scholarly journals De novo mutations and rare variants occurring in NMDA receptors

2018 ◽  
Vol 2 ◽  
pp. 27-35 ◽  
Author(s):  
Wenshu XiangWei ◽  
Yuwu Jiang ◽  
Hongjie Yuan
Keyword(s):  
Nmda Receptors ◽  
Rare Variants ◽  
De Novo ◽  
De Novo Mutations

scholarly journals A Systematic Review on Extreme Phenotype Strategies to Search for Rare Variants in Genetic Studies of Complex Disorders

2020 ◽  
Author(s):  
Sana Amanat ◽  
Teresa Requena ◽  
Jose Antonio Lopez-Escamez
Keyword(s):  
Systematic Review ◽  
Candidate Genes ◽  
Rare Variants ◽  
De Novo ◽  
Complex Diseases ◽  
De Novo Mutations ◽  
Genetic Studies ◽  
Complex Disorders ◽  
Extreme Phenotype ◽  
Age Related

Exome sequencing has been commonly used in rare diseases by selecting multiplex families or singletons with an extreme phenotype (EP) to search for rare variants in coding regions. The EP strategy covers both extreme ends of a disease spectrum and it has been also used to investigate the contribution of rare variants to heritability in complex clinical traits. We have conducted a systematic review to find evidence supporting the use of EP strategies to search for rare variants in genetic studies of complex diseases, to highlight the contribution of rare variation to the genetic structure of multiallelic conditions. After performing the quality assessment of the retrieved records, we selected 19 genetic studies considering EP to demonstrate genetic association. All the studies successfully identified several rare variants, de novo mutations and many novel candidate genes were also identified by selecting an EP. There is enough evidence to support that the EP approach in patients with an early onset of the disease can contribute to the identification of rare variants in candidate genes or pathways involved in complex diseases. EP patients may contribute to a better understanding of the underlying genetic architecture of common heterogeneous disorders such as tinnitus or age-related hearing loss.

Novel IRF6 Mutations Detected in Orofacial Cleft Patients by Targeted Massively Parallel Sequencing

2016 ◽  
Vol 96 (2) ◽  
pp. 179-185 ◽  
Author(s):  
K.D. Khandelwal ◽  
N. Ishorst ◽  
H. Zhou ◽  
K.U. Ludwig ◽  
H. Venselaar ◽  
...  
Keyword(s):  
Cleft Lip ◽  
Rare Variants ◽  
De Novo ◽  
Massively Parallel Sequencing ◽  
De Novo Mutation ◽  
De Novo Mutations ◽  
Orofacial Clefting ◽  
Unaffected Parent ◽  
Molecular Inversion Probes ◽  
Multiplex Sequencing

Common variants in interferon regulatory factor 6 ( IRF6) have been associated with nonsyndromic cleft lip with or without cleft palate (NSCL/P) as well as with tooth agenesis (TA). These variants contribute a small risk towards the 2 congenital conditions and explain only a small percentage of heritability. On the other hand, many IRF6 mutations are known to be a monogenic cause of disease for syndromic orofacial clefting (OFC). We hypothesize that IRF6 mutations in some rare instances could also cause nonsyndromic OFC. To find novel rare variants in IRF6 responsible for nonsyndromic OFC and TA, we performed targeted multiplex sequencing using molecular inversion probes (MIPs) in 1,072 OFC patients, 67 TA patients, and 706 controls. We identified 3 potentially pathogenic de novo mutations in OFC patients. In addition, 3 rare missense variants were identified, for which pathogenicity could not unequivocally be shown, as all variants were either inherited from an unaffected parent or the parental DNA was not available. Retrospective investigation of the patients with these variants revealed the presence of lip pits in one of the patients with a de novo mutation suggesting a Van der Woude syndrome (VWS) phenotype, whereas, in other patients, no lip pits were identified.

scholarly journals Association of De Novo RNF213 Variants With Childhood Onset Moyamoya Disease and Diffuse Occlusive Vasculopathy

Neurology ◽  
2021 ◽  
Vol 96 (13) ◽  
pp. e1783-e1791
Author(s):  
Amélie Pinard ◽  
Maximillian D.J. Fiander ◽  
Alana C. Cecchi ◽  
Andrea L. Rideout ◽  
Mohamed Azouz ◽  
...  
Keyword(s):  
Amino Acids ◽  
Exome Sequencing ◽  
Moyamoya Disease ◽  
Abdominal Aorta ◽  
Rare Variants ◽  
De Novo ◽  
Ring Domain ◽  
Vascular Lesions ◽  
De Novo Mutations ◽  
Limited Region

ObjectiveTo test the hypothesis that de novo genetic variants are responsible for moyamoya disease (MMD) in children with unaffected relatives, we performed exome sequencing of 28 affected children and their unaffected parents.MethodsExome sequencing was performed on 28 trios of affected patients with MMD and unaffected parents.ResultsWe identified 3 novel rare de novo RNF213 variants, 1 in the RING domain and 2 in a highly conserved region distal to the RING domain (4,114–4,120). These de novo cases of MMD present at a young age with aggressive MMD and uniquely have additional occlusive vascular lesions, including renal artery stenosis. Two previously reported cases had de novo variants in the same limited region and presented young with aggressive MMD, and 1 case had narrowing of the inferior abdominal aorta.ConclusionsThese results indicate a novel syndrome associated with RNF213 rare variants defined by de novo mutations disrupting highly conserved amino acids in the RING domain and a discrete region distal to the RING domain delimited by amino acids 4,114 to 4,120 leading to onset of severe MMD before 3 years of age and occlusion of other arteries, including the abdominal aorta, renal, iliac, and femoral arteries.

scholarly journals Rare Variants in Complex Traits: Novel Identification Strategies and the Role of de novo Mutations

2012 ◽  
Vol 74 (3-4) ◽  
pp. 215-225 ◽  
Author(s):  
Loubna Jouan ◽  
Julie Gauthier ◽  
Patrick A. Dion ◽  
Guy A. Rouleau
Keyword(s):  
Complex Traits ◽  
Rare Variants ◽  
De Novo ◽  
De Novo Mutations

Identification of de novo mutations and rare variants in hypoplastic left heart syndrome

2011 ◽  
Vol 81 (6) ◽  
pp. 542-554 ◽  
Author(s):  
M Iascone ◽  
R Ciccone ◽  
L Galletti ◽  
D Marchetti ◽  
F Seddio ◽  
...  
Keyword(s):  
Hypoplastic Left Heart Syndrome ◽  
Rare Variants ◽  
De Novo ◽  
Left Heart ◽  
De Novo Mutations ◽  
Hypoplastic Left Heart ◽  
Left Heart Syndrome

scholarly journals A Novel WAC Loss of Function Mutation in an Individual Presenting with Encephalopathy Related to Status Epilepticus during Sleep (ESES)

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 344 ◽  
Author(s):  
Emanuela Leonardi ◽  
Mariagrazia Bellini ◽  
Maria C. Aspromonte ◽  
Roberta Polli ◽  
Anna Mercante ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Status Epilepticus ◽  
Behavioral Problems ◽  
Rare Variants ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Somatic Mosaicism ◽  
Coiled Coil ◽  
Loss Of Function ◽  
De Novo Mutations

WAC (WW Domain Containing Adaptor With Coiled-Coil) mutations have been reported in only 20 individuals presenting a neurodevelopmental disorder characterized by intellectual disability, neonatal hypotonia, behavioral problems, and mildly dysmorphic features. Using targeted deep sequencing, we screened a cohort of 630 individuals with variable degrees of intellectual disability and identified five WAC rare variants: two variants were inherited from healthy parents; two previously reported de novo mutations, c.1661_1664del (p.Ser554*) and c.374C>A (p.Ser125*); and a novel c.381+2T>C variant causing the skipping of exon 4 of the gene, inherited from a reportedly asymptomatic father with somatic mosaicism. A phenotypic evaluation of this individual evidenced areas of cognitive and behavioral deficits. The patient carrying the novel splicing mutation had a clinical history of encephalopathy related to status epilepticus during slow sleep (ESES), recently reported in another WAC individual. This first report of a WAC somatic mosaic remarks the contribution of mosaicism in the etiology of neurodevelopmental and neuropsychiatric disorders. We summarized the clinical data of reported individuals with WAC pathogenic mutations, which together with our findings, allowed for the expansion of the phenotypic spectrum of WAC-related disorders.

scholarly journals Retracted: Identification of de novo mutations in prenatal neurodevelopment-associated genes in schizophrenia in two Han Chinese patient-sibling family-based cohorts

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Shan Jiang ◽  
Daizhan Zhou ◽  
Yin-Ying Wang ◽  
Peilin Jia ◽  
Chunling Wan ◽  
...  
Keyword(s):  
Drug Targets ◽  
Developmental Disorders ◽  
Rare Variants ◽  
De Novo ◽  
Association Studies ◽  
Chinese Patient ◽  
Genome Wide Association Studies ◽  
De Novo Mutations ◽  
Burden Test ◽  
Family Based

AbstractSchizophrenia (SCZ) is a severe psychiatric disorder with a strong genetic component. High heritability of SCZ suggests a major role for transmitted genetic variants. Furthermore, SCZ is also associated with a marked reduction in fecundity, leading to the hypothesis that alleles with large effects on risk might often occur de novo. In this study, we conducted whole-genome sequencing for 23 families from two cohorts with unaffected siblings and parents. Two nonsense de novo mutations (DNMs) in GJC1 and HIST1H2AD were identified in SCZ patients. Ten genes (DPYSL2, NBPF1, SDK1, ZNF595, ZNF718, GCNT2, SNX9, AACS, KCNQ1, and MSI2) were found to carry more DNMs in SCZ patients than their unaffected siblings by burden test. Expression analyses indicated that these DNM implicated genes showed significantly higher expression in prefrontal cortex in prenatal stage. The DNM in the GJC1 gene is highly likely a loss function mutation (pLI = 0.94), leading to the dysregulation of ion channel in the glutamatergic excitatory neurons. Analysis of rare variants in independent exome sequencing dataset indicates that GJC1 has significantly more rare variants in SCZ patients than in unaffected controls. Data from genome-wide association studies suggested that common variants in the GJC1 gene may be associated with SCZ and SCZ-related traits. Genes co-expressed with GJC1 are involved in SCZ, SCZ-associated pathways, and drug targets. These evidences suggest that GJC1 may be a risk gene for SCZ and its function may be involved in prenatal and early neurodevelopment, a vulnerable period for developmental disorders such as SCZ.

scholarly journals Identification of de novo mutations in prenatal neurodevelopment-associated genes in schizophrenia in two Han Chinese patient-sibling family-based cohorts

2019 ◽  
Author(s):  
Shan Jiang ◽  
Daizhan Zhou ◽  
Yin-Ying Wang ◽  
Peilin Jia ◽  
Chunling Wan ◽  
...  
Keyword(s):  
Drug Targets ◽  
Developmental Disorders ◽  
Rare Variants ◽  
De Novo ◽  
Association Studies ◽  
Chinese Patient ◽  
Genome Wide Association Studies ◽  
De Novo Mutations ◽  
Burden Test ◽  
Family Based

AbstractSchizophrenia (SCZ) is a severe psychiatric disorder with a strong genetic component. High heritability of SCZ suggests a major role for transmitted genetic variants. Furthermore, SCZ is also associated with a marked reduction in fecundity, leading to the hypothesis that alleles with large effects on risk might often occur de novo. In this study, we conducted whole-genome sequencing for 23 families from two cohorts with matched unaffected siblings and parents. Two nonsense de novo mutations (DNMs) in GJC1 and HIST1H2AD were identified in SCZ patients. Ten genes (DPYSL2, NBPF1, SDK1, ZNF595, ZNF718, GCNT2, SNX9, AACS, KCNQ1 and MSI2) were found to carry more DNMs in SCZ patients than their unaffected siblings by burden test. Expression analyses indicated that these DNM implicated genes showed significantly higher expression in prefrontal cortex in prenatal stage. The DNM in the GJC1 gene is highly likely a loss function mutation (pLI = 0.94), leading to the dysregulation of ion channel in the glutamatergic excitatory neurons. Analysis of rare variants in independent exome sequencing dataset indicates that GJC1 has significantly more rare variants in SCZ patients than in unaffected controls. Data from genome-wide association studies suggested that common variants in the GJC1 gene may be associated with SCZ and SCZ-related traits. Genes co-expressed with GJC1 are involved in SCZ, SCZ-associated pathways and drug targets. These evidence suggest that GJC1 may be a risk gene for SCZ and its function may be involved in prenatal and early neurodevelopment, a vulnerable period for developmental disorders such as SCZ.

scholarly journals A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex

2021 ◽  
Author(s):  
Danny Antaki ◽  
Adam Maihofer ◽  
Marieke Klein ◽  
James Guevara ◽  
Jakob Grove ◽  
...  
Keyword(s):  
Genetic Factors ◽  
Rare Variants ◽  
De Novo ◽  
Autism Spectrum ◽  
Parental Age ◽  
De Novo Mutations ◽  
Polygenic Risk ◽  
Behavioral Traits ◽  
Sex Effects ◽  
Phenotypic Spectrum

The genetic etiology of autism spectrum disorder (ASD) is multifactorial with contributions from rare variants, polygenic risk, and sex. How combinations of factors determine risk for ASD is unclear. In 11,313 ASD families (N = 37,375 subjects), we investigated the effects rare and polygenic risk individually and in combination. We show that genetic liability for ASD differs by sex, with females having a greater polygenic load, and males having a lower liability threshold as evident by a negative correlation of rare and polygenic risk. Multiple genetic factors were associated with differing sets of behavioral traits with effects that differed by sex. Furthermore, the correlation of parental age with genetic risk for ASD was attributable to de novo mutations and sex-biased effects of inherited risk in parents. Our results demonstrate that a phenotypic spectrum of ASD is attributable to the relative loadings and gene-by-sex effects of rare and common variation.

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