Heterozygous HMGB1 loss‐of‐function variants are associated with developmental delay and microcephaly

2021 ◽  
Author(s):  
Kevin Uguen ◽  
Kilannin Krysiak ◽  
Séverine Audebert‐Bellanger ◽  
Sylvia Redon ◽  
Caroline Benech ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Loss Of Function

scholarly journals The de novo CACNA1A pathogenic variant Y1384C associated with hemiplegic migraine, early onset cerebellar atrophy and developmental delay leads to a loss of Cav2.1 channel function

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Maria A. Gandini ◽  
Ivana A. Souza ◽  
Laurent Ferron ◽  
A. Micheil Innes ◽  
Gerald W. Zamponi
Keyword(s):  
Developmental Delay ◽  
Early Onset ◽  
Structural Damage ◽  
De Novo ◽  
Splice Variants ◽  
Cerebellar Atrophy ◽  
Familial Hemiplegic Migraine ◽  
Significant Loss ◽  
Loss Of Function ◽  
Hemiplegic Migraine

AbstractCACNA1A pathogenic variants have been linked to several neurological disorders including familial hemiplegic migraine and cerebellar conditions. More recently, de novo variants have been associated with severe early onset developmental encephalopathies. CACNA1A is highly expressed in the central nervous system and encodes the pore-forming CaVα1 subunit of P/Q-type (Cav2.1) calcium channels. We have previously identified a patient with a de novo missense mutation in CACNA1A (p.Y1384C), characterized by hemiplegic migraine, cerebellar atrophy and developmental delay. The mutation is located at the transmembrane S5 segment of the third domain. Functional analysis in two predominant splice variants of the neuronal Cav2.1 channel showed a significant loss of function in current density and changes in gating properties. Moreover, Y1384 variants exhibit differential splice variant-specific effects on recovery from inactivation. Finally, structural analysis revealed structural damage caused by the tyrosine substitution and changes in electrostatic potentials.

scholarly journals Biallelic UBE4A loss-of-function variants cause intellectual disability and global developmental delay

2021 ◽  
Author(s):  
Uirá Souto Melo ◽  
Devon Bonner ◽  
Kevin C. Kent Lloyd ◽  
Ala Moshiri ◽  
Brandon Willis ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Global Developmental Delay ◽  
Loss Of Function

scholarly journals A Drosophila natural variation screen identifies NKCC1 as a substrate of NGLY1 deglycosylation and a modifier of NGLY1 deficiency

2020 ◽  
Author(s):  
Dana M. Talsness ◽  
Katie G. Owings ◽  
Emily Coelho ◽  
Gaelle Mercenne ◽  
John M. Pleinis ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Natural Variation ◽  
Evolutionary Rate ◽  
Phenotypic Variability ◽  
Loss Of Function ◽  
Ion Transporter ◽  
Phenotypic Spectrum ◽  
Mouse Cells ◽  
Covariation Analysis ◽  
Insight Into

AbstractN-Glycanase 1 (NGLY1) is a cytoplasmic deglycosylating enzyme. Loss-of-function mutations in the NGLY1 gene cause NGLY1 deficiency, which is characterized by developmental delay, seizures, and a lack of sweat and tears. To model the phenotypic variability observed among patients, we crossed a Drosophila model of NGLY1 deficiency onto a panel of genetically diverse strains. The resulting progeny showed a phenotypic spectrum from 0-100% lethality. Association analysis on the lethality phenotype as well as an evolutionary rate covariation analysis generated lists of modifying genes, providing insight into NGLY1 function and disease. The top association hit was Ncc69 (human NKCC1/2), a conserved ion transporter. Analyses in NGLY1 -/- mouse cells demonstrated that NKCC1 is misglycosylated and has reduced function, making it only the second confirmed NGLY1 enzymatic substrate. The misregulation of this ion transporter may explain the observed defects in secretory epithelium function in NGLY1 deficiency patients.

scholarly journals Diseases Associated with Defects in tRNA CCA Addition

2020 ◽  
Vol 21 (11) ◽  
pp. 3780 ◽  
Author(s):  
Angelo Slade ◽  
Ribal Kattini ◽  
Chloe Campbell ◽  
Martin Holcik
Keyword(s):  
Retinitis Pigmentosa ◽  
B Cell ◽  
Developmental Delay ◽  
Cellular Systems ◽  
Loss Of Function ◽  
Partial Loss ◽  
Sideroblastic Anemia ◽  
Current State ◽  
Nucleotidyl Transferase ◽  
Essential Enzyme

tRNA nucleotidyl transferase 1 (TRNT1) is an essential enzyme catalyzing the addition of terminal cytosine-cytosine-adenosine (CCA) trinucleotides to all mature tRNAs, which is necessary for aminoacylation. It was recently discovered that partial loss-of-function mutations in TRNT1 are associated with various, seemingly unrelated human diseases including sideroblastic anemia with B-cell immunodeficiency, periodic fevers and developmental delay (SIFD), retinitis pigmentosa with erythrocyte microcytosis, and progressive B-cell immunodeficiency. In addition, even within the same disease, the severity and range of the symptoms vary greatly, suggesting a broad, pleiotropic impact of imparting TRNT1 function on diverse cellular systems. Here, we describe the current state of knowledge of the TRNT1 function and the phenotypes associated with mutations in TRNT1.

scholarly journals Clinical, genetic, and molecular characterization of hyperphosphatasia with mental retardation: a case report and literature review

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Layal Abi Farraj ◽  
Wassim Daoud Khatoun ◽  
Naji Abou Chebel ◽  
Victor Wakim ◽  
Katia Dawali ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Mental Retardation ◽  
Intellectual Disability ◽  
Developmental Delay ◽  
Novel Mutation ◽  
Blood Levels ◽  
Facial Dysmorphism ◽  
Loss Of Function ◽  
Clinical Genetic ◽  
Severe Intellectual Disability

Abstract Background Hyperphosphatasia with mental retardation syndrome (HPMRS) is a recessive disorder characterized by high blood levels of alkaline phosphatase together with typical dysmorphic signs such as cleft palate, intellectual disability, cardiac abnormalities, and developmental delay. Genes involved in the glycosylphosphatidylinositol pathway and known to be mutated in HPMRS have never been characterized in the Lebanese population. Case presentation Herein, we describe a pair of monozygotic twins presenting with severe intellectual disability, distinct facial dysmorphism, developmental delay, and increased alkaline phosphatase level. Two individuals underwent whole exome sequencing followed by Sanger sequencing to confirm the co-segregation of the mutation in the consanguineous family. A biallelic loss of function mutation in PGAP3 was detected. Both patients were homozygous for the c.203delC (p.C68LfsX88) mutation and the parents were carriers confirming the founder effect of the mutation. High ALP serum levels confirmed the molecular diagnosis. Conclusion Our findings have illustrated the genomic profile of PGAP3-related HPMRS which is essential for targeted molecular and genetic testing. Moreover, we found previously unreported clinical findings such as hypodontia and skin hyperpigmentation. These features, together with the novel mutation expand the phenotypic and genotypic spectrum of this rare recessive disorder.

scholarly journals Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features

Brain ◽  
2017 ◽  
Vol 140 (11) ◽  
pp. 2879-2894 ◽  
Author(s):  
Cristina Elena Niturad ◽  
Dorit Lev ◽  
Vera M Kalscheuer ◽  
Agnieszka Charzewska ◽  
Julian Schubert ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Gabaa Receptor ◽  
Xenopus Laevis Oocytes ◽  
Incomplete Penetrance ◽  
Single Mutation ◽  
Loss Of Function ◽  
Missense Variants ◽  
Dysmorphic Features ◽  
Α3 Subunit

Abstract Genetic epilepsies are caused by mutations in a range of different genes, many of them encoding ion channels, receptors or transporters. While the number of detected variants and genes increased dramatically in the recent years, pleiotropic effects have also been recognized, revealing that clinical syndromes with various degrees of severity arise from a single gene, a single mutation, or from different mutations showing similar functional defects. Accordingly, several genes coding for GABAA receptor subunits have been linked to a spectrum of benign to severe epileptic disorders and it was shown that a loss of function presents the major correlated pathomechanism. Here, we identified six variants in GABRA3 encoding the α3-subunit of the GABAA receptor. This gene is located on chromosome Xq28 and has not been previously associated with human disease. Five missense variants and one microduplication were detected in four families and two sporadic cases presenting with a range of epileptic seizure types, a varying degree of intellectual disability and developmental delay, sometimes with dysmorphic features or nystagmus. The variants co-segregated mostly but not completely with the phenotype in the families, indicating in some cases incomplete penetrance, involvement of other genes, or presence of phenocopies. Overall, males were more severely affected and there were three asymptomatic female mutation carriers compared to only one male without a clinical phenotype. X-chromosome inactivation studies could not explain the phenotypic variability in females. Three detected missense variants are localized in the extracellular GABA-binding NH2-terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the α3-subunit. Functional studies in Xenopus laevis oocytes revealed a variable but significant reduction of GABA-evoked anion currents for all mutants compared to wild-type receptors. The degree of current reduction correlated partially with the phenotype. The microduplication disrupted GABRA3 expression in fibroblasts of the affected patient. In summary, our results reveal that rare loss-of-function variants in GABRA3 increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay and dysmorphic features, presenting in some pedigrees with an X-linked inheritance pattern. 10.1093/brain/awx236_video1 awx236media1 5636589232001

scholarly journals Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

2021 ◽  
Author(s):  
Marjolein J. A. Weerts ◽  
Kristina Lanko ◽  
Francisco J. Guzmán-Vega ◽  
Adam Jackson ◽  
Reshmi Ramakrishnan ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Neurodevelopmental Disorder ◽  
Epileptic Activity ◽  
Language Delay ◽  
Global Developmental Delay ◽  
Sequence Variants ◽  
Loss Of Function ◽  
Phenotypic Spectrum

Abstract Purpose Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. Methods We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Results Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Conclusion Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

scholarly journals A novel de novo hemizygous ARHGEF9 mutation associated with severe intellectual disability and epilepsy: a case report

2021 ◽  
Vol 49 (11) ◽  
pp. 030006052110583
Author(s):  
Tong Qiu ◽  
Qian Dai ◽  
Qiu Wang
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Developmental Delay ◽  
De Novo ◽  
Clinical Symptoms ◽  
Genetic Diagnosis ◽  
Epileptic Seizures ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Severe Intellectual Disability

ARHGEF9 encodes collybistin, a brain-specific guanosine diphosphate-guanosine-5′-triphosphate exchange factor that plays an important role in clustering of gephyrin and γ-aminobutyric acid type A receptors in the postsynaptic membrane. Overwhelming evidence suggests that defects in this protein can cause X-linked intellectual disability, which comprises a series of clinical phenotypes, including autism spectrum disorder, behavior disorder, intellectual disability, and febrile seizures. Here, we report a boy with clinical symptoms of severe intellectual disability, epilepsy, and developmental delay and regression. Trio exome sequencing ( trio-clinical exome sequencing) identified a novel hemizygous deletion, c.656_c.669delACTTCTTTGAGGCC (p. His219Leu fs*9), in exon 5 of ARHGEF9. This variant was not reported in either the Genome Aggregation Database or our database of 309 patients with neurodevelopmental disorders. Oxcarbazepine and levetiracetam reduced the frequency of the patient’s epileptic seizures to a certain extent, but psychomotor developmental delay and developmental regression became more obvious with age. This case study seeks to report a de novo loss-of-function mutation of ARHGEF9, aiming to emphasize the genetic diagnosis of X-linked intellectual disability and further improve knowledge of the ethnic distribution of ARHGEF9 mutations.

scholarly journals A Japanese boy with double diagnoses of 2p15p16.1 microdeletion syndrome and RP2-associated retinal disorder

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Kazuki Yamazawa ◽  
Kenji Shimizu ◽  
Hirofumi Ohashi ◽  
Hidenori Haruna ◽  
Satomi Inoue ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Retinal Disease ◽  
Recurrence Risk ◽  
Therapeutic Options ◽  
Loss Of Function ◽  
Childhood Onset ◽  
Microdeletion Syndrome ◽  
Dysmorphic Features ◽  
Inherited Retinal Disease ◽  
Retinal Disorder

Abstract2p15p16.1 microdeletion syndrome is a recently recognized congenital disorder characterized by developmental delay and dysmorphic features. RP2-associated retinal disorder (RP2-RD) is an X-linked inherited retinal disease with a childhood onset caused by a loss-of-function variant in the RP2 gene. Here, we describe a 14-year-old boy with double diagnoses of 2p15p16.1 microdeletion syndrome and RP2-RD. The recurrence risk of each condition and the indication for potential therapeutic options for RP2-RD are discussed.

scholarly journals Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of AP-4 complex assembly

2014 ◽  
Vol 24 (8) ◽  
pp. 2218-2227 ◽  
Author(s):  
Katia Hardies ◽  
Patrick May ◽  
Tania Djémié ◽  
Oana Tarta-Arsene ◽  
Tine Deconinck ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Loss Of Function ◽  
Spastic Paraplegia ◽  
Complex Assembly ◽  
Mild Fever
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