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.

RHOBTB2 p.Arg511Trp Mutation in Early Infantile Epileptic Encephalopathy-64: Review and Case Report

2021 ◽  
Author(s):  
J Fonseca ◽  
C Melo ◽  
C Ferreira ◽  
M Sampaio ◽  
R Sousa ◽  
...  
Keyword(s):  
Case Report ◽  
Intellectual Disability ◽  
Status Epilepticus ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Epileptic Encephalopathy ◽  
Btb Domain ◽  
Pathogenic Variants ◽  
Severe Intellectual Disability ◽  
Whole Exome

AbstractEarly infantile epileptic encephalopathy-64 (EIEE 64), also called RHOBTB2-related developmental and epileptic encephalopathy (DEE), is caused by heterozygous pathogenic variants (EIEE 64; MIM#618004) in the Rho-related BTB domain-containing protein 2 (RHOBTB2) gene. To date, only 13 cases with RHOBTB2-related DEE have been reported. We add to the literature the 14th case of EIEE 64, identified by whole exome sequencing, caused by a heterozygous pathogenic variant in RHOBTB2 (c.1531C > T), p.Arg511Trp. This additional case supports the main features of RHOBTB2-related DEE: infantile-onset seizures, severe intellectual disability, impaired motor functions, postnatal microcephaly, recurrent status epilepticus, and hemiparesis after seizures.

The First Case Report of Kabuki Syndrome from the National Iranian Registry of Primary Immunodeficiencies

2021 ◽  
Vol 21 ◽  
Author(s):  
Molood Safarirad ◽  
Ali Abbaszadeh Ganji ◽  
Saba Fekrvand ◽  
Reza Yazdani ◽  
Ahmad Vosughi Motlagh ◽  
...  
Keyword(s):  
Congenital Anomaly ◽  
Intellectual Disability ◽  
Definitive Diagnosis ◽  
Facial Features ◽  
Kabuki Syndrome ◽  
Rare Congenital Anomaly ◽  
Dysmorphic Features ◽  
Pathogenic Variants ◽  
First Case ◽  
Whole Exome

: Kabuki syndrome is a rare congenital anomaly/mental retardation syndrome characterized by intellectual disability, developmental delay, short stature, facial dysmorphic features including ectropion of the lateral third of the lower eyelids and long palpebral fissures, and prominent finger pads. Pathogenic variants of KMT2D (MLL2) and KDM6A are found to be the major causes of Kabuki syndrome. Here, we report the first Iranian case with Kabuki syndrome with an IQ of 79, two episodes of viral pneumonia and distinctive facial features, prominent ears and persistent fetal fingertip pads. These characteristics raised our suspicion for performing whole-exome sequencing (WES), which revealed 2 heterozygous pathogenic missense variants in the KMT2D gene: c.C10024T in exon 34 leading to p.R3342C and c.G15005A in exon 48 leading to p.R5002Q. Hence, the definitive diagnosis of Kabuki syndrome was made based on molecular findings along with the intellectual disability and characteristic facial features.

scholarly journals Two novel Warburg micro syndrome 1 cases caused by pathogenic variants in RAB3GAP1

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Omid Alavi ◽  
Hossein Jafari Khamirani ◽  
Sina Zoghi ◽  
Afrooz Feili ◽  
Seyed Alireza Dastgheib ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Corpus Callosum ◽  
Exome Sequencing ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
Drug Resistant ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Warburg Micro Syndrome ◽  
Craniofacial Features

AbstractIn this study, we detected a novel pathogenic variant and a previously reported variant in RAB3GAP1 by whole-exome sequencing (NM_001172435.2: c.1552C>T, p.Gln518*; c.1471C>T, p.Arg491*). The first patient is a 3-year-old girl who presented with bilateral congenital cataracts, developmental delay, abnormal craniofacial features, drug-resistant constipation, and corpus callosum hypoplasia. The proband of the second family is a 13-year-old boy who suffers from developmental delay, quadriplegia, intellectual disability, abnormal craniofacial features, and corpus callosum hypoplasia.

scholarly journals ST3GAL5-Related Disorders: A Deficiency in Ganglioside Metabolism and a Genetic Cause of Intellectual Disability and Choreoathetosis

2018 ◽  
Vol 33 (13) ◽  
pp. 825-831 ◽  
Author(s):  
Eliza Gordon-Lipkin ◽  
Julie S. Cohen ◽  
Siddharth Srivastava ◽  
Bruno P. Soares ◽  
Eric Levey ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Neurodevelopmental Disorder ◽  
Failure To Thrive ◽  
Ganglioside Gm3 ◽  
Normal Birth ◽  
Pathogenic Variants ◽  
Gm3 Synthase ◽  
Whole Exome ◽  
Ganglioside Metabolism ◽  
Autosomal Recessive Condition

GM3 synthase deficiency is due to biallelic pathogenic variants in ST3GAL5, which encodes a sialyltransferase that synthesizes ganglioside GM3. Key features of this rare autosomal recessive condition include profound intellectual disability, failure to thrive and infantile onset epilepsy. We expand the phenotypic spectrum with 3 siblings who were found by whole exome sequencing to have a homozygous pathogenic variant in ST3GAL5, and we compare these cases to those previously described in the literature. The siblings had normal birth history, subsequent developmental stagnation, profound intellectual disability, choreoathetosis, failure to thrive, and visual and hearing impairment. Ichthyosis and self-injurious behavior are newly described in our patients and may influence clinical management. We conclude that GM3 synthase deficiency is a neurodevelopmental disorder with consistent features of profound intellectual disability, choreoathetosis, and deafness. Other phenotypic features have variable expressivity, including failure to thrive, epilepsy, regression, vision impairment, and skin findings. Our analysis demonstrates a broader phenotypic range of this potentially under-recognized disorder.

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.

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 Novel variants identified in CKAP2L in two siblings with Filippi Syndrome

2021 ◽  
pp. mcs.a006130
Author(s):  
Ryan J Patrick ◽  
Jill M Weimer ◽  
Laura Davis-Keppen ◽  
Megan L Landsverk
Keyword(s):  
Intellectual Disability ◽  
Autosomal Recessive ◽  
Missense Variant ◽  
Facial Features ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
The Family ◽  
Novel Variants ◽  
In Trans

Pathogenic variants in CKAP2L have previously been reported in Filippi Syndrome (FS), a rare autosomal recessive, craniodigital syndrome characterized by microcephaly, syndactyly, short stature, intellectual disability, and dysmorphic facial features. To date, fewer than ten patients with pathogenic variants in CKAP2L associated with FS have been reported. All of the previously reported probands have presumed loss-of-function variants (frameshift, canonical splice site, starting methionine) and all but one have been homozygous for a pathogenic variant. Here we describe two brothers who presented with microcephaly, micrognathia, syndactyly, dysmorphic features, and intellectual disability. Whole exome sequencing of the family identified a missense variant, c.2066G>A (p.Arg689His), in trans with a frameshift variant, c.1169_1173del (p.Ile390LysfsTer4), in CKAP2L. To our knowledge, these are the first patients with FS to be reported with a missense variant in CKAP2L and only the second family to be reported with two variants in trans.

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 Mutations in genes encoding regulators of mRNA decapping and translation initiation: links to intellectual disability

2020 ◽  
Vol 48 (3) ◽  
pp. 1199-1211 ◽  
Author(s):  
Dominique Weil ◽  
Amélie Piton ◽  
Davor Lessel ◽  
Nancy Standart
Keyword(s):  
Intellectual Disability ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Sequencing Data ◽  
Rna Helicases ◽  
Mrna Decapping ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Genes Encoding ◽  
Post Transcriptional Regulation

Intellectual disability (ID) affects at least 1% of the population, and typically presents in the first few years of life. ID is characterized by impairments in cognition and adaptive behavior and is often accompanied by further delays in language and motor skills, as seen in many neurodevelopmental disorders (NDD). Recent widespread high-throughput approaches that utilize whole-exome sequencing or whole-genome sequencing have allowed for a considerable increase in the identification of these pathogenic variants in monogenic forms of ID. Notwithstanding this progress, the molecular and cellular consequences of the identified mutations remain mostly unknown. This is particularly important as the associated protein dysfunctions are the prerequisite to the identification of targets for novel drugs of these rare disorders. Recent Next-Generation sequencing-based studies have further established that mutations in genes encoding proteins involved in RNA metabolism are a major cause of NDD. Here, we review recent studies linking germline mutations in genes encoding factors mediating mRNA decay and regulators of translation, namely DCPS, EDC3, DDX6 helicase and ID. These RNA-binding proteins have well-established roles in mRNA decapping and/or translational repression, and the mutations abrogate their ability to remove 5′ caps from mRNA, diminish their interactions with cofactors and stabilize sub-sets of transcripts. Additional genes encoding RNA helicases with roles in translation including DDX3X and DHX30 have also been linked to NDD. Given the speed in the acquisition, analysis and sharing of sequencing data, and the importance of post-transcriptional regulation for brain development, we anticipate mutations in more such factors being identified and functionally characterized.

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