scholarly journals The role of de novo mutations in adult-onset neurodegenerative disorders

2018 ◽  
Vol 137 (2) ◽  
pp. 183-207 ◽  
Author(s):  
Gaël Nicolas ◽  
Joris A. Veltman
Keyword(s):  
Neurodegenerative Disorders ◽  
De Novo ◽  
Adult Onset ◽  
De Novo Mutations

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 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 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

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 The consequences of genomic architecture on ecological speciation in postglacial fishes

2013 ◽  
Vol 59 (1) ◽  
pp. 53-71 ◽  
Author(s):  
Sean M. Rogers ◽  
Jonathan A. Mee ◽  
Ella Bowles
Keyword(s):  
De Novo ◽  
Empirical Studies ◽  
Ecological Speciation ◽  
Population Persistence ◽  
Population Divergence ◽  
De Novo Mutations ◽  
Trait Divergence ◽  
Migration Rates ◽  
Genomic Architecture

Abstract The quest for the origin of species has entered the genomics era. Despite decades of evidence confirming the role of the environment in ecological speciation, an understanding of the genomics of ecological speciation is still in its infancy. In this review, we explore the role of genomic architecture in ecological speciation in postglacial fishes. Growing evidence for the number, location, effect size, and interactions among the genes underlying population persistence, adaptive trait divergence, and reproductive isolation in these fishes reinforces the importance of considering genomic architecture in studies of ecological speci-ation. Additionally, these populations likely adapt to new freshwater environments by selection on standing genetic variation, as de novo mutations are unlikely under such recent divergence times. We hypothesize that modular genomic architectures in postglacial fish taxa may be associated with the probability of population persistence. Empirical studies have confirmed the genic nature of ecological speciation, implicating surprisingly extensive linkage disequilibrium across the genome. An understanding of these genomic mosaics and how they contribute to reproductive barriers remains unclear, but migration rates and the strength of selection at these loci is predicted to influence the likelihood of population divergence. Altogether, understanding the role of ge-nomic architecture is an important component of speciation research and postglacial fishes continue to provide excellent organisms to test these questions, both from the perspective of variation in architectures among taxa, and with respect to the distinct environments they have colonized. However, more empirical tests of ecological speciation predictions are needed.

scholarly journals The role of de novo mutations in the development of amyotrophic lateral sclerosis

2017 ◽  
Vol 38 (11) ◽  
pp. 1534-1541 ◽  
Author(s):  
Perry T.C. Doormaal ◽  
Nicola Ticozzi ◽  
Jochen H. Weishaupt ◽  
Kevin Kenna ◽  
Frank P. Diekstra ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
De Novo ◽  
De Novo Mutations ◽  
Lateral Sclerosis

scholarly journals A de novo paradigm for male infertility

2021 ◽  
Author(s):  
Joris Veltman ◽  
Manon Oud ◽  
Roos Smits ◽  
Hannah Smith ◽  
Francesco Mastrorosa ◽  
...  
Keyword(s):  
Male Infertility ◽  
De Novo ◽  
P Value ◽  
Missense Mutations ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Systematic Analysis ◽  
Significant Enrichment

Abstract De novo mutations (DNMs) are known to play a prominent role in many sporadic disorders with reduced fitness. We hypothesize that DNMs play an important role in male infertility and explain a significant fraction of the genetic causes of this understudied disorder. We performed a trio-based exome-sequencing study 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=1.00x10-5) as well as predicted pathogenic missense DNMs in missense-intolerant genes (p-value=5.01x10-4). One DNM gene identified, RBM5, is an essential regulator of male germ cell pre-mRNA splicing. 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 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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