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

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.

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

BMC Medical Genomics ◽

10.1186/s12920-021-01104-9 ◽

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.

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

Journal of Pediatric Genetics ◽

10.1055/s-0040-1722288 ◽

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.

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

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530321666210114153920 ◽

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.

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Fetal Anomalies Associated with Novel Pathogenic Variants in TMEM94

Genes ◽

10.3390/genes11090967 ◽

2020 ◽

Vol 11 (9) ◽

pp. 967

Author(s):

Mohamed H. Al-Hamed ◽

Nada Alsahan ◽

Maha Tulbah ◽

Wesam Kurdi ◽

Wafa’a I. Ali ◽

...

Keyword(s):

Developmental Disorder ◽

Chromosomal Microarray ◽

Global Developmental Delay ◽

Facial Features ◽

Chromosomal Microarray Analysis ◽

Speech Delay ◽

Loss Of Function ◽

Pathogenic Variants ◽

Antenatal Sonography ◽

First Time

Background: Intellectual developmental disorder with cardiac defects and dysmorphic facies (IDDCDF, MIM 618316) is a newly described disorder. It is characterized by global developmental delay, intellectual disability and speech delay, congenital cardiac malformations, and dysmorphic facial features. Biallelic pathogenic variants of TMEM94 are associated with IDDCDF. Methods and Results: In a prenatal setting, where fetal abnormalities were detected using antenatal sonography, we used trio-exome sequencing (trio-ES) in conjunction with chromosomal microarray analysis (CMA) to identify two novel homozygous loss of function variants in the TMEM94 gene (c.606dupG and c.2729-2A>G) in two unrelated Saudi Arabian families. Conclusions: This study provides confirmation that TMEM94 variants may cause IDDCDF. For the first time we describe the pathogenicity of TMEM94 defects detected during the prenatal period.

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A Novel Multi-Exon Deletion of PACS1 in a Three-Generation Pedigree: Supplements to PACS1 Neurodevelopmental Disorder Spectrum

Frontiers in Genetics ◽

10.3389/fgene.2021.690216 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yuan Liu ◽

Hongke Ding ◽

Tizhen Yan ◽

Ling Liu ◽

Lihua Yu ◽

...

Keyword(s):

Neurodevelopmental Disorder ◽

Dominant Negative ◽

Facial Features ◽

Missense Mutations ◽

Loss Of Function ◽

Pathogenic Variants ◽

Cognitive Delay ◽

Whole Exome ◽

Before And After ◽

Exon Deletion

PACS1 neurodevelopmental disorder (PACS1-NDD) is a category of rare disorder characterized by intellectual disability, speech delay, dysmorphic facial features, and developmental delay. Other various physical abnormalities of PACS1-NDD might involve all organs and systems. Notably, there were only two unique missense mutations [c.607C > T (p.Arg203Trp) and c.608G > A (p.Arg203Gln)] in PACS1 that had been identified as pathogenic variants for PACS1-NDD or Schuurs-Hoeijmakers syndrome (SHMS). Previous reports suggested that these common missense variants were likely to act through dominant-negative or gain-of-function effects manner. It is still uncertain whether the intragenic deletion or duplication in PACS1 will be disease-causing. By using whole-exome sequencing, we first identified a novel heterozygous multi-exon deletion covering exons 12–24 in PACS1 (NM_018026) in four individuals (two brothers and their father and grandfather) in a three-generation family. The younger brother was referred to our center prenatally and was evaluated before and after the birth. Unlike SHMS, no typical dysmorphic facial features, intellectual problems, and structural brain anomalies were observed among these four individuals. The brothers showed a mild hypermyotonia of their extremities at the age of 3 months old and recovered over time. Mild speech and cognitive delay were also noticed in the two brothers at the age of 13 and 27 months old, respectively. However, their father and grandfather showed normal language and cognitive competence. This study might supplement the spectrum of PACS1-NDD and demonstrates that the loss of function variation in PACS1 displays no contributions to the typical SHMS which is caused by the recurrent c.607C > T (p.Arg203Trp) variant.

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

Human Genome Variation ◽

10.1038/s41439-021-00171-9 ◽

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.

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Case Report: Novel mutations in TBC1D24 are associated with autosomal dominant tonic-clonic and myoclonic epilepsy and recessive Parkinsonism, psychosis, and intellectual disability

F1000Research ◽

10.12688/f1000research.10588.1 ◽

2017 ◽

Vol 6 ◽

pp. 553 ◽

Cited By ~ 13

Author(s):

Erika Banuelos ◽

Keri Ramsey ◽

Newell Belnap ◽

Malavika Krishnan ◽

Chris D. Balak ◽

...

Keyword(s):

Intellectual Disability ◽

Autosomal Dominant ◽

Epileptic Encephalopathy ◽

Myoclonic Epilepsy ◽

Compound Heterozygous ◽

Missense Mutations ◽

Single Family ◽

Whole Exome ◽

Neurological Phenotype ◽

Syndromic Hearing Loss

Mutations disrupting presynaptic protein TBC1D24 are associated with a variable neurological phenotype, including DOORS syndrome, myoclonic epilepsy, early-infantile epileptic encephalopathy, and non-syndromic hearing loss. In this report, we describe a family segregating autosomal dominant epilepsy, and a 37-year-old Caucasian female with a severe neurological phenotype including epilepsy, Parkinsonism, psychosis, visual and auditory hallucinations, gait ataxia and intellectual disability. Whole exome sequencing revealed two missense mutations in the TBC1D24 gene segregating within this family (c.1078C>T; p.Arg360Cys and c.404C>T; p.Pro135Leu). The female proband who presents with a severe neurological phenotype carries both of these mutations in a compound heterozygous state. The p.Pro135Leu variant, however, is present in the proband’s mother and sibling as well, and is consistent with an autosomal dominant pattern linked to tonic-clonic and myoclonic epilepsy. In conclusion, we describe a single family in which TBC1D24 mutations cause expanded dominant and recessive phenotypes. In addition, we discuss and highlight that some variants in TBC1D24 might cause a dominant susceptibility to epilepsy

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Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families

10.1101/092346 ◽

2016 ◽

Author(s):

Ricardo Harripaul ◽

Nasim Vasli ◽

Anna Mikhailov ◽

Muhammad Arshad Rafiq ◽

Kirti Mittal ◽

...

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Autosomal Recessive ◽

De Novo ◽

Clinical Diagnostics ◽

High Yield ◽

Disease Genes ◽

Missense Mutations ◽

Loss Of Function ◽

Whole Exome

Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations(ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7,andUSP44),and missense mutations include the first reports of variants inBDNForTET1associated with ID. The genes identified also showed overlap withde novogene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.

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

Journal of Child Neurology ◽

10.1177/0883073818791099 ◽

2018 ◽

Vol 33 (13) ◽

pp. 825-831 ◽

Cited By ~ 3

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.

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

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2018-0505 ◽

2019 ◽

Vol 32 (4) ◽

pp. 409-413 ◽

Cited By ~ 3

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.

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