scholarly journals SCN2A Pathogenic Variants- Important Causes of Epilepsy and Developmental Delay

2021 ◽  
Vol 7 (5) ◽  
Author(s):  
Ernesto Gonzalez-Giraldo
Keyword(s):  
Developmental Delay ◽  
Pathogenic Variants

scholarly journals Pitt Hopkins-Like Syndrome 1 with Novel CNTNAP2 Mutation in Siblings

2021 ◽  
Vol 8 ◽  
pp. 2329048X2110553
Author(s):  
Rea Mittal ◽  
Ashutosh Kumar ◽  
Roger Ladda ◽  
Gayatra Mainali ◽  
Ermal Aliu
Keyword(s):  
Developmental Delay ◽  
Focal Epilepsy ◽  
Autism Spectrum ◽  
Compound Heterozygous ◽  
Sequencing Analysis ◽  
Gait Abnormality ◽  
Pathogenic Variants ◽  
Obstructive Sleep ◽  
Management Guidance ◽  
Intragenic Deletions

Pitt Hopkins-like syndrome 1 (PTHLS1, OMIM # 610042) is an ultra-rare autosomal recessive condition with a prevalence of <1/1,000,000. Intragenic deletions of CNTNAP2 has been implicated in PTHLS1, however to our knowledge a compound heterozygous deletion of exon 4 and a c.1977_1989del13; p.V660Ffsx9 frameshift variant have not been published previously. In this case report, the proband is a seven year old female with PTHLS1, developmental delay, autism spectrum disorder, focal epilepsy, hypotonia, refractory errors, strabismus, and obstructive sleep apnea. Whole exome sequencing analysis revealed biallelic pathogenic variants of the CNTNAP2 gene. Proband has a three year old sister who has who has a similar phenotype including, developmental delay, epilepsy, gait abnormality, refractory errors, strabismus. Family variants were tested and she shared the same CNTNAP2 variants as her sister. The sisters described highlight two novel variants leading to PTHLS1. Genetic workup is essential in identification and management guidance in these populations.

The identification of two pathogenic variants in a family with mild and severe forms of developmental delay

2020 ◽  
Author(s):  
Noriko Miyake ◽  
Shermineh Heydari ◽  
Masoud Garshasbi ◽  
Shinji Saitoh ◽  
Jafar Nasiri ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Pathogenic Variants

scholarly journals X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3

PLoS Genetics ◽  
2021 ◽  
Vol 17 (6) ◽  
pp. e1009608
Author(s):  
Jia-Hui Sun ◽  
Jiang Chen ◽  
Fernando Eduardo Ayala Valenzuela ◽  
Carolyn Brown ◽  
Diane Masser-Frye ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Prolonged Exposure ◽  
De Novo ◽  
Missense Variant ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
Decay Kinetics ◽  
Gain Of Function ◽  
Ca1 Neurons ◽  
Pathogenic Variants

The X-linked GRIA3 gene encodes the GLUA3 subunit of AMPA-type glutamate receptors. Pathogenic variants in this gene were previously reported in neurodevelopmental diseases, mostly in male patients but rarely in females. Here we report a de novo pathogenic missense variant in GRIA3 (c.1979G>C; p. R660T) identified in a 1-year-old female patient with severe epilepsy and global developmental delay. When exogenously expressed in human embryonic kidney (HEK) cells, GLUA3_R660T showed slower desensitization and deactivation kinetics compared to wildtype (wt) GLUA3 receptors. Substantial non-desensitized currents were observed with the mutant but not for wt GLUA3 with prolonged exposure to glutamate. When co-expressed with GLUA2, the decay kinetics were similarly slowed in GLUA2/A3_R660T with non-desensitized steady state currents. In cultured cerebellar granule neurons, miniature excitatory postsynaptic currents (mEPSCs) were significantly slower in R660T transfected cells than those expressing wt GLUA3. When overexpressed in hippocampal CA1 neurons by in utero electroporation, the evoked EPSCs and mEPSCs were slower in neurons expressing R660T mutant compared to those expressing wt GLUA3. Therefore our study provides functional evidence that a gain of function (GoF) variant in GRIA3 may cause epileptic encephalopathy and global developmental delay in a female subject by enhancing synaptic transmission.

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 Bi-allelic Pathogenic Variants in HS2ST1 Cause a Syndrome Characterized by Developmental Delay and Corpus Callosum, Skeletal, and Renal Abnormalities

2020 ◽  
Vol 107 (6) ◽  
pp. 1044-1061
Author(s):  
Pauline E. Schneeberger ◽  
Leonie von Elsner ◽  
Emma L. Barker ◽  
Peter Meinecke ◽  
Iris Marquardt ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
Developmental Delay ◽  
Pathogenic Variants ◽  
Renal Abnormalities

Biallelic variants in PSMB1 encoding the proteasome subunit β6 cause impairment of proteasome function, microcephaly, intellectual disability, developmental delay and short stature

2020 ◽  
Vol 29 (7) ◽  
pp. 1132-1143 ◽  
Author(s):  
Muhammad Ansar ◽  
Frédéric Ebstein ◽  
Hayriye Özkoç ◽  
Sohail A Paracha ◽  
Justyna Iwaszkiewicz ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Autosomal Recessive ◽  
Brain Size ◽  
Autosomal Recessive Disorders ◽  
Proteasome Subunit ◽  
Pathogenic Variants ◽  
The Family ◽  
Proteasome Subunits ◽  
Recessive Disorders

Abstract The molecular cause of the majority of rare autosomal recessive disorders remains unknown. Consanguinity due to extensive homozygosity unravels many recessive phenotypes and facilitates the detection of novel gene-disease links. Here, we report two siblings with phenotypic signs, including intellectual disability (ID), developmental delay and microcephaly from a Pakistani consanguineous family in which we have identified homozygosity for p(Tyr103His) in the PSMB1 gene (Genbank NM_002793) that segregated with the disease phenotype. PSMB1 encodes a β-type proteasome subunit (i.e. β6). Modeling of the p(Tyr103His) variant indicates that this variant weakens the interactions between PSMB1/β6 and PSMA5/α5 proteasome subunits and thus destabilizes the 20S proteasome complex. Biochemical experiments in human SHSY5Y cells revealed that the p(Tyr103His) variant affects both the processing of PSMB1/β6 and its incorporation into proteasome, thus impairing proteasome activity. CRISPR/Cas9 mutagenesis or morpholino knock-down of the single psmb1 zebrafish orthologue resulted in microcephaly, microphthalmia and reduced brain size. Genetic evidence in the family and functional experiments in human cells and zebrafish indicates that PSMB1/β6 pathogenic variants are the cause of a recessive disease with ID, microcephaly and developmental delay due to abnormal proteasome assembly.

Neurodevelopmental phenotypes associated with pathogenic variants in SLC6A1

2021 ◽  
pp. jmedgenet-2021-107694
Author(s):  
Ashley Kahen ◽  
Haluk Kavus ◽  
Alexa Geltzeiler ◽  
Catherine Kentros ◽  
Cora Taylor ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Language Disorder ◽  
Synaptic Cleft ◽  
Binding Pocket ◽  
Autism Spectrum ◽  
Gamma Aminobutyric Acid ◽  
Vineland Adaptive Behavior Scales ◽  
Care Givers ◽  
Pathogenic Variants

BackgroundSLC6A1 encodes GAT-1, a major gamma-aminobutyric acid (GABA) transporter in the brain. GAT-1 maintains neurotransmitter homeostasis by removing excess GABA from the synaptic cleft. Pathogenic variants in SLC6A1 disrupt the reuptake of GABA and are associated with a neurobehavioural phenotype.MethodsMedical history interviews, seizure surveys, Vineland Adaptive Behavior Scales Second Edition and other behavioural surveys were completed by primary care givers of 28 participants in Simons Searchlight. All participants underwent clinical whole exome sequencing or gene panel sequencing. Additional cases from the medical literature with comparable data were included.ResultsWe identified 28 individuals with largely de novo pathogenic/likely pathogenic variants including missense (15/21 or 71%) and truncating variants (6/21 or 29%). Missense variants were largely clustered around the sixth and seventh transmembrane domains, which functions as a GABA binding pocket. The phenotype of individuals with pathogenic variants in SLC6A1 includes hypotonia, intellectual disability/developmental delay, language disorder/speech delay, autism spectrum disorder, sleep issues and seizures.ConclusionPathogenic variants in SLC6A1 are associated with a clinical phenotype of developmental delay, behaviour problems and seizures. Understanding of the genotype–phenotype correlation within SLC6A1 may provide opportunities to develop new treatments for GABA-related conditions.

scholarly journals Expanding the Phenotype of TUBB2A-Related Tubulinopathy: Three Cases of a Novel, Heterozygous TUBB2A Pathogenic Variant p.Gly98Arg

2020 ◽  
pp. 1-8
Author(s):  
Lindsey Schmidt ◽  
Karen E. Wain ◽  
Catherine Hajek ◽  
Juvianee I. Estrada-Veras ◽  
Maria J. Guillen Sacoto ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Case Series ◽  
Missense Variant ◽  
Autism Spectrum ◽  
Cortical Dysplasia ◽  
Global Developmental Delay ◽  
Tubulin Genes ◽  
Pathogenic Variants ◽  
Brain Malformations ◽  
History Of

Tubulinopathies are a group of conditions caused by variants in 6 tubulin genes that present with a spectrum of brain malformations. One of these conditions is <i>TUBB2A</i>-related tubulinopathy. Currently, there are 9 reported individuals with pathogenic variants within the <i>TUBB2A</i> gene, with common manifestations including, but not limited to, global developmental delay, seizures, cortical dysplasia, and dysmorphic corpus callosum. We report 3 patients identified by exome and genome sequencing to have a novel, pathogenic, missense variant in <i>TUBB2A</i> (p.Gly98Arg). They presented similarly with intellectual disability, hypotonia, and global developmental delay and varied with respect to the type of cortical brain malformation, seizure history, diagnosis of autism spectrum disorder, and other features. This case series expands the natural history of <i>TUBB2A</i>-related tubulinopathy while describing the presentation of a novel, pathogenic, missense variant in 3 patients.

Novel pathogenic variant c.2714C>A (p. Thr905Lys) in the HK1 gene causing severe haemolytic anaemia with developmental delay in an Indian family

2020 ◽  
pp. jclinpath-2020-206960
Author(s):  
Rashmi Dongerdiye ◽  
Sujatha Jagadeesh ◽  
Beena Suresh ◽  
Aruna Rajendran ◽  
Rati Devendra ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Haemolytic Anaemia ◽  
Severe Disease ◽  
Female Child ◽  
Red Cell ◽  
Multiple Sequence ◽  
Pathogenic Variants ◽  
Targeted Analysis ◽  
Whole Exome ◽  
The Impact

Hexokinase (EC 2.7.1.1, Adenosine Tri Phosphate (ATP): D-hexose-6-phosphotransferase) is a crucial regulatory enzyme of the glycolytic pathway (Embden-Meyerhof pathway). Hexokinase deficiency is associated with chronic non-spherocytic haemolytic anaemia (HA) with some exceptional cases showing psychomotor/mental retardation and fetus death. The proband is a four-and-half-year-old female child born of a four-degree consanguineous marriage hailing from South India with autosomal recessive congenital HA associated with developmental delay. She was well till 3 months of her age post an episode of diarrhoea when she was noted to be severely anaemic and requiring regular transfusions. The common causes of HA, haemoglobinopathies, red cell membranopathies and common red cell enzymopathies (G6PD, GPI, PK and P5N) were ruled out. Targeted analysis of whole exome sequencing (WES) using an insilico gene panel for hereditary anaemia was performed to identify pathogenic variants in the patient. Next-generation sequencing revealed a novel homozygous variant in hexokinase gene c.2714C>A (p. Thr905Lys) in exon-18. The pathogenic nature of the variant p. Thr905Lys in the HK1 gene was confirmed collectively by biochemical and molecular studies. Insilico analysis (PolyPhen-2, Provean, Mutation Taster) predicted the variant to be severe disease causing. Multiple sequence alignment demonstrated the conservation of p. Thr905 across the species. The impact of the mutation on the protein structure was studied by PyMOL and Swiss Protein databank viewer.

scholarly journals Novel LAMA2 variants identified in a patient with white matter abnormalities

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Keiko Yamamoto-Shimojima ◽  
Hiroaki Ono ◽  
Taichi Imaizumi ◽  
Toshiyuki Yamamoto
Keyword(s):  
Creatine Kinase ◽  
White Matter ◽  
Muscular Dystrophy ◽  
Developmental Delay ◽  
Congenital Muscular Dystrophy ◽  
Genomic Analysis ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
White Matter Abnormalities ◽  
Pathogenic Variants

AbstractComprehensive genomic analysis was performed in a patient with mild psychomotor developmental delay, elevated creatine kinase, and white matter abnormalities. The results revealed biallelic pathogenic variants in the gene related to merosin-deficient congenital muscular dystrophy, NM_000426.3(LAMA2):c.1338_1339del [p.Gly447Phefs*7] and c.2749 + 2dup, which consist of compound heterozygous involvement with predicted loss-of-function and splicing abnormalities.

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