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

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 Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 and ALYREF as new candidate risk genes

2021 ◽  
Author(s):  
Lu Qiao ◽  
Le Xu ◽  
Lan Yu ◽  
Julia Wynn ◽  
Rebecca Hernan ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Rare Variants ◽  
De Novo ◽  
Disease Genes ◽  
Risk Genes ◽  
Association Analyses ◽  
Significant Enrichment ◽  
Coding Variants

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (Lon Peptidase 1, Mitochondrial) and ALYREF (Aly/REF Export Factor) as novel candidate CDH genes based on de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 cases and 11,220 ancestry-matched population controls and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in familial cases. Approximately 3% of our CDH cohort was heterozygous with ultra-rare predicted damaging variants in LONP1 who have a range of clinical phenotypes including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium specific deletion of Lonp1 die immediately after birth and have reduced lung growth and branching that may at least partially explain the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.

scholarly journals A de novo paradigm for male infertility

2021 ◽  
Author(s):  
MS Oud ◽  
RM Smits ◽  
HE Smith ◽  
FK Mastrorosa ◽  
GS Holt ◽  
...  
Keyword(s):  
Male Infertility ◽  
De Novo ◽  
P Value ◽  
Missense Mutations ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Systematic Analysis ◽  
Significant Enrichment

IntroductionDe novo mutations (DNMs) are known to play a prominent role in sporadic disorders with reduced fitness1. We hypothesize that DNMs play an important role in male infertility and explain a significant fraction of the genetic causes of this understudied disorder. To test this hypothesis, we performed trio-based exome-sequencing in a unique cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare protein altering DNMs were classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of Loss-of-Function (LoF) DNMs in LoF-intolerant genes (p-value=1.00×10-5) as well as predicted pathogenic missense DNMs in missense-intolerant genes (p-value=5.01×10-4). One DNM gene identified, RBM5, is an essential regulator of male germ cell pre-mRNA splicing2. In a follow-up study, 5 rare pathogenic missense mutations affecting this gene were observed in a cohort of 2,279 infertile patients, with no such mutations found in a cohort of 5,784 fertile men (p-value=0.009). Our results provide the first evidence for the role of DNMs in severe male infertility and point to many new candidate genes affecting fertility.

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 New insights into the generation and role of de novo mutations in health and disease

2016 ◽  
Vol 17 (1) ◽  
Author(s):  
Rocio Acuna-Hidalgo ◽  
Joris A. Veltman ◽  
Alexander Hoischen
Keyword(s):  
De Novo ◽  
De Novo Mutations ◽  
Health And Disease

scholarly journals Unexpected role of SIX1 variants in craniosynostosis: expanding the phenotype of SIX1-related disorders

2021 ◽  
pp. jmedgenet-2020-107459
Author(s):  
Eduardo Calpena ◽  
Maud Wurmser ◽  
Simon J McGowan ◽  
Rodrigo Atique ◽  
Débora R Bertola ◽  
...  
Keyword(s):  
De Novo ◽  
Population Data ◽  
Cranial Sutures ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Data Enrichment ◽  
Whole Exome ◽  
Lambdoid Synostosis ◽  
Suture Fusion

BackgroundPathogenic heterozygous SIX1 variants (predominantly missense) occur in branchio-otic syndrome (BOS), but an association with craniosynostosis has not been reported.MethodsWe investigated probands with craniosynostosis of unknown cause using whole exome/genome (n=628) or RNA (n=386) sequencing, and performed targeted resequencing of SIX1 in 615 additional patients. Expression of SIX1 protein in embryonic cranial sutures was examined in the Six1nLacZ/+ reporter mouse.ResultsFrom 1629 unrelated cases with craniosynostosis we identified seven different SIX1 variants (three missense, including two de novo mutations, and four nonsense, one of which was also present in an affected twin). Compared with population data, enrichment of SIX1 loss-of-function variants was highly significant (p=0.00003). All individuals with craniosynostosis had sagittal suture fusion; additionally four had bilambdoid synostosis. Associated BOS features were often attenuated; some carrier relatives appeared non-penetrant. SIX1 is expressed in a layer basal to the calvaria, likely corresponding to the dura mater, and in the mid-sagittal mesenchyme.ConclusionCraniosynostosis is associated with heterozygous SIX1 variants, with possible enrichment of loss-of-function variants compared with classical BOS. We recommend screening of SIX1 in craniosynostosis, particularly when sagittal±lambdoid synostosis and/or any BOS phenotypes are present. These findings highlight the role of SIX1 in cranial suture homeostasis.

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.

The Autism Spectrum

2018 ◽  
pp. 243-260
Author(s):  
Marco Del Giudice
Keyword(s):  
Risk Factors ◽  
De Novo ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Evolutionary Models ◽  
De Novo Mutations ◽  
Life History Variation ◽  
New Directions ◽  
Developmental Features

The chapter discusses autism spectrum disorder (ASD). Autism is defined by a triad of symptoms: impairments in social interaction, impairments in communication, and restricted/repetitive behaviors and interests. After an overview of this disorder, its developmental features, and the main risk factors identified in the epidemiological literature, the chapter critically reviews existing evolutionary models and suggests new directions for research. The final section applies the criteria developed earlier in the book to classify the disorder within the fast-slow-defense (FSD) model and identify functionally distinct subtypes. The author proposes to distinguish between a slow spectrum subtype with normal or high IQ and a major role of common alleles (S-ASD) and a subtype unrelated to life history variation, with high rates of intellectual disability and a major role of rare and de novo mutations (O-ASD).

scholarly journals A de novo paradigm for male infertility

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
M. S. Oud ◽  
R. M. Smits ◽  
H. E. Smith ◽  
F. K. Mastrorosa ◽  
G. S. Holt ◽  
...  
Keyword(s):  
Male Infertility ◽  
De Novo ◽  
Missense Mutations ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Systematic Analysis ◽  
Significant Enrichment ◽  
Infertile Patients

AbstractDe novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10−5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10−4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.

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