scholarly journals A catalogue of new incidence estimates of monogenic neurodevelopmental disorders caused by de novo variants

Brain ◽  
2020 ◽  
Vol 143 (4) ◽  
pp. 1099-1105 ◽  
Author(s):  
Javier A López-Rivera ◽  
Eduardo Pérez-Palma ◽  
Joseph Symonds ◽  
Amanda S Lindy ◽  
Dianalee A McKnight ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Large Scale ◽  
De Novo ◽  
Disease Incidence ◽  
Large Fraction ◽  
Strategic Decision ◽  
P Value ◽  
Monogenic Disorders ◽  
Kendall’S Τ ◽  
De Novo Variant

Abstract A large fraction of rare and severe neurodevelopmental disorders are caused by sporadic de novo variants. Epidemiological disease estimates are not available for the vast majority of these de novo monogenic neurodevelopmental disorders because of phenotypic heterogeneity and the absence of large-scale genomic screens. Yet, knowledge of disease incidence is important for clinicians and researchers to guide health policy planning. Here, we adjusted a statistical method based on genetic data to predict, for the first time, the incidences of 101 known de novo variant-associated neurodevelopmental disorders as well as 3106 putative monogenic disorders. Two corroboration analyses supported the validity of the calculated estimates. First, greater predicted gene-disorder incidences positively correlated with larger numbers of pathogenic variants collected from patient variant databases (Kendall’s τ = 0.093, P-value = 6.9 × 10−6). Second, for six of seven (86%) de novo variant associated monogenic disorders for which epidemiological estimates were available (SCN1A, SLC2A1, SALL1, TBX5, KCNQ2, and CDKL5), the predicted incidence estimates matched the reported estimates. We conclude that in the absence of epidemiological data, our catalogue of 3207 incidence estimates for disorders caused by de novo variants can guide patient advocacy groups, clinicians, researchers, and policymakers in strategic decision-making.

scholarly journals Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Tianyun Wang ◽  
◽  
Kendra Hoekzema ◽  
Davide Vecchio ◽  
Huidan Wu ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Large Scale ◽  
De Novo ◽  
Targeted Sequencing ◽  
Published Data ◽  
De Novo Mutations ◽  
Risk Genes ◽  
Mutation Burden ◽  
Number Of Patients ◽  
Significant Burden

Abstract Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E−06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E−07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype–genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.

scholarly journals Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability

2017 ◽  
Vol 55 (8) ◽  
pp. 561-566 ◽  
Author(s):  
Genay O Pilarowski ◽  
Hilary J Vernon ◽  
Carolyn D Applegate ◽  
Leandros Boukas ◽  
Megan T Cho ◽  
...  
Keyword(s):  
Large Scale ◽  
De Novo ◽  
Large Fraction ◽  
Chromatin Modification ◽  
Dominant Negative ◽  
Chromatin Remodeler ◽  
Cultured Fibroblasts ◽  
Human Phenotype ◽  
Missense Variants ◽  
Neurological Phenotype

BackgroundThe list of Mendelian disorders of the epigenetic machinery has expanded rapidly during the last 5 years. A few missense variants in the chromatin remodeler CHD1 have been found in several large-scale sequencing efforts focused on uncovering the genetic aetiology of autism.ObjectivesTo explore whether variants in CHD1 are associated with a human phenotype.MethodsWe used GeneMatcher to identify other physicians caring for patients with variants in CHD1. We also explored the epigenetic consequences of one of these variants in cultured fibroblasts.ResultsHere we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features. Importantly, three of these variants occurred de novo. We also report on a subject with a de novo deletion covering a large fraction of the CHD1 gene without any obvious neurological phenotype. Finally, we demonstrate increased levels of the closed chromatin modification H3K27me3 in fibroblasts from a subject carrying a de novo variant in CHD1.ConclusionsOur results suggest that variants in CHD1 can lead to diverse phenotypic outcomes; however, the neurodevelopmental phenotype appears to be limited to patients with missense variants, which is compatible with a dominant negative mechanism of disease.

scholarly journals Two different presentations of de novo variants of CSNK2B: two case reports

2022 ◽  
Vol 16 (1) ◽  
Author(s):  
Matheus V. M. B Wilke ◽  
Bibiana M. Oliveira ◽  
Alessandra Pereira ◽  
Maria Juliana R. Doriqui ◽  
Fernando Kok ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
De Novo ◽  
Case Reports ◽  
Neurologic Disorder ◽  
Left Hand ◽  
Dysmorphic Features ◽  
Chief Complaints ◽  
Severe Hypotonia ◽  
De Novo Variant ◽  
Caucasian Female

Abstract Background Poirier–Bienvenu neurodevelopmental syndrome is a neurologic disorder caused by mutations in the CSNK2B gene. It is mostly characterized by early-onset seizures, hypotonia, and mild dysmorphic features. Craniodigital syndrome is a recently described disorder also related to CSNK2B, with a single report in the literature. Objective To report two unrelated cases of children harboring CSNK2B variants (NM_001320.6) who presented with distinct diseases. Case report Case 1 is a 7-month-old, Caucasian, female patient with chief complaints of severe hypotonia and drug-refractory myoclonic epilepsy, with a likely pathogenic de novo variant c.494A>G (p.His165Arg). Case 2 is a 5-year-old male, Latino patient with craniodigital intellectual disability syndrome subjacent to a de novo, likely pathogenic variant c.94G>T (p.Asp32Tyr). His dysmorphic features included facial dysmorphisms, supernumerary nipples, and left-hand postaxial polydactyly. Conclusion This report suggest that the CSNK2B gene may be involved in the physiopathology of neurodevelopmental disorders and variable dysmorphic features.

scholarly journals Protein phosphatase 2A – structure, function and role in neurodevelopmental disorders

2021 ◽  
Vol 134 (13) ◽  
Author(s):  
Priyanka Sandal ◽  
Chian Ju Jong ◽  
Ronald A. Merrill ◽  
Jianing Song ◽  
Stefan Strack
Keyword(s):  
Neurodevelopmental Disorders ◽  
Protein Phosphatase ◽  
Mammalian Cells ◽  
Large Scale ◽  
De Novo ◽  
Protein Phosphatase 2A ◽  
Cell Types ◽  
De Novo Mutations ◽  
Sequencing Studies ◽  
Phosphatase 2A

ABSTRACT Neurodevelopmental disorders (NDDs), including intellectual disability (ID), autism and schizophrenia, have high socioeconomic impact, yet poorly understood etiologies. A recent surge of large-scale genome or exome sequencing studies has identified a multitude of mostly de novo mutations in subunits of the protein phosphatase 2A (PP2A) holoenzyme that are strongly associated with NDDs. PP2A is responsible for at least 50% of total Ser/Thr dephosphorylation in most cell types and is predominantly found as trimeric holoenzymes composed of catalytic (C), scaffolding (A) and variable regulatory (B) subunits. PP2A can exist in nearly 100 different subunit combinations in mammalian cells, dictating distinct localizations, substrates and regulatory mechanisms. PP2A is well established as a regulator of cell division, growth, and differentiation, and the roles of PP2A in cancer and various neurodegenerative disorders, such as Alzheimer's disease, have been reviewed in detail. This Review summarizes and discusses recent reports on NDDs associated with mutations of PP2A subunits and PP2A-associated proteins. We also discuss the potential impact of these mutations on the structure and function of the PP2A holoenzymes and the etiology of NDDs.

scholarly journals Ultra-rare disruptive and damaging mutations influence educational attainment in the general population

2016 ◽  
Author(s):  
Andrea Ganna ◽  
Giulio Genovese ◽  
Daniel P. Howrigan ◽  
Andrea Byrnes ◽  
Mitja Kurki ◽  
...  
Keyword(s):  
General Population ◽  
Neurodevelopmental Disorders ◽  
Cognitive Abilities ◽  
Rare Variants ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
P Value ◽  
Sequencing Data ◽  
Whole Exome ◽  
Number Variation

Ultra-rare inherited and de novo disruptive variants in highly constrained (HC) genes are enriched in neurodevelopmental disorders 1–5. However, their impact on cognition in the general population has not been explored. We hypothesize that disruptive and damaging ultra-rare variants (URVs) in HC genes not only confer risk to neurodevelopmental disorders, but also influence general cognitive abilities measured indirectly by years of education (YOE). We tested this hypothesis in 14,133 individuals with whole exome or genome sequencing data. The presence of one or more URVs was associated with a decrease in YOE (3.1 months less for each additional mutation; P-value=3.3×10−8) and the effect was stronger in HC genes enriched for brain expression (6.5 months less, P-value=3.4×10−5). The effect of these variants was more pronounced than the estimated effects of runs of homozygosity and pathogenic copy number variation 6–9. Our findings suggest that effects of URVs in HC genes are not confined to severe neurodevelopmental disorder, but influence the cognitive spectrum in the general population

scholarly journals A Survey of Copy Number Variants Associated with Neurodevelopmental Disorders in a Large-Scale, Multi-Ancestry Biobank

2021 ◽  
Author(s):  
Rebecca Birnbaum ◽  
Behrang Mahjani ◽  
Ruth Loos ◽  
Andrew Sharp
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Large Scale ◽  
Clinical Presentation ◽  
Copy Number Variants ◽  
P Value ◽  
Congenital Disorders ◽  
Major Depressive ◽  
Clinical Assessments ◽  
Obstructive Sleep

BACKGROUND: Past clinical genetic studies have identified rare, copy number variants (CNVs) as risk factors for multiple, neurodevelopmental disorders (NDD), including autism spectrum disorder and schizophrenia. However, the broad, clinical characterization of these NDD-CNVs in large population cohorts, especially of diverse ancestry, is relatively understudied. We characterized the clinical presentation of NDD-CNVs in the BioMe biobank, comprising ~25,000 individuals across diverse ancestry, medical and neuropsychiatric clinical presentation, with a mean age of 50.3 years. METHODS: Individuals within the BioMe biobank harboring NDD-CNVs were identified using a consensus of two CNV calling algorithms, based on whole-exome sequencing and genotype array data, followed by a series of novel, in-silico clinical assessments. RESULTS: The overall prevalence of a set of 64 NDD-CNVs was calculated at ~2.5%, with prevalence varying by locus, corroborating the presence of some relatively, highly-prevalent NDD-CNVs (i.e., 15q11.2 deletion/duplication, 2q13(NPHP1) deletion/duplication). An aggregate set of rare, NDD-CNVs were enriched for congenital disorders (OR=1.8, p-value=0.02) and major depressive disorders (OR=1.3, p-value=0.04) in multi-ancestry analyses, and major depressive-disorder in an African ancestry-stratified group (OR=1.8, p-value=0.01). In a meta-analysis of medical diagnoses (n=195 hierarchically-clustered diagnostic codes), an aggregated set of rare, NDD-CNVs was significantly associated with obstructive sleep apnea (Z-score=3.6 p=3.2x10-4). Further, an aggregated set of rare, NDD-CNVs was associated with increased body mass index (BMI) in a multi-ancestry analysis (Beta=0.14, p-value=0,04), and in Hispanic-stratified analyses (Beta=0.30, p-value=4.2x10-3). For 38 common serum laboratory tests, there was no identified association with the aggregate set of NDD-CNVs. CONCLUSION: The current analyses elucidated clinical features of individuals harboring NDD-CNVs, in a large-scale, multi-ancestry biobank, identifying enrichments for congenital disorders and major depressive disorder, as well as identifying associations with obesity-related phenotypes, obstructive sleep apnea and increased BMI. Future recall of individuals harboring NDD-CNVs will allow for further clinical assessments beyond the electronic health records (EHR) presently analyzed, including neurocognitive and neuroimaging outcomes.

Target-Templated de novo Design of Macrocyclic D-/L-Peptides: Inhibitors of the PD-1/PD-L1 Interaction

2020 ◽  
Author(s):  
Salvador Guardiola ◽  
Monica Varese ◽  
Xavier Roig ◽  
Jesús Garcia ◽  
Ernest Giralt
Keyword(s):  
Protein Interactions ◽  
Cyclic Peptides ◽  
General Framework ◽  
Large Scale ◽  
De Novo ◽  
Inhibitory Effect ◽  
Original Text ◽  
Protein Protein Interactions ◽  
Retraction Notice ◽  
Pharmaceutical Properties

<p>NOTE: This preprint has been retracted by consensus from all authors. See the retraction notice in place above; the original text can be found under "Version 1", accessible from the version selector above.</p><p><br></p><p>------------------------------------------------------------------------</p><p><br></p><p>Peptides, together with antibodies, are among the most potent biochemical tools to modulate challenging protein-protein interactions. However, current structure-based methods are largely limited to natural peptides and are not suitable for designing target-specific binders with improved pharmaceutical properties, such as macrocyclic peptides. Here we report a general framework that leverages the computational power of Rosetta for large-scale backbone sampling and energy scoring, followed by side-chain composition, to design heterochiral cyclic peptides that bind to a protein surface of interest. To showcase the applicability of our approach, we identified two peptides (PD-<i>i</i>3 and PD-<i>i</i>6) that target PD-1, a key immune checkpoint, and work as protein ligand decoys. A comprehensive biophysical evaluation confirmed their binding mechanism to PD-1 and their inhibitory effect on the PD-1/PD-L1 interaction. Finally, elucidation of their solution structures by NMR served as validation of our <i>de novo </i>design approach. We anticipate that our results will provide a general framework for designing target-specific drug-like peptides.<i></i></p>

A Target-Based Method for Designing Heterochiral Cyclic Peptide Binders: De Novo Inhibitors of the PD-1/PD-L1 Interaction

2020 ◽  
Author(s):  
Salvador Guardiola ◽  
Monica Varese ◽  
Xavier Roig ◽  
Jesús Garcia ◽  
Ernest Giralt
Keyword(s):  
Protein Interactions ◽  
Cyclic Peptides ◽  
General Framework ◽  
Large Scale ◽  
Cyclic Peptide ◽  
De Novo ◽  
Inhibitory Effect ◽  
Original Text ◽  
Retraction Notice ◽  
Pharmaceutical Properties

<p>NOTE: This preprint has been retracted by consensus from all authors. See the retraction notice in place above; the original text can be found under "Version 1", accessible from the version selector above.</p><p><br></p><p>------------------------------------------------------------------------</p><p><br></p><p>Peptides, together with antibodies, are among the most potent biochemical tools to modulate challenging protein-protein interactions. However, current structure-based methods are largely limited to natural peptides and are not suitable for designing target-specific binders with improved pharmaceutical properties, such as macrocyclic peptides. Here we report a general framework that leverages the computational power of Rosetta for large-scale backbone sampling and energy scoring, followed by side-chain composition, to design heterochiral cyclic peptides that bind to a protein surface of interest. To showcase the applicability of our approach, we identified two peptides (PD-<i>i</i>3 and PD-<i>i</i>6) that target PD-1, a key immune checkpoint, and work as protein ligand decoys. A comprehensive biophysical evaluation confirmed their binding mechanism to PD-1 and their inhibitory effect on the PD-1/PD-L1 interaction. Finally, elucidation of their solution structures by NMR served as validation of our <i>de novo </i>design approach. We anticipate that our results will provide a general framework for designing target-specific drug-like peptides.<i></i></p>

Target-Templated de novo Design of Macrocyclic D-/L-Peptides: Inhibitors of the PD-1/PD-L1 Interaction

2020 ◽  
Author(s):  
Salvador Guardiola ◽  
Monica Varese ◽  
Xavier Roig ◽  
Jesús Garcia ◽  
Ernest Giralt
Keyword(s):  
Protein Interactions ◽  
Cyclic Peptides ◽  
General Framework ◽  
Large Scale ◽  
De Novo ◽  
Inhibitory Effect ◽  
Original Text ◽  
Protein Protein Interactions ◽  
Retraction Notice ◽  
Pharmaceutical Properties

<p>NOTE: This preprint has been retracted by consensus from all authors. See the retraction notice in place above; the original text can be found under "Version 1", accessible from the version selector above.</p><p><br></p><p>------------------------------------------------------------------------</p><p><br></p><p>Peptides, together with antibodies, are among the most potent biochemical tools to modulate challenging protein-protein interactions. However, current structure-based methods are largely limited to natural peptides and are not suitable for designing target-specific binders with improved pharmaceutical properties, such as macrocyclic peptides. Here we report a general framework that leverages the computational power of Rosetta for large-scale backbone sampling and energy scoring, followed by side-chain composition, to design heterochiral cyclic peptides that bind to a protein surface of interest. To showcase the applicability of our approach, we identified two peptides (PD-<i>i</i>3 and PD-<i>i</i>6) that target PD-1, a key immune checkpoint, and work as protein ligand decoys. A comprehensive biophysical evaluation confirmed their binding mechanism to PD-1 and their inhibitory effect on the PD-1/PD-L1 interaction. Finally, elucidation of their solution structures by NMR served as validation of our <i>de novo </i>design approach. We anticipate that our results will provide a general framework for designing target-specific drug-like peptides.<i></i></p>

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