Genotype and phenotype correlations for SHANK3 de novo mutations in neurodevelopmental disorders

2018 ◽  
Author(s):  
Ying Li ◽  
Xiangbin Jia ◽  
Huidan Wu ◽  
Guanglei Xun ◽  
Jianjun Ou ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
De Novo ◽  
De Novo Mutations

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 De novo mutations in regulatory elements in neurodevelopmental disorders

Nature ◽  
2018 ◽  
Vol 555 (7698) ◽  
pp. 611-616 ◽  
Author(s):  
Patrick J. Short ◽  
Jeremy F. McRae ◽  
Giuseppe Gallone ◽  
Alejandro Sifrim ◽  
Hyejung Won ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
De Novo ◽  
Regulatory Elements ◽  
De Novo Mutations

scholarly journals Recapitulation of the EEF1A2 D252H neurodevelopmental disorder-causing missense mutation in mice reveals a toxic gain of function

2020 ◽  
Vol 29 (10) ◽  
pp. 1592-1606 ◽  
Author(s):  
Faith C J Davies ◽  
Jilly E Hope ◽  
Fiona McLachlan ◽  
Grant F Marshall ◽  
Laura Kaminioti-Dumont ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Molecular Modelling ◽  
Neurodevelopmental Disorders ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Elongation Factor ◽  
Missense Mutations ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Gain Of Function

Abstract Heterozygous de novo mutations in EEF1A2, encoding the tissue-specific translation elongation factor eEF1A2, have been shown to cause neurodevelopmental disorders including often severe epilepsy and intellectual disability. The mutational profile is unusual; ~50 different missense mutations have been identified but no obvious loss of function mutations, though large heterozygous deletions are known to be compatible with life. A key question is whether the heterozygous missense mutations operate through haploinsufficiency or a gain of function mechanism, an important prerequisite for design of therapeutic strategies. In order both to address this question and to provide a novel model for neurodevelopmental disorders resulting from mutations in EEF1A2, we created a new mouse model of the D252H mutation. This mutation causes the eEF1A2 protein to be expressed at lower levels in brain but higher in muscle in the mice. We compared both heterozygous and homozygous D252H and null mutant mice using behavioural and motor phenotyping alongside molecular modelling and analysis of binding partners. Although the proteomic analysis pointed to a loss of function for the D252H mutant protein, the D252H homozygous mice were more severely affected than null homozygotes on the same genetic background. Mice that are heterozygous for the missense mutation show no behavioural abnormalities but do have sex-specific deficits in body mass and motor function. The phenotyping of our novel mouse lines, together with analysis of molecular modelling and interacting proteins, suggest that the D252H mutation results in a gain of function.

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 Environmental carcinogens disproportionally mutate genes implicated in neurodevelopmental disorders

2021 ◽  
Author(s):  
Brennan H Baker ◽  
Shaoyi Zhang ◽  
Jeremy M Simon ◽  
Sarah M McLarnan ◽  
Wendy K Chung ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Developmental Disorders ◽  
De Novo ◽  
Autism Spectrum ◽  
Disease Genes ◽  
Environmental Carcinogens ◽  
De Novo Mutations ◽  
New Paradigm ◽  
Disease Etiology ◽  
Neurodevelopmental Disease

De novo mutations contribute to a large proportion of sporadic psychiatric and developmental disorders, yet the potential role of environmental carcinogens as drivers of causal de novo mutations in neurodevelopmental disorders is poorly studied. We demonstrate that several mutagens, including polycyclic aromatic hydrocarbons (PAHs), disproportionately mutate genes related to neurodevelopmental disorders including autism spectrum disorders (ASD), schizophrenia, and attention deficit hyperactivity disorder (ADHD). Other disease genes including amyotrophic lateral sclerosis (ALS), Alzheimers disease, congenital heart disease, orofacial clefts, and coronary artery disease were generally not mutated more than expected. Our findings support a new paradigm of neurodevelopmental disease etiology driven by a contribution of environmentally induced rather than random mutations.

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