3 loss-of-function variants lead to macrocephaly via downregulation of the Wnt pathway. In summary, we present WDFY3 as a novel gene linked to mild to moderate neurodevelopmental delay and intellectual disability and conclude that variants putatively causing haploinsufficiency lead to macrocephaly, while an opposing pathomechanism due to variants in the PH-domain of WDFY3 leads to microcephaly.

MYT1L mutation in a patient causes intellectual disability and early onset of obesity: a case report and review of the literature

2019 ◽  
Vol 32 (4) ◽  
pp. 409-413 ◽  
Author(s):  
Abeer Al Tuwaijri ◽  
Majid Alfadhel
Keyword(s):  
Intellectual Disability ◽  
Early Onset ◽  
De Novo ◽  
Copy Number Variants ◽  
Speech Delay ◽  
Single Nucleotide Variants ◽  
Genome Wide ◽  
Whole Exome ◽  
Syndromic Obesity ◽  
The Central Nervous System

Abstract Background Obesity has become one of the greatest health risks worldwide. Recently, there was an explosion of information regarding the role of the central nervous system (CNS) in the development of monogenic and syndromic obesity. Case presentation Over the last decade, terminal and interstitial submicroscopic deletions of copy number variants (CNVs) in 2p25.3 and single nucleotide variants (SNVs) in myelin transcription factor 1 like (MYT1L) were detected by genome-wide array analysis and whole exome sequencing (WES) in patients with a nonspecific clinical phenotype that commonly includes intellectual disability (ID), early onset of obesity and speech delay. Here, we report the first Saudi female patient with mild to moderate ID, early onset of obesity and speech delay associated with a de novo pathogenic SNV in the MYT1L gene (c. 1585G>A [Gly529Arg]), which causes an amino acid change from Gly to Arg at position 529 that leads to mental retardation, autosomal dominant 39.

Advances in identification of genes involved in autosomal recessive intellectual disability: a brief review

2019 ◽  
Vol 56 (9) ◽  
pp. 567-573 ◽  
Author(s):  
Yaser Rafiq Mir ◽  
Raja Amir Hassan Kuchay
Keyword(s):  
Intellectual Disability ◽  
Large Scale ◽  
Autosomal Recessive ◽  
Biological Processes ◽  
Autozygosity Mapping ◽  
Whole Exome ◽  
Recessive Disorders ◽  
And Control ◽  
Very High ◽  
Dominant Genes

Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1%–3% of the general population. The number of ID-causing genes is high. Many X-linked genes have been implicated in ID. Autosomal dominant genes have recently been the focus of several large-scale studies. The total number of autosomal recessive ID (ARID) genes is estimated to be very high, and most are still unknown. Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that cause ARID has lagged behind, predominantly due to non-availability of sizeable families. A commonly used approach to identify genetic loci for recessive disorders in consanguineous families is autozygosity mapping and whole-exome sequencing. Combination of these two approaches has recently led to identification of many genes involved in ID. These genes have diverse function and control various biological processes. In this review, we will present an update regarding genes that have been recently implicated in ID with focus on ARID.

scholarly journals A Novel Frameshift Mutation in KAT6A Is Associated with Pancraniosynostosis

2020 ◽  
Author(s):  
Fady P. Marji ◽  
Jennifer A. Hall ◽  
Erin Anstadt ◽  
Suneeta Madan-Khetarpal ◽  
Jesse A. Goldstein ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Frameshift Mutation ◽  
De Novo ◽  
Cranial Sutures ◽  
Speech Delay ◽  
First Case ◽  
Whole Exome ◽  
Suture Fusion

AbstractDe novo heterozygous mutations in the KAT6A gene give rise to a distinct intellectual disability syndrome, with features including speech delay, cardiac anomalies, craniofacial dysmorphisms, and craniosynostosis. Here, we reported a 16-year-old girl with a novel pathogenic variant of the KAT6A gene. She is the first case to possess pancraniosynostosis, a rare suture fusion pattern, affecting all her major cranial sutures. The diagnosis of KAT6A syndrome is established via recognition of its inherent phenotypic features and the utilization of whole exome sequencing. Thorough craniofacial evaluation is imperative, craniosynostosis may require operative intervention, the delay of which may be detrimental.

scholarly journals Phenotypic and molecular spectra of patients with switch/sucrose nonfermenting complex-related intellectual disability disorders in Korea

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yena Lee ◽  
Yunha Choi ◽  
Go Hun Seo ◽  
Gu-Hwan Kim ◽  
Changwon Keum ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Disorders ◽  
Molecular Spectra ◽  
Speech Delay ◽  
Dna Accessibility ◽  
Pathogenic Variants ◽  
Disease Spectrum ◽  
Chromatin Remodeling Complex ◽  
Whole Exome ◽  
Altered Gene

Abstract Background The switch/sucrose nonfermenting (SWI/SNF) complex is an adenosine triphosphate-dependent chromatin-remodeling complex associated with the regulation of DNA accessibility. Germline mutations in the components of the SWI/SNF complex are related to human developmental disorders, including the Coffin–Siris syndrome (CSS), Nicolaides–Baraitser syndrome (NCBRS), and nonsyndromic intellectual disability. These disorders are collectively referred to as SWI/SNF complex-related intellectual disability disorders (SSRIDDs). Methods Whole-exome sequencing was performed in 564 Korean patients with neurodevelopmental disorders. Twelve patients with SSRIDDs (2.1%) were identified and their medical records were retrospectively analyzed. Results ARID1B, found in eight patients, was the most frequently altered gene. Four patients harbored pathogenic variants in SMARCA4, SMARCB1, ARID2, and SMARCA2. Ten patients were diagnosed with CSS, and one patient without a typical phenotype was diagnosed with ARID1B-related nonsyndromic intellectual disability. Another patient harboring the SMARCA2 pathogenic variant was diagnosed with NCBRS. All pathogenic variants in ARID1B were truncating, whereas variants in SMARCA2, SMARCB1, and SMARCA4 were nontruncating (missense). Frequently observed phenotypes were thick eyebrows (10/12), hypertrichosis (8/12), coarse face (8/12), thick lips (8/12), and long eyelashes (8/12). Developmental delay was observed in all patients, and profound speech delay was also characteristic. Agenesis or hypoplasia of the corpus callosum was observed in half of the patients (6/12). Conclusions SSRIDDs have a broad disease spectrum, including NCBRS, CSS, and ARID1B-related nonsyndromic intellectual disability. Thus, SSRIDDs should be considered as a small but important cause of human developmental disorders.

scholarly journals Phenotypic and Molecular Spectrum of Patients With Switch/sucrose Nonfermenting Complex-related Intellectual Disabilities in Korea

2021 ◽  
Author(s):  
Yena Lee ◽  
Yunha Choi ◽  
Go Hun Seo ◽  
Gu-Hwan Kim ◽  
Changwon Keum ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Disorder ◽  
Missense Mutations ◽  
Speech Delay ◽  
Dna Accessibility ◽  
Pathogenic Variants ◽  
Disease Spectrum ◽  
Whole Exome ◽  
Altered Gene ◽  
Spectrum Of Patients

Abstract Background: The switch/sucrose nonfermenting (SWI/SNF) complex is an adenosine triphosphate (ATP)-dependent chromatin-remodeling complex associated with the regulation of DNA accessibility. Germline mutations in the components of the SWI/SNF complex are related to human developmental disorder, including the Coffin–Siris syndrome (CSS), Nicolaides–Baraitser syndrome (NCBRS), and nonsyndromic intellectual disability. These disorders are collectively referred to as SWI/SNF-related intellectual disability (SSRIDD).Methods: Whole exome sequencing was performed in 564 Korean patients with neurodevelopmental disorders. Twelve patients with SSRIDDs (2.1%) were included, and their medical records were retrospectively analyzed. Results: ARID1B, found in eight patients, were the most frequently-altered gene. Four patients harbored mutations in SMARCA4, SMARCB1, ARID2, and SMARCA2. Ten patients were diagnosed with CSS, and one patient without typical phenotypes was classified as ARID1B-related intellectual disability. Another patient harboring the SMARCA2 mutation was diagnosed with NCBRS. All pathogenic variants in ARID1B were truncating, whereas variants in SMARCA2, SMARCB1, and SMARCA4 were nontruncating (missense) mutations. Frequently-observed phenotypes were thick eyebrows (10/12), hypertrichosis (8/12), coarse face (8/12), thick lips (8/12), and long eyelashes (8/12). Developmental delay was observed in all patients, and profound speech delay was also characteristic. Agenesis or hypoplasia of the corpus callosum was found in half of the patients (6/12).Conclusions: SSRIDD holds a broad disease spectrum, including NCBRS, CSS, and ARID1B-related intellectual disability. Thus, the SSRIDD should be considered as a small but important cause of human developmental disorder.

scholarly journals Intellectual disability-associated gain-of-function mutations in CERT1 that encodes the ceramide transport protein CERT

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243980
Author(s):  
Hiroaki Murakami ◽  
Norito Tamura ◽  
Yumi Enomoto ◽  
Kentaro Shimasaki ◽  
Kenji Kurosawa ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Biochemical Analysis ◽  
Developmental Disorder ◽  
Adaptive Functioning ◽  
Transport Protein ◽  
Evidence Based ◽  
Sequencing Analysis ◽  
Gain Of Function ◽  
Whole Exome ◽  
Organelle Trafficking

Intellectual disability (ID) is a developmental disorder that includes both intellectual and adaptive functioning deficits in conceptual, social, and practical domains. Although evidence-based interventions for patients have long been desired, their progress has been hindered due to various determinants. One of these determinants is the complexity of the origins of ID. The ceramide transport protein (CERT) encoded by CERT1 mediates inter-organelle trafficking of ceramide for the synthesis of intracellular sphingomyelin. Utilizing whole exome sequencing analysis, we identified a novel CERT variant, which substitutes a serine at position 135 (S135) for a proline in a patient with severe ID. Biochemical analysis showed that S135 is essential for hyperphosphorylation of a serine-repeat motif of CERT, which is required for down-regulation of CERT activity. Amino acid replacements of S135 abnormally activated CERT and induced an intracellular punctate distribution pattern of this protein. These results identified specific ID-associated CERT1 mutations that induced gain-of-function effects on CERT activity. These findings provide a possible molecular basis for not only new diagnostics but also a conceivable pharmaceutical intervention for ID disorders caused by gain-of-function mutations in CERT1.

scholarly journals PPP2R5D-Related Intellectual Disability and Neurodevelopmental Delay: A Review of the Current Understanding of the Genetics and Biochemical Basis of the Disorder

2020 ◽  
Vol 21 (4) ◽  
pp. 1286 ◽  
Author(s):  
Dayita Biswas ◽  
Whitney Cary ◽  
Jan A. Nolta
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Intellectual Disability ◽  
Protein Phosphatase ◽  
Autism Spectrum ◽  
Current Understanding ◽  
Biochemical Basis ◽  
Neurodevelopmental Delay ◽  
Wide Range ◽  
The Brain

Protein Phosphatase 2 Regulatory Subunit B′ Delta (PPP2R5D)-related intellectual disability (ID) and neurodevelopmental delay results from germline de novo mutations in the PPP2R5D gene. This gene encodes the protein PPP2R5D (also known as the B56 delta subunit), which is an isoform of the subunit family B56 of the enzyme serine/threonine-protein phosphatase 2A (PP2A). Clinical signs include intellectual disability (ID); autism spectrum disorder (ASD); epilepsy; speech problems; behavioral challenges; and ophthalmologic, skeletal, endocrine, cardiac, and genital malformations. The association of defective PP2A activity in the brain with a wide range of severity of ID, along with its role in ASD, Alzheimer’s disease, and Parkinson’s-like symptoms, have recently generated the impetus for further research into mutations within this gene. PP2A, together with protein phosphatase 1 (PP1), accounts for more than 90% of all phospho-serine/threonine dephosphorylations in different tissues. The specificity for a wide variety of substrates is determined through nearly 100 different PP2A holoenzymes that are formed by at least 23 types of regulatory B subunits, and two isoforms each of the catalytic subunit C and the structural subunit A. In the mammalian brain, PP2A-mediated protein dephosphorylation plays an important role in learning and memory. The PPP2R5D subunit is highly expressed in the brain and the PPP2A–PPP2R5D holoenzyme plays an important role in maintaining neurons and regulating neuronal signaling. From 2015 to 2017, 25 individuals with PPP2R5D-related developmental disorder were diagnosed. Since then, Whole-Exome Sequencing (WES) has helped to identify more unrelated individuals clinically diagnosed with a neurodevelopmental disorder with pathological variants of PPP2R5D. In this review, we discuss the current understanding of the clinical and genetic aspects of the disorder in the context of the known functions of the PP2A–PPP2R5D holoenzyme in the brain, as well as the pathogenic mutations in PPP2R5D that lead to deficient PP2A–PPP2R5D dephosphorylation and their implications during development and in the etiology of autism, Parkinson’s disease, Alzheimer’s disease, and so forth. In the future, tools such as transgenic animals carrying pathogenic PPP2R5D mutations, and patient-derived induced pluripotent stem cell lines need to be developed in order to fully understand the effects of these mutations on different neural cell types.

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