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

In this study, we used DNA polymorphisms for carrier detection and prenatal diagnosis of hemophilia A in a large group of Italian families. The restriction fragment length polymorphisms (RFLPs) investigated were the intragenic polymorphic Bc/I site within the factor VIII gene; the extragenic multiallelic Taq I system at the St14 locus; and the extragenic Bg/II site at the DX13 locus. The factor VIII probe was informative in 30%, St14 in 82%, and DX13 in 60% of obligate carriers. The combination of factor VIII-Bc/I and St14-Taq I showed that 91% of obligate carriers were heterozygotes for one or both; with all three probes, only 4% of obligate carriers were noninformative. In families clearly segregating for hemophilia A, RFLP analysis allowed us to define the carrier status for the hemophilia A gene in all 27 women tested. RFLP analysis allowed us to exclude the carrier status in 39 of 45 female relatives of sporadic patients. The combination of RFLP analysis and biological assay of factor VIII allowed us to identify a de novo mutation in the maternal grandfather in 7 of 12 of the families with sporadic cases, for which members of three generations were available for study. Nine of 10 couples requesting prenatal diagnosis provided informative RFLP DNA pattern. Carrier status was excluded in two women, two fetuses were shown to be female, and prenatal diagnosis was carried out in five pregnancies by DNA analysis. Prenatal testing was successful in three instances and failed in two because a sufficient amount of chorionic villous DNA was not obtained for the analysis.

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Hemophilia A: carrier detection and prenatal diagnosis by DNA analysis

Blood ◽

10.1182/blood.v70.2.531.531 ◽

1987 ◽

Vol 70 (2) ◽

pp. 531-535 ◽

Cited By ~ 20

Author(s):

M Pecorara ◽

L Casarino ◽

PG Mori ◽

M Morfini ◽

G Mancuso ◽

...

Keyword(s):

Prenatal Diagnosis ◽

Factor Viii ◽

Dna Analysis ◽

Hemophilia A ◽

De Novo ◽

Rflp Analysis ◽

Carrier Detection ◽

Dna Polymorphisms ◽

De Novo Mutation ◽

Carrier Status

Abstract In this study, we used DNA polymorphisms for carrier detection and prenatal diagnosis of hemophilia A in a large group of Italian families. The restriction fragment length polymorphisms (RFLPs) investigated were the intragenic polymorphic Bc/I site within the factor VIII gene; the extragenic multiallelic Taq I system at the St14 locus; and the extragenic Bg/II site at the DX13 locus. The factor VIII probe was informative in 30%, St14 in 82%, and DX13 in 60% of obligate carriers. The combination of factor VIII-Bc/I and St14-Taq I showed that 91% of obligate carriers were heterozygotes for one or both; with all three probes, only 4% of obligate carriers were noninformative. In families clearly segregating for hemophilia A, RFLP analysis allowed us to define the carrier status for the hemophilia A gene in all 27 women tested. RFLP analysis allowed us to exclude the carrier status in 39 of 45 female relatives of sporadic patients. The combination of RFLP analysis and biological assay of factor VIII allowed us to identify a de novo mutation in the maternal grandfather in 7 of 12 of the families with sporadic cases, for which members of three generations were available for study. Nine of 10 couples requesting prenatal diagnosis provided informative RFLP DNA pattern. Carrier status was excluded in two women, two fetuses were shown to be female, and prenatal diagnosis was carried out in five pregnancies by DNA analysis. Prenatal testing was successful in three instances and failed in two because a sufficient amount of chorionic villous DNA was not obtained for the analysis.

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Case Report: Development of Factor VIII Inhibitor in a Patient with an Uncommon de novo Mutation in the Factor VIII Gene

Acta Haematologica ◽

10.1159/000495559 ◽

2019 ◽

Vol 141 (3) ◽

pp. 129-134

Author(s):

Kirk D. Wyatt ◽

Lea M. Coon ◽

Dawn N. Rusk ◽

Vilmarie Rodriguez ◽

Deepti M. Warad

Keyword(s):

Factor Viii ◽

Hemophilia A ◽

De Novo ◽

De Novo Mutation ◽

Factor Viii Inhibitor ◽

Severe Hemophilia ◽

Factor Viii Gene ◽

Patient Reported ◽

Viii Inhibitor ◽

Mixed Ethnicity

The development of factor VIII inhibitors remains a significant clinical challenge in the management of hemophilia A. We present a patient of mixed ethnicity with severe hemophilia A who was found to have a F8 gene hemizygous c.5815G>T mutation resulting in an Ala1939Ser substitution (Ala1920Ser in legacy nomenclature) and possible splice site change that has been reported in only 1 patient previously. He developed an inhibitor shortly after starting replacement recombinant factor VIII (Advate®; Baxalta, Bannockburn, IL, USA) and was successfully treated with immune tolerance therapy. Our report describes the second patient reported to have severe hemophilia due to this mutation and the only case of a factor VIII inhibitor associated with this mutation.

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Severe neonatal subgaleal hemorrhage as the first presentation of hemophilia A

Srpski arhiv za celokupno lekarstvo ◽

10.2298/sarh1604204r ◽

2016 ◽

Vol 144 (3-4) ◽

pp. 204-206 ◽

Cited By ~ 1

Author(s):

Tanja Radovanovic ◽

Slobodan Spasojevic ◽

Vesna Stojanovic ◽

Aleksandra Doronjski

Keyword(s):

Hemophilia A ◽

De Novo ◽

Bleeding Disorder ◽

De Novo Mutation ◽

Successful Outcome ◽

Vacuum Extraction ◽

Spontaneous Vaginal Delivery ◽

Emissary Veins ◽

Male Neonate

Introduction. Subgaleal hemorrhage is a rare but potentially fatal birth trauma. It is caused by rupture of the emissary veins (connections between the dural sinuses and scalp veins), followed by the accumulation of blood between the epicranial aponeurosis and the periosteum. Usually, it is associated with instrumental delivery (vacuum extraction, forceps delivery), but it may also occur spontaneously, suggesting the possibility of congenital bleeding disorder. Case Outline. A full term male neonate was born at 40 weeks gestation by spontaneous vaginal delivery, with birth weight of 3,700 g. The Apgar scores were 9 and 10 at 1 and 5 minutes, respectively. At the age of 23 hours, the baby became pale and lethargic. Large fluctuant swelling on his head was noted. He developed severe anemia and hypovolemia as a result of massive subgaleal hemorrhage. After successful treatment, the baby fully recovered. Follow-up and further evaluation revealed hemophilia A as a result of a de novo mutation. Conclusion. This case illustrates that subgaleal hemorrhage may be the first presentation of hemophilia A. Infants without obvious risk factors for developing subgaleal hemorrhage should be evaluated for congenital bleeding disorder. Successful outcome in affected infants requires early diagnosis, careful monitoring and prompt treatment.

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De novo mutation in DMD gene in a patient with combined hemophilia A and Duchenne muscular dystrophy

International Journal of Hematology ◽

10.1007/s12185-013-1488-4 ◽

2013 ◽

Vol 99 (2) ◽

pp. 184-187 ◽

Cited By ~ 2

Author(s):

Lana Strmecki ◽

Petra Hudler ◽

Majda Benedik-Dolničar ◽

Radovan Komel

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Hemophilia A ◽

De Novo ◽

De Novo Mutation ◽

Dmd Gene

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

Diagnostics ◽

10.3390/diagnostics10010007 ◽

2019 ◽

Vol 10 (1) ◽

pp. 7 ◽

Cited By ~ 1

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.

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Direct Transmission of Within-Host Mycobacterium Tuberculosis Diversity to Secondary Cases Can Lead to Variable Between-Host Heterogeneity Without De Novo Mutation: A Genomic Investigation

SSRN Electronic Journal ◽

10.2139/ssrn.3384856 ◽

2019 ◽

Author(s):

Marie Séraphin ◽

Anders Norman ◽

Erik Michael Rasmussen ◽

Alexandra M. Gerace ◽

Calin Chiribau ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

De Novo ◽

De Novo Mutation ◽

Direct Transmission ◽

Host Heterogeneity

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Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

Molecular Brain ◽

10.1186/s13041-021-00769-8 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Kohei Kitagawa ◽

Kensuke Matsumura ◽

Masayuki Baba ◽

Momoka Kondo ◽

Tomoya Takemoto ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Social Behavior ◽

Mouse Model ◽

Mouse Models ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

De Novo Mutation ◽

Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

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The L1-dependant and Pol III transcribed Alu retrotransposon, from its discovery to innate immunity

Molecular Biology Reports ◽

10.1007/s11033-021-06258-4 ◽

2021 ◽

Vol 48 (3) ◽

pp. 2775-2789

Author(s):

Ludwig Stenz

Keyword(s):

Human Genome ◽

Viral Infections ◽

De Novo ◽

Current Knowledge ◽

Innate Immune ◽

De Novo Mutation ◽

Neuronal Diversity ◽

Alu Sequences ◽

Pol Iii ◽

The Brain

AbstractThe 300 bp dimeric repeats digestible by AluI were discovered in 1979. Since then, Alu were involved in the most fundamental epigenetic mechanisms, namely reprogramming, pluripotency, imprinting and mosaicism. These Alu encode a family of retrotransposons transcribed by the RNA Pol III machinery, notably when the cytosines that constitute their sequences are de-methylated. Then, Alu hijack the functions of ORF2 encoded by another transposons named L1 during reverse transcription and integration into new sites. That mechanism functions as a complex genetic parasite able to copy-paste Alu sequences. Doing that, Alu have modified even the size of the human genome, as well as of other primate genomes, during 65 million years of co-evolution. Actually, one germline retro-transposition still occurs each 20 births. Thus, Alu continue to modify our human genome nowadays and were implicated in de novo mutation causing diseases including deletions, duplications and rearrangements. Most recently, retrotransposons were found to trigger neuronal diversity by inducing mosaicism in the brain. Finally, boosted during viral infections, Alu clearly interact with the innate immune system. The purpose of that review is to give a condensed overview of all these major findings that concern the fascinating physiology of Alu from their discovery up to the current knowledge.

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