scholarly journals Prenatal Diagnosis of Cystic Fibrosis and Hemophilia: Incidental Findings and Weak Points

Diagnostics ◽  
2019 ◽  
Vol 10 (1) ◽  
pp. 7 ◽  
Author(s):  
Marika Comegna ◽  
Giuseppe Maria Maruotti ◽  
Laura Sarno ◽  
Gustavo Cernera ◽  
Monica Gelzo ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Prenatal Diagnosis ◽  
Incidental Findings ◽  
De Novo ◽  
Genetic Diseases ◽  
Legal Aspects ◽  
De Novo Mutation ◽  
De Novo Mutations ◽  
Weak Points ◽  
Genetics And Genomics

Because of the progression of genetics and genomics, the demand for prenatal diagnosis (PD) for inherited genetic diseases has increased. However, several incidental findings may emerge during PD, like misattributed paternity, the evidence of disease in a parent, and the possible misinterpretation of the results because of complex alleles or de novo mutations that have several implications. In a retrospective observational study on all the couples referred to our Medical School (1993–2018) for PD of genetic inherited diseases (n = 1502), we selected the cases of PD for cystic fibrosis (CF, n = 239) and hemophilia A and B (HA, HB, n = 47), revising all incidental findings previously mentioned. We found one case in which a technical error led to PD of carrier in two siblings that were born affected by CF, four cases of misattributed paternity, eight cases of asymptomatic parents revealed as affected by CF transmembrane regulator (CFTR)-related disorders, a case of a novel complex allele that could have caused the diagnosis of CF in a carrier fetus, and a case of a de novo mutation in a mother (already a carrier) that caused hemophilia in a child that PD had revealed as healthy. We present these conditions as clinical cases and discuss the technical, clinical, ethical, and legal aspects to be considered.

scholarly journals Prenatal diagnosis for de novo mutations: Experience from a tertiary center over a 10‐year period

2019 ◽  
Vol 7 (4) ◽  
pp. e00573 ◽  
Author(s):  
Ori Eyal ◽  
Michal Berkenstadt ◽  
Haike Reznik‐Wolf ◽  
Hana Poran ◽  
Tomer Ziv‐Baran ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
De Novo ◽  
De Novo Mutations ◽  
Tertiary Center

scholarly journals SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect

Brain ◽  
2020 ◽  
Vol 143 (8) ◽  
pp. 2380-2387 ◽  
Author(s):  
Alisdair McNeill ◽  
Emanuela Iovino ◽  
Luke Mansard ◽  
Christel Vache ◽  
David Baux ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Developmental Disorders ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Sensorineural Deafness ◽  
Sensorineural Hearing ◽  
De Novo Mutation ◽  
Xenopus Laevis Oocytes ◽  
De Novo Mutations

Abstract The SLC12 gene family consists of SLC12A1–SLC12A9, encoding electroneutral cation-coupled chloride co-transporters. SCL12A2 has been shown to play a role in corticogenesis and therefore represents a strong candidate neurodevelopmental disorder gene. Through trio exome sequencing we identified de novo mutations in SLC12A2 in six children with neurodevelopmental disorders. All had developmental delay or intellectual disability ranging from mild to severe. Two had sensorineural deafness. We also identified SLC12A2 variants in three individuals with non-syndromic bilateral sensorineural hearing loss and vestibular areflexia. The SLC12A2 de novo mutation rate was demonstrated to be significantly elevated in the deciphering developmental disorders cohort. All tested variants were shown to reduce co-transporter function in Xenopus laevis oocytes. Analysis of SLC12A2 expression in foetal brain at 16–18 weeks post-conception revealed high expression in radial glial cells, compatible with a role in neurogenesis. Gene co-expression analysis in cells robustly expressing SLC12A2 at 16–18 weeks post-conception identified a transcriptomic programme associated with active neurogenesis. We identify SLC12A2 de novo mutations as the cause of a novel neurodevelopmental disorder and bilateral non-syndromic sensorineural hearing loss and provide further data supporting a role for this gene in human neurodevelopment.

Empirical investigation of mutation rate for herbicide resistance

Weed Science ◽  
2019 ◽  
Vol 67 (4) ◽  
pp. 361-368 ◽  
Author(s):  
Federico A. Casale ◽  
Darci A. Giacomini ◽  
Patrick J. Tranel
Keyword(s):  
Mutation Rate ◽  
Herbicide Resistance ◽  
De Novo ◽  
Selection Process ◽  
Theoretical Calculations ◽  
Acetolactate Synthase ◽  
De Novo Mutation ◽  
De Novo Mutations ◽  
Sources Of Resistance ◽  
Resistant Mutants

AbstractIn a predictable natural selection process, herbicides select for adaptive alleles that allow weed populations to survive. These resistance alleles may be available immediately from the standing genetic variation within the population or may arise from immigration via pollen or seeds from other populations. Moreover, because all populations are constantly generating new mutant genotypes by de novo mutations, resistant mutants may arise spontaneously in any herbicide-sensitive weed population. Recognizing that the relative contribution of each of these three sources of resistance alleles influences what strategies should be applied to counteract herbicide-resistance evolution, we aimed to add experimental information to the resistance evolutionary framework. Specifically, the objectives of this experiment were to determine the de novo mutation rate conferring herbicide resistance in a natural plant population and to test the hypothesis that the mutation rate increases when plants are stressed by sublethal herbicide exposure. We used grain amaranth (Amaranthus hypochondriacus L.) and resistance to acetolactate synthase (ALS)-inhibiting herbicides as a model system to discover spontaneous herbicide-resistant mutants. After screening 70.8 million plants, however, we detected no spontaneous resistant genotypes, indicating the probability of finding a spontaneous ALS-resistant mutant in a given sensitive population is lower than 1.4 × 10−8. This empirically determined upper limit is lower than expected from theoretical calculations based on previous studies. We found no evidence that herbicide stress increased the mutation rate, but were not able to robustly test this hypothesis. The results found in this study indicate that de novo mutations conferring herbicide resistance might occur at lower frequencies than previously expected.

De novo mutation in hemophilia A established by DNA haplotype analysis and precluding prenatal diagnosis

1986 ◽  
Vol 74 (3) ◽  
Author(s):  
M. Delpech ◽  
N Deburgrave ◽  
M. Baudis ◽  
P. Maissonneuve ◽  
J.M. Bardin ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Haplotype Analysis ◽  
Hemophilia A ◽  
De Novo ◽  
De Novo Mutation

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 Soft sweeps predominate recent positive selection in bonobos (Pan paniscus) and chimpanzees (Pan troglodytes)

2020 ◽  
Author(s):  
Colin M Brand ◽  
Frances J White ◽  
Nelson Ting ◽  
Timothy H Webster
Keyword(s):  
Positive Selection ◽  
De Novo ◽  
Pan Paniscus ◽  
Novel Mutation ◽  
Simulated Data ◽  
Supervised Machine Learning ◽  
De Novo Mutation ◽  
De Novo Mutations ◽  
Recent Positive Selection ◽  
Neural Network Classifiers

Two modes of positive selection have been recognized: 1) hard sweeps that result in the rapid fixation of a beneficial allele typically from a de novo mutation and 2) soft sweeps that are characterized by intermediate frequencies of at least two haplotypes that stem from standing genetic variation or recurrent de novo mutations. While many populations exhibit both hard and soft sweeps throughout the genome, there is increasing evidence that soft sweeps, rather than hard sweeps, are the predominant mode of adaptation in many species, including humans. Here, we use a supervised machine learning approach to assess the extent of hard and soft sweeps in the closest living relatives of humans: bonobos and chimpanzees (genus Pan). We trained convolutional neural network classifiers using simulated data and applied these classifiers to population genomic data for 71 individuals representing all five extant Pan lineages, of which we successfully analyzed 60 individuals from four lineages. We found that recent adaptation in Pan is largely the result of soft sweeps, ranging from 73.1 to 97.7% of all identified sweeps. While few hard sweeps were shared among lineages, we found that between 19 and 267 soft sweep windows were shared by at least two lineages. We also identify novel candidate genes subject to recent positive selection. This study emphasizes the importance of shifts in the physical and social environment, rather than novel mutation, in shaping recent adaptations in bonobos and chimpanzees.

scholarly journals Noninvasive prenatal diagnosis of duchenne muscular dystrophy in five Chinese families based on relative mutation dosage approach

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Ganye Zhao ◽  
Xiaofeng Wang ◽  
Lina Liu ◽  
Peng Dai ◽  
Xiangdong Kong
Keyword(s):  
Prenatal Diagnosis ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Single Molecule ◽  
De Novo ◽  
Dna Barcode ◽  
De Novo Mutations ◽  
Molecular Alteration ◽  
Noninvasive Prenatal Diagnosis ◽  
Exon Deletion

Abstract Background Relative haplotype dosage (RHDO) approach has been applied in noninvasive prenatal diagnosis (NIPD) of Duchenne muscular dystrophy (DMD). However, the RHDO procedure is relatively complicated and the parental haplotypes need to be constructed. Furthermore, it is not suitable for the diagnosis of de novo mutations or mosaicism in germ cells. Here, we investigated NIPD of DMD using a relative mutation dosage (RMD)-based approach—cell-free DNA Barcode-Enabled Single-Molecule Test (cfBEST), which has not previously been applied in the diagnosis of exon deletion. Methods Five DMD families caused by DMD gene point mutations or exon deletion were recruited for this study. After the breakpoints of exon deletion were precisely mapped with multiple PCR, the genotypes of the fetuses from the five DMD families were inferred using cfBEST, and were further validated by invasive prenatal diagnosis. Results The cfBEST results of the five families indicated that one fetus was female and did not carry the familial molecular alteration, three fetuses were carriers and one was male without the familial mutation. The invasive prenatal diagnosis results were consistent with those of the cfBEST procedure. Conclusion This is the first report of NIPD of DMD using the RMD-based approach. We extended the application of cfBEST from point mutation to exon deletion mutation. The results showed that cfBEST would be suitable for NIPD of DMD caused by different kinds of mutation types.

scholarly journals M-DATA: A Statistical Approach to Jointly Analyzing De Novo Mutations for Multiple Traits

2021 ◽  
Author(s):  
Yuhan Xie ◽  
Mo Li ◽  
Weilai Dong ◽  
Wei Jiang ◽  
Hongyu Zhao
Keyword(s):  
Statistical Power ◽  
De Novo ◽  
Expectation Maximization Algorithm ◽  
De Novo Mutation ◽  
Joint Analysis ◽  
De Novo Mutations ◽  
Multiple Traits ◽  
Disease Etiology ◽  
Degree Of Association ◽  
Shared Risk

Recent studies have demonstrated that multiple early-onset diseases have shared risk genes, based on findings from de novo mutations (DMNs). Therefore, we may leverage information from one trait to improve statistical power to identify genes for another trait. However, there are few methods that can jointly analyze DNMs from multiple traits. In this study, we develop a framework called M-DATA (Multi-trait framework for De novo mutation Association Test with Annotations) to increase the statistical power of association analysis by integrating data from multiple correlated traits and their functional annotations. Using the number of DNMs from multiple diseases, we develop a method based on an Expectation-Maximization algorithm to both infer the degree of association between two diseases as well as to estimate the gene association probability for each disease. We apply our method to a case study of jointly analyzing data from congenital heart disease (CHD) and autism. Our method was able to identify 23 genes from joint analysis, including 12 novel genes, which is substantially more than single-trait analysis, leading to novel insights into CHD disease etiology.

Expanding Phenotype of De Novo Mutations in GNAO1: Four New Cases and Review of Literature

2017 ◽  
Vol 48 (05) ◽  
pp. 371-377 ◽  
Author(s):  
Tobias Dietel ◽  
Christina Evers ◽  
Katrin Hinderhofer ◽  
Rudolf Korinthenberg ◽  
Daniel Ezzo ◽  
...  
Keyword(s):  
De Novo ◽  
Involuntary Movement ◽  
Epileptic Encephalopathy ◽  
De Novo Mutation ◽  
Guanine Nucleotide ◽  
Review Of Literature ◽  
De Novo Mutations ◽  
Guanine Nucleotide Binding Protein ◽  
Guanine Nucleotide Binding ◽  
Severe Epilepsy

AbstractMutations in GNAO1 (guanine nucleotide-binding protein, alpha-activating activity polypeptide O) were recently identified as being causative for early epileptic encephalopathy. Since then approximately 27 patients with severe developmental delay and different neurological phenotypes for epilepsy and involuntary movement disorder have been reported. We report four additional patients with mutations in GNAO1 including a report of siblings of different sex harboring the same de novo mutation (c.736G > A, p.Glu246Lys) but showing differences in phenotype with pronounced dystonia in the boy and epilepsy in his sister. Another de novo mutation in GNAO1 (c.607G > A, p.Gly203Arg) was identified in two unrelated girls with severe epilepsy. Both girls later also developed severe dystonia with severe nonepileptic spasms. An extensive review of published cases revealed that epilepsy was reported in only one male patient so far. Thus it appears possible that epilepsy is a sex-dependent phenotypic feature of GNAO1-related diseases.

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