scholarly journals Quantifying concordant genetic effects of de novo mutations on multiple disorders

2021 ◽  
Author(s):  
Hanmin Guo ◽  
Lin Hou ◽  
Yu Shi ◽  
Sheng Chih Jin ◽  
Xue Zeng ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
De Novo ◽  
Statistical Significance ◽  
Genetic Effects ◽  
Incomplete Penetrance ◽  
De Novo Mutations ◽  
Risk Genes ◽  
Fetal Tissues ◽  
Statistical Framework ◽  
Shared Genetic

AbstractExome sequencing on tens of thousands of parent-proband trios has identified numerous deleterious de novo mutations (DNMs) and implicated risk genes for many disorders. Recent studies have suggested shared genes and pathways are enriched for DNMs across multiple disorders. However, existing analytic strategies only focus on genes that reach statistical significance for multiple disorders and require large trio samples in each study. As a result, these methods are not able to characterize the full landscape of genetic sharing due to polygenicity and incomplete penetrance. In this work, we introduce EncoreDNM, a novel statistical framework to quantify shared genetic effects between two disorders characterized by concordant enrichment of DNMs in the exome. EncoreDNM makes use of exome-wide, summary-level DNM data, including genes that do not reach statistical significance in single-disorder analysis, to evaluate the overall and annotation-partitioned genetic sharing between two disorders. Applying EncoreDNM to DNM data of nine disorders, we identified abundant pairwise enrichment correlations, especially in genes intolerant to pathogenic mutations and genes highly expressed in fetal tissues. These results suggest that EncoreDNM improves current analytic approaches and may have broad applications in DNM studies.

scholarly journals A Statistical Framework for Mapping Risk Genes from De Novo Mutations in Whole-Genome-Sequencing Studies

2018 ◽  
Vol 102 (6) ◽  
pp. 1031-1047 ◽  
Author(s):  
Yuwen Liu ◽  
Yanyu Liang ◽  
A. Ercument Cicek ◽  
Zhongshan Li ◽  
Jinchen Li ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
De Novo ◽  
Whole Genome ◽  
De Novo Mutations ◽  
Risk Genes ◽  
Statistical Framework ◽  
Sequencing Studies

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 Identification of a β-Arrestin 2 Mutation Related to Autism by Whole-Exome Sequencing

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Yunfei Tang ◽  
Yamei Liu ◽  
Lei Tong ◽  
Shini Feng ◽  
Dongshu Du ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Developmental Stages ◽  
De Novo ◽  
Repetitive Behavior ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Potential Contribution ◽  
De Novo Mutations ◽  
Whole Exome

Autism spectrum disorder (ASD) is a complex neurological disease characterized by impaired social communication and interaction skills, rigid behavior, decreased interest, and repetitive activities. The disease has a high degree of genetic heterogeneity, and the genetic cause of ASD in many autistic individuals is currently unclear. In this study, we report a patient with ASD whose clinical features included social interaction disorder, communication disorder, and repetitive behavior. We examined the patient’s genetic variation using whole-exome sequencing technology and found new de novo mutations. After analysis and evaluation, ARRB2 was identified as a candidate gene. To study the potential contribution of the ARRB2 gene to the human brain development and function, we first evaluated the expression profile of this gene in different brain regions and developmental stages. Then, we used weighted gene coexpression network analysis to analyze the associations between ARRB2 and ASD risk genes. Additionally, the spatial conformation and stability of the ARRB2 wild type and mutant proteins were examined by simulations. Then, we further established a mouse model of ASD. The results showed abnormal ARRB2 expression in the mouse ASD model. Our study showed that ARRB2 may be a risk gene for ASD, but the contribution of de novo ARRB2 mutations to ASD is unclear. This information will provide references for the etiology of ASD and aid in the mechanism-based drug development and treatment.

scholarly journals Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Ute I Scholl ◽  
Gabriel Stölting ◽  
Carol Nelson-Williams ◽  
Alfred A Vichot ◽  
Murim Choi ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Primary Aldosteronism ◽  
Early Onset ◽  
De Novo ◽  
Incomplete Penetrance ◽  
De Novo Mutations ◽  
Channel Inactivation ◽  
Aldosterone Production ◽  
Genome Level ◽  
Insight Into

Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5%) shared the identical, previously unidentified, heterozygous CACNA1HM1549V mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (CaV3.2) expressed in adrenal glomerulosa. CACNA1HM1549V showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca2+, the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension.

scholarly journals Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Hui Guo ◽  
Tianyun Wang ◽  
Huidan Wu ◽  
Min Long ◽  
Bradley P. Coe ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
De Novo Mutations ◽  
Risk Genes ◽  
Multifactorial Model

scholarly journals mTADA: a framework for analyzing de novo mutations in multiple traits

2018 ◽  
Author(s):  
Hoang T. Nguyen ◽  
Amanda Dobbyn ◽  
Joseph Buxbaum ◽  
Dalila Pinto ◽  
Shaun M Purcell ◽  
...  
Keyword(s):  
De Novo ◽  
Neuropsychiatric Disorders ◽  
Joint Analysis ◽  
Data Sets ◽  
Analysis Method ◽  
De Novo Mutations ◽  
Multiple Traits ◽  
Risk Genes ◽  
Trait Analysis ◽  
Chd Risk

AbstractJoint analysis of multiple traits can result in the identification of associations not found through the analysis of each trait in isolation. In addition, approaches that consider multiple traits can aid in the characterization of shared genetic etiology among those traits. In recent years, parent-offspring trio studies have reported an enrichment of de novo mutations (DNMs) in neuropsychiatric disorders. The analysis of DNM data in the context of neuropsychiatric disorders has implicated multiple putatively causal genes, and a number of reported genes are shared across disorders. However, a joint analysis method designed to integrate de novo mutation data from multiple studies has yet to be implemented. We here introduce multi pi e-trait TAD A (mTADA) which jointly analyzes two traits using DNMs from non-overlapping family samples. mTADA uses two single-trait analysis data sets to estimate the proportion of overlapping risk genes, and reports genes shared between and specific to the relevant disorders. We applied mTADA to >13,000 trios for six disorders: schizophrenia (SCZ), autism spectrum disorder (ASD), developmental disorders (DD), intellectual disability (ID), epilepsy (EPI), and congenital heart disease (CHD). We report the proportion of overlapping risk genes and the specific risk genes shared for each pair of disorders. A total of 153 genes were found to be shared in at least one pair of disorders. The largest percentages of shared risk genes were observed for pairs of DD, ID, ASD, and CHD (>20%) whereas SCZ, CHD, and EPI did not show strong overlaps In risk gene set between them. Furthermore, mTADA identified additional SCZ, EPI and CHD risk genes through integration with DD de novo mutation data. For CHD, using DD information, 31 risk genes with posterior probabilities > 0.8 were identified, and 20 of these 31 genes were not in the list of known CHD genes. We find evidence that most significant CHD risk genes are strongly expressed in prenatal stages of the human genes. Finally, we validated our findings for CHD and EPI in independent cohorts comprising 1241 CHD trios, 226 CHD singletons and 197 EPI trios. Multiple novel risk genes identified by mTADA also had de novo mutations in these independent data sets. The joint analysis method introduced here, mTADA, is able to identify risk genes shared by two traits as well as additional risk genes not found through single-trait analysis only. A number of risk genes reported by mTADA are identified only through joint analysis, specifically when ASD, DD, or ID are one of the two traits examined. This suggests that novel genes for the trait or a new trait might converge to a core gene list of the three traits.

scholarly journals TU47. EXOME SEQUENCING STUDY FOR IDENTIFICATION OF DE NOVO MUTATIONS OF IDIOPATHIC INTELLECTUAL DISABILITY IN CHILDREN FROM THE 2004 PELOTAS (BRAZIL) BIRTH COHORT

2021 ◽  
Vol 51 ◽  
pp. e120
Author(s):  
Karen Sánchez-Luquez ◽  
Simone Menezes Karam ◽  
Alicia Matijasevich ◽  
Iná da Silva dos Santos ◽  
Aluísio J D Barros ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Birth Cohort ◽  
De Novo ◽  
De Novo Mutations

scholarly journals Novel de novo heterozygous mutation on SYNGAP1 from the Indian population

2020 ◽  
Author(s):  
Vijaya Verma ◽  
Amit Mandora ◽  
Abhijeet Botre ◽  
James Premdoss Clement
Keyword(s):  
Exome Sequencing ◽  
De Novo ◽  
Novel Mutation ◽  
Autism Spectrum ◽  
Current Treatment ◽  
Developmental Trajectory ◽  
Global Developmental Delay ◽  
Heterozygous Mutation ◽  
Specific Gene ◽  
De Novo Mutations

Abstract Background : Exome sequencing is a prominent tool to identify novel and deleterious mutations which could be nonsense, frameshift, and canonical splice-site mutations in a specific gene. De novo mutations in SYNGAP1 , which codes for synaptic RAS-GTPase activating the protein, causes Intellectual disability (ID) and Autism Spectrum Disorder (ASD). SYNGAP1 related ASD/ID is one of the rare diseases that is detrimental to the normal neuronal developmental and disrupts the global development of a child. Results: We report a case of a child of 2-year old with global developmental delay, microcephaly subtle dysmorphism, absence seizures, disrupted sleep, delay in learning a language, and eating problems. Upon further validation, the child has a few traits of ASD. Here, based on focused exome sequencing, we report a de novo heterozygous mutation in SYNGAP1 exon 11 with c. 1861 C>T (p.arg612ter). Currently, the child is on atorvastatin and has shown considerable improvement in global behaviour and cognitive development. The long-term follow up of the child’s development would contribute to the already existing knowledge of the developmental trajectory in individuals with SYNGAP1 heterozygous mutation. Conclusion: In this report, we discuss the finding of a novel mutation in one of the genes, SYNGAP1 , implicated in ASD/ID. In addition, we discuss the current treatment prescribed to the patient and the progress of global developmental of the child.

102 Exome Sequencing Identifies Novel Molecular Determinants of Human Congenital Hydrocephalus

Neurosurgery ◽  
2017 ◽  
Vol 64 (CN_suppl_1) ◽  
pp. 220-220
Author(s):  
Charuta Gavankar Furey ◽  
Jungmin Choi ◽  
Daniel Duran ◽  
Andrew T Timberlake ◽  
Xue Zeng ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Statistical Significance ◽  
The United States ◽  
Congenital Hydrocephalus ◽  
Common Disease ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Whole Exome

Abstract INTRODUCTION Congenital hydrocephalus (CH), with an estimated prevalence of 1 in 1000 births, is the most common disease treated by pediatric neurosurgeons, and exerts a tremendous burden on the United States health care budget, consuming over $2 billion annually. Paradoxically, CH treatments remain inadequate, crude, and primarily symptomatic, comprised largely of surgical shunts riddled with infectious and mechanical complications. Despite evidence that genetic factors play a major role in the pathogenesis of CH an estimated 40% of human CH has a genetic etiology our knowledge of specific CH-causing mutations and their pathogenic mechanisms remains primitive. Understanding critical genetic drivers underlying human CH holds promise for the development of targeted therapies. However, traditional genetic approaches have been limited in their ability to identify causative CH genes because kindreds are rare, small in size, or appear to have sporadic inheritance patterns. Next-generation sequencing, and specifically whole exome sequencing (WES), can overcome these barriers to gene discovery. METHODS We performed whole-exome sequencing on DNA isolated from 130 patient-parent trios (affected patient and unaffected parents) and an additional 57 probands for a total of 187 CH patients with non-L1CAM primary CH. Exome-sequencing data from these 447 individuals was then analyzed to identify rare, de novo and transmitted mutations contributing to CH, and candidate mutations were subsequently confirmed by Sanger sequencing. RESULTS >Exome sequencing identified multiple novel and recurrent de novo and transmitted loss-of function gene mutations enriched in neurodevelopmental and ciliogenesis pathways. Binomial and case-control analyses confirmed exome-wide statistical significance of candidate genes, and functional modeling in Xenopus established gene causality. CONCLUSION These findings reveal novel disease-causing mutations in human CH, thereby providing new opportunities for improved prognostic assessment and non-invasive therapies.

Sign in / Sign up

Export Citation Format

Share Document