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 Prominent and Regressive Brain Developmental Disorders Associated with Nance-Horan Syndrome

2021 ◽  
Vol 11 (9) ◽  
pp. 1150
Author(s):  
Celeste Casto ◽  
Valeria Dipasquale ◽  
Ida Ceravolo ◽  
Antonella Gambadauro ◽  
Emanuela Aliberto ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Disorders ◽  
Developmental Disorder ◽  
Adaptive Skills ◽  
Facial Features ◽  
Loss Of Function ◽  
Dental Anomalies ◽  
Congenital Cataracts ◽  
Disease Mechanisms ◽  
Whole Exome

Nance-Horan syndrome (NHS) is a rare X-linked developmental disorder caused mainly by loss of function variants in the NHS gene. NHS is characterized by congenital cataracts, dental anomalies, and distinctive facial features, and a proportion of the affected individuals also present intellectual disability and congenital cardiopathies. Despite identification of at least 40 distinct hemizygous variants leading to NHS, genotype-phenotype correlations remain largely elusive. In this study, we describe a Sicilian family affected with congenital cataracts and dental anomalies and diagnosed with NHS by whole-exome sequencing (WES). The affected boy from this family presented a late regression of cognitive, motor, language, and adaptive skills, as well as broad behavioral anomalies. Furthermore, brain imaging showed corpus callosum anomalies and periventricular leukoencephalopathy. We expand the phenotypic and mutational NHS spectrum and review potential disease mechanisms underlying the central neurological anomalies and the potential neurodevelopmental features associated with NHS.

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 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.

Homozygosity mapping of autosomal recessive intellectual disability loci in 11 consanguineous Pakistani families

2014 ◽  
Vol 27 (1) ◽  
pp. 38-47 ◽  
Author(s):  
Iltaf Ahmed ◽  
Muhammad Arshad Rafiq ◽  
John B. Vincent ◽  
Attya Bhatti ◽  
Muhammad Ayub ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Autosomal Recessive ◽  
Homozygosity Mapping ◽  
Recessive Mutation ◽  
Sequencing Analysis ◽  
Causative Gene ◽  
Whole Exome ◽  
Next Generation Sequencing Analysis ◽  
Number Variation ◽  
Recessive Genes

BackgroundAutosomal recessive intellectual disability (ID) is genetically heterogeneous and most of the genes causing it remain undiscovered.ObjectiveWe have ascertained 11 consanguineous families multiplex for IDs in order to identify new loci for autosomal recessive genes for non-syndromic ID, or to aid pinpointing mutations in known causative gene/loci.MethodologyMicroarray genotyping (Affymatrix 250K) was performed to identify homozygosity-by-descent (HBD) in all affected families.ResultsAnalysis of genotypes revealed 45 potential HBD regions across the families, although these may be rationalised down to 39. Two families share an overlapping HBD region on 7q11.21. In one family, X-linkage also looks plausible, and a new ID gene near the centromere may be a likely cause. In one family, no HBD region was found, and thus we exclude autosomal recessive mutation as the likely cause in this family. Copy-number variation (CNV) was also performed and revealed no CNVs, homozygous or heterozygous, segregating with the phenotype.ConclusionThe homozygous loci identified in this study might harbour candidate genes for ID in these studied families. Therefore, we are proceeding with next-generation sequencing analysis of the families, using whole-exome approaches, and anticipate that this will identify the causative gene/mutation within the identified HBD regions for many of the families studied here.

Kindler's Syndrome with Recurrent Neutropenia: Report of Two Cases from Saudi Arabia

2020 ◽  
Author(s):  
Yousef Binamer ◽  
Muzamil A. Chisti
Keyword(s):  
Autosomal Recessive ◽  
Common Mechanism ◽  
Sequencing Analysis ◽  
Loss Of Function ◽  
Skin Atrophy ◽  
Whole Exome ◽  
Infancy And Childhood ◽  
Genetics And Genomics ◽  
New Feature ◽  
Generation Sequencing

AbstractKindler syndrome (KS) is a rare photosensitivity disorder with autosomal recessive mode of inheritance. It is characterized by acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. Besides these major features, many minor presentations have also been reported in the literature. We are reporting two cases with atypical features of the syndrome and a new feature of recurrent neutropenia. Whole exome sequencing analysis was done using next-generation sequencing which detected a homozygous loss-of-function (LOF) variant of FERMT1 in both patients. The variant is classified as a pathogenic variant as per the American College of Medical Genetics and Genomics guidelines. Homozygous LOF variants of FERMT1 are a common mechanism of KS and as such confirm the diagnosis of KS in our patients even though the presentation was atypical.

scholarly journals Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

2021 ◽  
Author(s):  
Adam L. Numis ◽  
Gilberto da Gente ◽  
Elliott H. Sherr ◽  
Hannah C. Glass
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
List Type ◽  
Sequencing Analysis ◽  
Neonatal Seizures ◽  
Pathogenic Variants ◽  
Targeted Analysis ◽  
Whole Exome ◽  
Epilepsy Gene

Abstract Background The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known. Methods Case–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches. Results Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy. Conclusions In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy. Impact We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy. Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

A mixed-methods examination of the gap between intelligence and adaptive functioning in autistic young adults without intellectual disability

Autism ◽  
2021 ◽  
pp. 136236132110183
Author(s):  
Nicole L Matthews ◽  
Kyla Christenson ◽  
Sarah Kiefer ◽  
Christopher J Smith
Keyword(s):  
Young Adults ◽  
Intellectual Disability ◽  
Statistical Analysis ◽  
Qualitative Analysis ◽  
Independent Living ◽  
Adaptive Functioning ◽  
Parent Report ◽  
Intellectual Ability ◽  
Standardized Assessments ◽  
Service Needs

This study examined adaptive functioning, strategies used to develop adaptive functioning skills, and areas where additional services could benefit autistic young adults without intellectual disability. Participants were 21 autistic young adults and at least one parent of each young adult. Quantitative analyses replicated previous reports of an adaptive functioning disadvantage relative to intellectual functioning such that adaptive functioning standard scores were significantly lower than intelligence quotient scores. Qualitative analysis utilized grounded theory methodology and yielded a conceptual model describing the nature and development of adaptive functioning in this demographic. Together, findings provide a more nuanced understanding of the gap between intellectual and adaptive functioning in autistic young adults without intellectual disability. Lay abstract Adaptive functioning describes the age-appropriate skills necessary for independent living. Research suggests that autistic children, adolescents, and adults who do not have an intellectual disability demonstrate adaptive functioning challenges relative to their intellectual ability. Thus, even though many of these individuals have the intellectual capacity to excel in mainstream educational and vocational settings, their adaptive functioning challenges may serve as an obstacle to independence. The research on adaptive functioning in autistic adults is focused on statistical analysis of standardized assessments (e.g. parent-report on multiple choice questionnaires). Qualitative research that examines the narratives of young adults and their parents is needed to better understand adaptive functioning in young adults and their resulting service needs. This study combined statistical analysis of standardized assessments with qualitative analysis of interview responses from autistic young adults without intellectual disability and their parents. Findings replicated previous reports of adaptive functioning challenges and identified influences on adaptive functioning development, consequences of independence, and service needs. Taken together, findings indicate the need for interventions and services that facilitate adaptive functioning development in autistic adolescents and young adults and provide insight into potential intervention targets and strategies.

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