Nos défauts génétiques cachés

A systematic study analysing the exomes of several thousand individuals indicates that each of them carries at least one strongly deleterious mutation that is innocuous in a heterozygote but results in a severe phenotype in the homozygous state. Most of these mutations are very rare, while a few are present in 1 or 2% of the population. The frequency of at-risk couples is approximately 1.5%, but increases dramatically to 25% if the partners of the couple are first cousins. This work has important implications for carrier screening and population genetics in general.

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The Rate of Spontaneous Mutation for Life-History Traits in Caenorhabditis elegans

Genetics ◽

10.1093/genetics/151.1.119 ◽

1999 ◽

Vol 151 (1) ◽

pp. 119-129 ◽

Cited By ~ 4

Author(s):

Larissa L Vassilieva ◽

Michael Lynch

Keyword(s):

Life History ◽

Caenorhabditis Elegans ◽

Mutation Rate ◽

Life History Traits ◽

Deleterious Mutation ◽

Spontaneous Mutation ◽

Spontaneous Mutations ◽

Homozygous State ◽

Mutational Effect ◽

Biological Differences

Abstract Spontaneous mutations were accumulated in 100 replicate lines of Caenorhabditis elegans over a period of ∼50 generations. Periodic assays of these lines and comparison to a frozen control suggest that the deleterious mutation rate for typical life-history characters in this species is at least 0.05 per diploid genome per generation, with the average mutational effect on the order of 14% or less in the homozygous state and the average mutational heritability ∼0.0034. While the average mutation rate per character and the average mutational heritability for this species are somewhat lower than previous estimates for Drosophila, these differences can be reconciled to a large extent when the biological differences between these species are taken into consideration.

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Genetic Modulators: Prevalence and Their Effect on the Phenotype of HbE/β Thalassemia Patients.

Blood ◽

10.1182/blood.v112.11.1862.1862 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1862-1862

Author(s):

Vineeta Sharma ◽

Renu Saxena

Keyword(s):

Disease Severity ◽

Asian Indian ◽

Clinical Severity ◽

Compound Heterozygous ◽

Heterozygous State ◽

Severe Phenotype ◽

Homozygous State ◽

Disease Heterogeneity ◽

Pcr Rflp ◽

Xmni Polymorphism

Abstract HbE, a β-globin chain variant occurs due to GAG to AAG i.e. Glu-Lys substitution at codon 26.In heterozygous and homozygous state it usually remain asymptomatic but the compound heterozygous state with β thalassemia (HbE/β thalassemia) results in a variable and often severe anemia, with the phenotype ranging from transfusion dependence to a complete lack of symptoms. The basis of the interaction and the cause of the variability remains unexplained. Some of the possible explanations for the observed variable clinical severity are coinheritance of mild β mutations, Effect of alpha gene number and increased production of HbF. Aims of the study are to determine the frequency of primary (β mutations) and secondary modulators (α deletion and α triplication, XmnI polymorphism, HPFH-3 and Asian-Indian Inv/DelGγ(Aγδbeta;)0 deletion) in HbE/β thalassemia patients and to study their effect on the phenotype of the Patients. Subjects were 180 HbE/β thalassemia patients diagnosed by HPLC and confirmed by PCR-RFLP. Patients were divided into three subgroups according to a scoring system based on seven clinical criteria as mild (score 0–3.5)[Gp1], moderate (score 4–7)[Gp2] and severe (score 7.5–10) [Gp3]. β-mutations were studied by ARMS PCR, XmnI polymorphism was studied by PCR-RFLP while α deletions, HPFH-3 and Asian-Indian Inv/DelGγ (Aγ δβ)0 deletions were studied by GAPPCR and alpha triplication by a modified single tube PCR. The frequency of β mutation was almost similar in all the groups (IVS 1–5 G-C (58.8%) was the predominant one). α deletion was found in 19 (10.5%) out of which 13 (12 αα/−α3.7 & 1 αα /--SA) were from Gp1 and 6 (αα/-α3.7) were from Gp2. α triplication was found in 11(6.1%) out of these 11 patients 8 were (αα/αααanti3.7) from Gp3 and 3 were (αα/αααanti3.7) from Gp2. XmnI was found in 112(62.2%), out of which 98 were heterozygous (+/−) and 14 were homozygous (+/+).XmnI +/+ was present in 10 Gp1 & 4 Gp2 patients, while XmnI +/− was present in 36 Gp1 ,43 Gp2 & 33 Gp3 patients.HPFH-3 deletion was present in 8 (4.4%) out of which 5 were from Gp1 and 3 were from Gp2. Asian-Indian Inv/DelGγ (Aγδβ)0 deletion was present in 2(1.1%) patients one from Gp2 and another from GP3. Primary modulator (β mutation) is not the actual factor responsible for the disease heterogeneity. Patients with coexisting α deletion required lesser transfusions and had less severe phenotype while patients with α triplication were on frequent transfusions and had severe phenotype. XmnI polymorphism in homozygous state was observed to alleviate the severity while in heterozygous state it had no effect on the disease severity except the delay of the onset of disease up to some extent. Patients having HPFH3 deletions and Asian-Indian Inv/DelG γ (Aγδβ)0 deletion showed mild to moderate disease severity. Thus it can be concluded that secondary modulators play an important role in the disease heterogeneity of HbE/βthalassemia.

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A Data-Driven Evaluation of the Size and Content of Expanded Carrier Screening Panels

10.1101/430546 ◽

2018 ◽

Cited By ~ 1

Author(s):

Rotem Ben-Shachar ◽

Svenson MS Ashley ◽

James D. Goldberg ◽

Dale Muzzey

Keyword(s):

At Risk ◽

Detection Rate ◽

Carrier Screening ◽

Data Driven ◽

Carrier Rate ◽

Expanded Carrier Screening ◽

Clinical Detection ◽

The Impact ◽

Variable Impact ◽

Panel Design

ABSTRACTPurposeThe American College of Obstetricians and Gynecologists (ACOG) proposed seven criteria for expanded carrier screening (ECS) panel design. To ensure that screening for a condition is sufficiently sensitive to identify carriers and reduce residual risk of non-carriers, one criterion requires a per-condition carrier rate greater than 1-in-100. However, it is unestablished whether this threshold corresponds with a loss in clinical detection. The impact of the proposed panel-design criteria on at-risk couple detection warrants data-driven evaluation.MethodsCarrier rates and at-risk couple rates were calculated in 56,281 patients who underwent a 176-condition ECS and evaluated for panels satisfying various criteria. Condition-specific clinical detection rate was estimated via simulation.ResultsDifferent interpretations of the 1-in-100 criterion have variable impact: a compliant panel would include between 3 and 38 conditions, identify 11%-81% fewer at-risk couples, and detect 36%-79% fewer carriers than a 176-condition panel. If the carrier-rate threshold must be exceeded in all ethnicities, ECS panels would lack prevalent conditions like cystic fibrosis. Simulations suggest that clinical detection rate remains >84% for conditions with carrier rates as low as 1-in-1000.ConclusionsThe 1-in-100 criterion limits at-risk couple detection and should be reconsidered.

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Clinical Utility of Expanded Carrier Screening: Reproductive Behaviors of At-Risk Couples

10.1101/069393 ◽

2016 ◽

Cited By ~ 3

Author(s):

Caroline Ghiossi ◽

James D. Goldberg ◽

Imran S. Haque ◽

Gabriel A. Lazarin ◽

Kenny K. Wong

Keyword(s):

Decision Making ◽

At Risk ◽

Clinical Utility ◽

Carrier Screening ◽

Reproductive Behaviors ◽

Reproductive Risk ◽

Expanded Carrier Screening ◽

Reproductive Decision Making ◽

Recessive Genes ◽

Professional Guidelines

ABSTRACTPurposeExpanded carrier screening (ECS) analyzes dozens or hundreds of recessive genes for determining reproductive risk. Data on clinical utility of screening conditions beyond professional guidelines is scarce.MethodsIndividuals underwent ECS for up to 110 genes. 537 at-risk couples (ARC), those in which both partners carry the same recessive disease, were invited to a retrospective IRB-approved survey of their reproductive decision making after receiving ECS results.Results64 eligible ARC completed the survey. Of 45 respondents screened preconceptionally, 62% (n=28) planned IVF with PGD or prenatal diagnosis (PNDx) in future pregnancies. 29% (n=13) were not planning to alter reproductive decisions. The remaining 9% (n=4) of responses were unclear.Of 19 pregnant respondents, 42% (n=8) elected PNDx, 11% (n=2) planned amniocentesis but miscarried, and 47% (n=9) considered the condition insufficiently severe to warrant invasive testing. Of the 8 pregnancies that underwent PNDx, 5 were unaffected and 3 were affected. 2 of 3 affected pregnancies were terminated.Disease severity was found to have significant association (p=0.000145) with changes in decision making, whereas guideline status of diseases, controlled for severity, was not (p=0.284).ConclusionMost ARC altered reproductive planning, demonstrating the clinical utility of ECS. Severity of conditions factored into decision making.

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A Novel Frameshift Mutation Associated with Hurler's Syndrome: A Case Report

Journal of Pediatric Genetics ◽

10.1055/s-0039-1685190 ◽

2019 ◽

Vol 08 (04) ◽

pp. 212-217

Author(s):

Mana Kamranjam ◽

Seyedeh Maryam Hosseini ◽

Mohammadreza Alaei

Keyword(s):

Frameshift Mutation ◽

Deleterious Mutation ◽

Clinical Manifestations ◽

Lysosomal Storage ◽

Intermediate Type ◽

Homozygous State ◽

Hurler’S Syndrome ◽

Idua Gene ◽

Severe Type ◽

Testing And Counseling

AbstractMucopolysaccharidosis 1 (MPS1) is a rare inherited lysosomal storage disorder resulting from the absence or reduction of lysosomal alpha-l-iduronidase due to mutations in the IDUA gene. Three major clinical manifestations have been established including Hurler's or severe type (OMIM 607914), Hurler–Scheie or intermediate type (MIM 607914) and Scheie's or attenuated type (MIM 607016). In the present study, a patient whose disease was diagnosed by biochemical and enzymatic assay was studied in our laboratory. Molecular analysis implemented by PCR-sequencing of all 14 exons and exon–intron junctions confirmed a novel deleterious mutation in a homozygous state. The result of this study has broadened the genotypic spectrum of MPS1 patients, assisting in a more effective approach for carrier testing and counseling.

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Estimating yields of prenatal carrier screening and implications for design of expanded carrier screening panels

10.1101/429050 ◽

2018 ◽

Author(s):

Michael H. Guo ◽

Anthony R. Gregg

Keyword(s):

At Risk ◽

Exome Sequencing ◽

East Asian ◽

Carrier Screening ◽

Carrier Rate ◽

Ashkenazi Jewish ◽

Careful Selection ◽

Recessive Condition ◽

Selection Of ◽

Genetic Carrier Screening

AbstractPurposePrenatal genetic carrier screening can identify parents at risk of having a child affected by a recessive condition. However, the conditions/genes most appropriate for screening remain a matter of debate. Estimates of carrier rates across genes are needed to guide construction of carrier screening panels.MethodsWe leveraged an exome sequencing database (n=123,136) to estimate carrier rates across 6 major ancestries for 416 genes associated with severe recessive conditions.Results36.5% (East Asian) to 65% (Ashkenazi Jewish) of individuals are variant carriers in at least one of the 416 genes. For couples, screening all 416 genes would identify 0.4-2.8% of couples as being at-risk for having a child affected by one of these conditions. Screening just the 47 genes with carrier rate > 1.0% would identify more than 85% of these at-risk couples. An ancestry-specific panel designed to capture genes with carrier rates > 1.0% would include 6 to 30 genes, while a comparable pan-ethnic panel would include 47 genes.ConclusionOur work guides the design of carrier screening panels and provides data to assist in counseling prospective parents. Our results highlight a high cumulative carrier rate across genes, underscoring the need for careful selection of genes for screening.

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Reproductive carrier screening

British Journal of Midwifery ◽

10.12968/bjom.2021.29.10.598 ◽

2021 ◽

Vol 29 (10) ◽

pp. 598-598

Author(s):

George Winter

Keyword(s):

At Risk ◽

Carrier Screening ◽

Slippery Slope

George Winter examines the implications of screening couples to discover if they are at risk of having children with particular conditions, and the slippery slope to which this may lead

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Pharmacotherapy of schizophrenia: toward a metabolomic-based approach

CNS Spectrums ◽

10.1017/s1092852918000962 ◽

2018 ◽

Vol 24 (03) ◽

pp. 281-286 ◽

Cited By ~ 2

Author(s):

Haythum O. Tayeb ◽

Hussam A. Murad ◽

Misbahuddin M. Rafeeq ◽

Frank I. Tarazi

Keyword(s):

At Risk ◽

Systematic Study ◽

Psychotic Disorders ◽

Response To Treatment ◽

Current Standard ◽

Biochemical Alterations ◽

Potential Development ◽

Novel Targets

Approximately 20%–30% of schizophrenia patients are resistant to current standard pharmacotherapies. Recent schizophrenia research aims to identify specific pathophysiological abnormalities and novel targets in the disease, with the goals of identifying at-risk individuals, facilitating diagnosis, prompting early and personalized interventions, and helping predict response to treatment. Metabolomics involves the systematic study of the profile of biochemical alterations early in the course of a given disorder. Major aspects of the schizophrenia metabolome have been characterized, uncovering potential selective biomarkers for the disease that may change how the disorder is diagnosed, and how patients are stratified and treated. This review focuses on the most common metabolomic fingerprints of the different pathways involved in the pathophysiology of schizophrenia, and the potential development of novel metabolomic-related pharmacotherapies for improved treatment of schizophrenia and other related idiopathic psychotic disorders.

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Evaluation Of Factor V Leiden, Prothrombin Mutations and The Homozygous mutation 677T In The MTHFR Gene In Patients With Venous Thrombosis

Blood ◽

10.1182/blood.v122.21.4798.4798 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4798-4798

Author(s):

Michele Pizzuti ◽

Alberto Santagostino ◽

Maria Antonietta Rizzo ◽

Daniela Dragonetti ◽

Maria Grazia Pietrafesa ◽

...

Keyword(s):

At Risk ◽

Venous Thrombosis ◽

Pulmonary Thromboembolism ◽

Factor V Leiden ◽

Mthfr Gene ◽

Homozygous Mutation ◽

Factor V ◽

Homozygous State ◽

The Impact ◽

Fvl Mutation

Over the last few years there has been increased interest in laboratory tests for thrombophilia. Testing is predominantly performed to identify asymptomatic individuals at risk for a first thrombosis or patients (pts) at risk of relapse. The results are not always concordant, and the impact on clinical practice is not yet defined, especially for heterozygous forms. We evaluated heterozygous and homozygous Factor V Leiden (FVL) and prothrombin (FII) mutations and the homozygous C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in 98 pts with venous thrombosis distinguishing idiopathic forms from forms that are secondary to malignancy, surgery, forced immobilization or hormone treatments. FII mutation was present in 17% of idiopathic and 5.8% of secondary forms. FVL mutation was present in respectively 17% and 15.8% and MTHFR homozygous state in 31.9% and 21.5%. At least one of FII or FVL mutations was present respectively in 31.9% and 19%, at least one of the three mutations examined was present in 57.4% and 36.2%. In pts with limb venous thrombosis (n-64), the percentages for each mutation are respectively: FII-23.5% and 6.6%, FVL-20.5% and 6.6%, MTHFR 35.2% and 16.6% .At least one mutation between FII and FVL is present respectively in 42.1% and 13.3% (P = 0,028) while at least one of the three mutations is present in 61.7% and 30.5% (P = 0,022) In our pts with pulmonary thromboembolism (n-36) FII mutation was absent while FVL mutation was present in 7.6% of idiopathic and 21.7% of the secondary thrombosis, MTHFR in 30.7% and in 30.4%. At least one of the three examined mutations was present in 38.4% and 47.8%. The mutations we have studied are generally more frequent in idiopathic forms. The difference reaches statistical significance in limb venous thrombosis where they seem to have a significant relevance, although in a heterozygous state, and to promote thrombosis even in absence of other causes. In pulmonary thromboembolism (PTE) pts FII mutation was absent, FVL mutation is less frequent in pts with idiopathic thrombosis and MTHFR homozygous state is equivalent between the two subgroups. Thus, they seem to not influence PTE pathogenesis that would be likely sought in different causes. Disclosures: No relevant conflicts of interest to declare.

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