scholarly journals Reply: De novo SPTAN1 mutation in axonal sensorimotor neuropathy and developmental disorder

Brain ◽  
2020 ◽  
Author(s):  
Liedewei Van de Vondel ◽  
Jonathan Baets ◽  
Danique Beijer
Keyword(s):  
Developmental Disorder ◽  
De Novo ◽  
Sensorimotor Neuropathy

scholarly journals De novo SPTAN1 mutation in axonal sensorimotor neuropathy and developmental disorder

Brain ◽  
2020 ◽  
Author(s):  
Emil Ylikallio ◽  
Niina Ritari ◽  
Markus Sainio ◽  
Jussi Toppila ◽  
Sirpa Kivirikko ◽  
...  
Keyword(s):  
Developmental Disorder ◽  
De Novo ◽  
Sensorimotor Neuropathy

scholarly journals De Novo Duplication in the CHD7 Gene Associated With Severe CHARGE Syndrome

2019 ◽  
Vol 12 ◽  
pp. 117863101983901 ◽  
Author(s):  
Laura Pranckėnienė ◽  
Eglė Preikšaitienė ◽  
Lucie Gueneau ◽  
Alexandre Reymond ◽  
Vaidutis Kučinskas
Keyword(s):  
Umbilical Hernia ◽  
Developmental Disorder ◽  
Autosomal Dominant ◽  
De Novo ◽  
Choanal Atresia ◽  
Sensory System ◽  
Charge Syndrome ◽  
Linea Alba ◽  
Congenital Hernia ◽  
Chd7 Gene

CHARGE syndrome is an autosomal dominant developmental disorder associated with a constellation of traits involving almost every organ and sensory system, in particular congenital anomalies, including choanal atresia and malformations of the heart, inner ear, and retina. Variants in CHD7 have been shown to cause CHARGE syndrome. Here, we report the identification of a novel de novo p.Asp2119_Pro2120ins6 duplication variant in a conserved region of CHD7 in a severely affected boy presenting with 3 and 5 of the CHARGE cardinal major and minor signs, respectively, combined with congenital umbilical hernia, congenital hernia at the linea alba, mildly hypoplastic inferior vermis, slight dilatation of the lateral ventricles, prominent metopic ridge, and hypoglycemic episodes.

De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy

2019 ◽  
Vol 57 (4) ◽  
pp. 283-288 ◽  
Author(s):  
Joohyun Park ◽  
Bianca R Flores ◽  
Katalin Scherer ◽  
Hanna Kuepper ◽  
Mari Rossi ◽  
...  
Keyword(s):  
Early Onset ◽  
Autosomal Recessive ◽  
De Novo ◽  
Brain Mri ◽  
Sensory Neuropathy ◽  
Sensorimotor Neuropathy ◽  
Charcot Marie Tooth Disease ◽  
Functional Characterisation ◽  
Potassium Influx ◽  
Tooth Disease

BackgroundCharcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous disorder of the peripheral nervous system. Biallelic variants in SLC12A6 have been associated with autosomal-recessive hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC). We identified heterozygous de novo variants in SLC12A6 in three unrelated patients with intermediate CMT.MethodsWe evaluated the clinical reports and electrophysiological data of three patients carrying de novo variants in SLC12A6 identified by diagnostic trio exome sequencing. For functional characterisation of the identified variants, potassium influx of mutated KCC3 cotransporters was measured in Xenopus oocytes.ResultsWe identified two different de novo missense changes (p.Arg207His and p.Tyr679Cys) in SLC12A6 in three unrelated individuals with early-onset progressive CMT. All presented with axonal/demyelinating sensorimotor neuropathy accompanied by spasticity in one patient. Cognition and brain MRI were normal. Modelling of the mutant KCC3 cotransporter in Xenopus oocytes showed a significant reduction in potassium influx for both changes.ConclusionOur findings expand the genotypic and phenotypic spectrum associated with SLC12A6 variants from autosomal-recessive HMSN/ACC to dominant-acting de novo variants causing a milder clinical presentation with early-onset neuropathy.

scholarly journals Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Nadja T. Hofer ◽  
Petronel Tuluc ◽  
Nadine J. Ortner ◽  
Yuliia V. Nikonishyna ◽  
Monica L. Fernándes-Quintero ◽  
...  
Keyword(s):  
High Risk ◽  
Neurodevelopmental Disorders ◽  
Developmental Disorder ◽  
De Novo ◽  
Disease Risk ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
De Novo Mutation ◽  
Loss Of Function ◽  
Gain Of Function

Abstract Background There is increasing evidence that de novo CACNA1D missense mutations inducing increased Cav1.3 L-type Ca2+-channel-function confer a high risk for neurodevelopmental disorders (autism spectrum disorder with and without neurological and endocrine symptoms). Electrophysiological studies demonstrating the presence or absence of typical gain-of-function gating changes could therefore serve as a tool to distinguish likely disease-causing from non-pathogenic de novo CACNA1D variants in affected individuals. We tested this hypothesis for mutation S652L, which has previously been reported in twins with a severe neurodevelopmental disorder in the Deciphering Developmental Disorder Study, but has not been classified as a novel disease mutation. Methods For functional characterization, wild-type and mutant Cav1.3 channel complexes were expressed in tsA-201 cells and tested for typical gain-of-function gating changes using the whole-cell patch-clamp technique. Results Mutation S652L significantly shifted the voltage-dependence of activation and steady-state inactivation to more negative potentials (~ 13–17 mV) and increased window currents at subthreshold voltages. Moreover, it slowed tail currents and increased Ca2+-levels during action potential-like stimulations, characteristic for gain-of-function changes. To provide evidence that only gain-of-function variants confer high disease risk, we also studied missense variant S652W reported in apparently healthy individuals. S652W shifted activation and inactivation to more positive voltages, compatible with a loss-of-function phenotype. Mutation S652L increased the sensitivity of Cav1.3 for inhibition by the dihydropyridine L-type Ca2+-channel blocker isradipine by 3–4-fold. Conclusions and limitations Our data provide evidence that gain-of-function CACNA1D mutations, such as S652L, but not loss-of-function mutations, such as S652W, cause high risk for neurodevelopmental disorders including autism. This adds CACNA1D to the list of novel disease genes identified in the Deciphering Developmental Disorder Study. Although our study does not provide insight into the cellular mechanisms of pathological Cav1.3 signaling in neurons, we provide a unifying mechanism of gain-of-function CACNA1D mutations as a predictor for disease risk, which may allow the establishment of a more reliable diagnosis of affected individuals. Moreover, the increased sensitivity of S652L to isradipine encourages a therapeutic trial in the two affected individuals. This can address the important question to which extent symptoms are responsive to therapy with Ca2+-channel blockers.

scholarly journals Transcriptomic and Epigenomic Landscape in Rett Syndrome

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 967
Author(s):  
Domenico Marano ◽  
Salvatore Fioriniello ◽  
Maurizio D'Esposito ◽  
Floriana Della Ragione
Keyword(s):  
Rett Syndrome ◽  
Transcriptional Activation ◽  
Large Scale ◽  
Developmental Disorder ◽  
De Novo ◽  
Current Knowledge ◽  
Biological Processes ◽  
De Novo Mutations ◽  
Protein Coding ◽  
Methylated Dna

Rett syndrome (RTT) is an extremely invalidating, cureless, developmental disorder, and it is considered one of the leading causes of intellectual disability in female individuals. The vast majority of RTT cases are caused by de novo mutations in the X-linked Methyl-CpG binding protein 2 (MECP2) gene, which encodes a multifunctional reader of methylated DNA. MeCP2 is a master epigenetic modulator of gene expression, with a role in the organization of global chromatin architecture. Based on its interaction with multiple molecular partners and the diverse epigenetic scenario, MeCP2 triggers several downstream mechanisms, also influencing the epigenetic context, and thus leading to transcriptional activation or repression. In this frame, it is conceivable that defects in such a multifaceted factor as MeCP2 lead to large-scale alterations of the epigenome, ranging from an unbalanced deposition of epigenetic modifications to a transcriptional alteration of both protein-coding and non-coding genes, with critical consequences on multiple downstream biological processes. In this review, we provide an overview of the current knowledge concerning the transcriptomic and epigenomic alterations found in RTT patients and animal models.

scholarly journals Systematic analysis of exonic germline and postzygotic de novo mutations in bipolar disorder

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Masaki Nishioka ◽  
An-a Kazuno ◽  
Takumi Nakamura ◽  
Naomi Sakai ◽  
Takashi Hayama ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Developmental Disorder ◽  
De Novo ◽  
Deleterious Mutations ◽  
Loss Of Function ◽  
Sequencing Data ◽  
De Novo Mutations ◽  
Significant Enrichment ◽  
Postzygotic Mutations ◽  
Depressive Episodes

AbstractBipolar disorder is a severe mental illness characterized by recurrent manic and depressive episodes. To better understand its genetic architecture, we analyze ultra-rare de novo mutations in 354 trios with bipolar disorder. For germline de novo mutations, we find significant enrichment of loss-of-function mutations in constrained genes (corrected-P = 0.0410) and deleterious mutations in presynaptic active zone genes (FDR = 0.0415). An analysis integrating single-cell RNA-sequencing data identifies a subset of excitatory neurons preferentially expressing the genes hit by deleterious mutations, which are also characterized by high expression of developmental disorder genes. In the analysis of postzygotic mutations, we observe significant enrichment of deleterious ones in developmental disorder genes (P = 0.00135), including the SRCAP gene mutated in two unrelated probands. These data collectively indicate the contributions of both germline and postzygotic mutations to the risk of bipolar disorder, supporting the hypothesis that postzygotic mutations of developmental disorder genes may contribute to bipolar disorder.

scholarly journals Non-coding variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms

2020 ◽  
Author(s):  
Caroline F Wright ◽  
Nicholas M Quaife ◽  
Laura Ramos-Hernández ◽  
Petr Danecek ◽  
Matteo P Ferla ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
Developmental Disorder ◽  
De Novo ◽  
Diagnostic Yield ◽  
Severe Disease ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Clinical Genetic ◽  
Protein Coding ◽  
Coding Variants

AbstractClinical genetic testing of protein-coding regions identifies a likely causative variant in only ∼35% of severe developmental disorder (DD) cases. We screened 9,858 patients from the Deciphering Developmental Disorders (DDD) study for de novo mutations in the 5’untranslated regions (5’UTRs) of dominant haploinsufficient DD genes. We identify four single nucleotide variants and two copy number variants upstream of MEF2C that cause DD through three distinct loss-of-function mechanisms, disrupting transcription, translation, and/or protein function. These non-coding variants represent 23% of disease-causing variants identified in MEF2C in the DDD cohort. Our analyses show that non-coding variants upstream of known disease-causing genes are an important cause of severe disease and demonstrate that analysing 5’UTRs can increase diagnostic yield, even using existing exome sequencing datasets. We also show how non-coding variants can help inform both the disease-causing mechanism underlying protein-coding variants, and dosage tolerance of the gene.

scholarly journals InDelible: Detection and Evaluation of Clinically-relevant Structural Variation from Exome Sequencing

2020 ◽  
Author(s):  
Eugene J. Gardner ◽  
Alejandro Sifrim ◽  
Sarah J. Lindsay ◽  
Elena Prigmore ◽  
Diana Rajan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Developmental Disorders ◽  
Structural Variation ◽  
Developmental Disorder ◽  
De Novo ◽  
Size Range ◽  
Diagnostic Yield ◽  
Structural Variations ◽  
Pathogenic Variants ◽  
Split Read

AbstractPurposeIdentifying structural variations (SVs) associated with developmental disorder (DD) patient phenotype missed by conventional approaches.MethodsWe have developed a novel SV discovery approach that mines split-read information, ‘InDelible’, and applied it to exome sequencing (ES) of 13,438 probands with severe DD recruited as part of the Deciphering Developmental Disorders (DDD) study.ResultsUsing InDelible we were able to find 59 previously undetected variants in genes previously associated with DD, of which 49.2% (29) had phenotypic features that accord with those of the patient in which they were found, and were deemed plausibly pathogenic. InDelible was particularly effective at ascertaining variants between 21-500 bps in size, and increased the total number of potentially pathogenic variants identified by DDD in this size range by 42.0% (n = 29 variants). Of particular interest were seven confirmed de novo SVs in the gene MECP2; these variants represent 31.8% of all de novo protein truncating variants in MECP2 among DDD patients.ConclusionInDelible provides a rapid framework for the discovery of likely pathogenic SVs that are likely to be missed by standard analytical workflows and has the potential to improve the diagnostic yield of ES.

scholarly journals De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder

2019 ◽  
Vol 104 (4) ◽  
pp. 709-720 ◽  
Author(s):  
Eduardo Calpena ◽  
Alexia Hervieu ◽  
Teresa Kaserer ◽  
Sigrid M.A. Swagemakers ◽  
Jacqueline A.C. Goos ◽  
...  
Keyword(s):  
Developmental Disorder ◽  
De Novo ◽  
Mediator Complex ◽  
Gene Encoding

scholarly journals Defective X-gating caused by de novo gain-of-function mutations in KCNK3 underlies a developmental disorder with sleep apnea

2021 ◽  
Author(s):  
Janina Soermann ◽  
Marcus Schewe ◽  
Peter Proks ◽  
Thibault Jouen-Tachoire ◽  
Shanlin Rao ◽  
...  
Keyword(s):  
Sleep Apnea ◽  
Developmental Disorder ◽  
De Novo ◽  
Therapeutic Strategies ◽  
K Channel ◽  
Global Public Health ◽  
Gain Of Function ◽  
Public Health Burden ◽  
Channel Opening ◽  
G Protein Coupled

Sleep apnea is a common disorder that represents a global public health burden. KCNK3 encodes TASK-1, a K+ channel implicated in the control of breathing, but its reported link with sleep apnea remains poorly understood. Here we describe a novel developmental disorder with sleep apnea caused by rare de novo gain-of-function mutations in KCNK3. The mutations cluster around the X-gate, a gating motif which controls channel opening, and produce overactive channels that no longer respond to inhibition by G-protein coupled receptor pathways but which can be inhibited by several clinically relevant drugs. These findings demonstrate a clear role for TASK-1 in sleep apnea and identify possible therapeutic strategies.

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