scholarly journals Pre- and Post-Zygotic TP53 De Novo Mutations in SHH-Medulloblastoma

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2503
Author(s):  
Jacopo Azzollini ◽  
Elisabetta Schiavello ◽  
Francesca Romana Buttarelli ◽  
Carlo Alfredo Clerici ◽  
Laura Tizzoni ◽  
...  
Keyword(s):  
Family History ◽  
De Novo ◽  
Wide Spectrum ◽  
De Novo Mutations ◽  
Autosomal Dominant Disorder ◽  
P53 Overexpression ◽  
Tp53 Mutations ◽  
Li Fraumeni Syndrome ◽  
First Case ◽  
Germline Testing

Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder caused by mutations in the TP53 gene, predisposing to a wide spectrum of early-onset cancers, including brain tumors. In medulloblastoma patients, the role of TP53 has been extensively investigated, though the prevalence of de novo mutations has not been addressed. We characterized TP53 mutations in a monocentric cohort of consecutive Sonic Hedgehog (SHH)-activated medulloblastoma patients. Germline testing was offered based on tumor p53 immunostaining positivity. Among 24 patients, three (12.5%) showed tumor p53 overexpression, of whom two consented to undergo germline testing and resulted as carriers of TP53 mutations. In the first case, family history was uneventful and the mutation was not found in either of the parents. The second patient, with a family history suggestive of LFS, unexpectedly resulted as a carrier of the mosaic mutation c.742=/C>T p.(Arg248=/Trp). The allele frequency was 26% in normal tissues and 42–77% in tumor specimens. Loss of heterozygosity (LOH) in the tumor was also confirmed. Notably, the mosaic case has been in complete remission for more than one year, while the first patient, as most TP53-mutated medulloblastoma cases from other cohorts, showed a severe and rapidly progressive disease. Our study reported the first TP53 mosaic mutation in medulloblastoma patients and confirmed the importance of germline testing in p53 overexpressed SHH-medulloblastoma, regardless of family history.

Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome

2017 ◽  
Vol 55 (3) ◽  
pp. 173-180 ◽  
Author(s):  
Mariette Renaux-Petel ◽  
Françoise Charbonnier ◽  
Jean-Christophe Théry ◽  
Pierre Fermey ◽  
Gwendoline Lienard ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
De Novo ◽  
Multiple Primary Cancers ◽  
Breast Cancers ◽  
De Novo Mutations ◽  
Li Fraumeni Syndrome ◽  
Medical Laboratories ◽  
Li Fraumeni ◽  
Adrenocortical Carcinomas ◽  
Generation Sequencing

BackgroundDevelopment of tumours such as adrenocortical carcinomas (ACC), choroid plexus tumours (CPT) or female breast cancers before age 31 or multiple primary cancers belonging to the Li-Fraumeni (LFS) spectrum is, independently of the familial history, highly suggestive of a germline TP53 mutation. The aim of this study was to determine the contribution of de novo and mosaic mutations to LFS.Methods and resultsAmong 328 unrelated patients harbouring a germline TP53 mutation identified by Sanger sequencing and/or QMPSF, we could show that the mutations had occurred de novo in 40 cases, without detectable parental age effect. Sanger sequencing revealed two mosaic mutations in a child with ACC and in an unaffected father of a child with medulloblastoma. Re-analysis of blood DNA by next-generation sequencing, performed at a depth above 500X, from 108 patients suggestive of LFS without detectable TP53 mutations, allowed us to identify 6 additional cases of mosaic TP53 mutations, in 2/49 children with ACC, 2/21 children with CPT, in 1/31 women with breast cancer before age 31 and in a patient who developed an osteosarcoma at age 12, a breast carcinoma and a breast sarcoma at age 35.ConclusionsThis study performed on a large series of TP53 mutation carriers allows estimating the contribution to LFS of de novo mutations to at least 14% (48/336) and suggests that approximately one-fifth of these de novo mutations occur during embryonic development. Considering the medical impact of TP53 mutation identification, medical laboratories in charge of TP53 testing should ensure the detection of mosaic mutations.

scholarly journals A SMARCA2 Mutation in the First Case Report of Nicolaides-Baraitser Syndrome in Latin America: Genotype-Phenotype Correlation

2017 ◽  
Vol 2017 ◽  
pp. 1-4 ◽  
Author(s):  
Ana Isabel Sánchez ◽  
Jorge Armando Rojas
Keyword(s):  
Latin America ◽  
Case Report ◽  
Language Impairment ◽  
De Novo ◽  
Signs And Symptoms ◽  
Facial Features ◽  
Missense Mutations ◽  
De Novo Mutations ◽  
Lower Lip ◽  
First Case

Nicolaides-Baraitser syndrome (NCBRS) is a rare and well-recognized entity that was first described in 1993, with a prevalence that is currently not known. It is recognized as a distinctive entity, with some variability in its signs and symptoms. The most important characteristics include intellectual disability, peculiar facial features including sparse scalp hair, coarse facial features, low frontal hairline, and microcephaly, and seizures. Additional features may include epicanthic folds, thin upper lip vermilion with thick lower lip vermilion, skeletal abnormalities, and severe language impairment. The disorder is inherited in an autosomal dominant manner caused by de novo mutations in the SMARCA2 gene, with most being missense mutations. We report a young adult patient with NCBRS and, to our knowledge, the first case report of the syndrome in Latin America with a confirmed molecular diagnosis and a mild-to-moderate phenotype.

A case of hereditary angioedema with late adulthood onset

2020 ◽  
Vol 17 (3) ◽  
pp. 93-96
Author(s):  
Julia P. Pokalyukhina ◽  
Natalia N. Abramova
Keyword(s):  
Family History ◽  
Hereditary Angioedema ◽  
De Novo ◽  
Clinical Manifestations ◽  
C1 Inhibitor ◽  
De Novo Mutations ◽  
Elderly Age ◽  
C1 Inhibitor Deficiency ◽  
Diagnostic Difficulties ◽  
Diagnosis Criteria

Over the last years, high attention is given to the hereditary angioedema (HAO). Practitioners can identify the disease by clinical manifestations and family history even before specific laboratory testing. More than 95% of HAO cases are associated with C-1inhibitor deficiency/dysfunction caused by a mutation inSERPING1gene. In 25% of patients without C1-inhibitor deficiency HAO is associated with heterozygous mutations in geneF12coding Hageman XII factor. In 20172018 years two more genes responsible for normal C1-inhibitor HAO were discovered: genesPLGandANGPT1. In clinical practice patients do not always meet typical HAO diagnosis criteria. Diagnostic difficulties appear when clinical picture is not confirmed by related genetic testing results, for example, mutations in genes not described earlier are detected. It should be noted that app. 25% of patients do not have any HAO family history, i.e. have so called de novo mutations. Normally HAO onset takes place within 2 first life decades. 40% of patients have disease progress before the age of 5, and 75% of patients before the age of 15 y.o. However, it can appear in elderly age, which means certain diagnostic difficulties. It is important to analyze thoroughly patients comorbidity and make differential diagnosis with a secondary angioedema.

A de novo deletional germline mutation in the MLH1 gene resulting in early onset colorectal cancer in a woman with a negative family history: A case report

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21067-21067
Author(s):  
D. Zakalik ◽  
N. S. Goldstein ◽  
W. L. Ducaine
Keyword(s):  
Colorectal Cancer ◽  
Family History ◽  
Early Onset ◽  
De Novo ◽  
Germline Mutations ◽  
De Novo Mutations ◽  
Mlh1 Gene ◽  
Negative Family History ◽  
Mmr Genes ◽  
Early Onset Colorectal Cancer

21067 Background: Hereditary non-polyposis colorectal cancer (HNPCC) is a genetic disorder that results in an increased risk of early onset colorectal cancer (CRC). HNPCC is caused by germline mutations in DNA mismatch repair (MMR) genes, including MLH1 and MSH2, and is transmitted in an autosomal dominant manner. De novo germline mutations in MMR genes are exceedingly rare. We now describe a case of a de novo germline mutation in MLH1 associated with early onset CRC in a young woman with a negative family history. Methods: We present a case of a 31-year-old Caucasian female who presented with abdominal pain. Colonoscopy revealed a moderately differentiated adenocarcinoma with focal mucin production involving the sigmoid colon, with a final staging of T4N0M0. Genetic testing was offered because of her young age at diagnosis, having fulfilled the Bethesda guidelines. Microsatellite instability (MSI) testing using a panel of six microsatellite loci was performed on the tumor sample from the affected patient. Immunohistochemistry (IHC) testing for MLH1 and MSH2 was performed. Following counseling and with informed consent, DNA was isolated and sequenced using bi-directional PCR of the MLH1 gene. All exons of MLH1 and MSH2 were analyzed by standard Southern blot methods. Paternity was established using eight genetic loci. Results: The patient's tumor revealed high MSI and complete absence of MLH1 immunoreactivity. MSH2 IHC staining was normal. A large deletional mutation involving exons 5–12 of MLH1 was identified by Southern blot analysis. The patient's parents and siblings were tested and found to have wild type MLH1. Paternity was confirmed with greater than 99.9% certainty. Conclusions: De novo mutations in MMR genes are a rare cause of HNPCC. We report the first case of a large de novo deletion in the MLH1 gene accounting for early onset CRC. Such de novo mutations, albeit rare, must be considered in patients who present with early onset CRC and a negative family history. These results support the use of the Bethesda guidelines to identify individuals who may carry mutations in the MMR genes. No significant financial relationships to disclose.

scholarly journals Autism and attention-deficit/hyperactivity disorder among individuals with a family history of alcohol use disorders

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Jan Sundquist ◽  
Kristina Sundquist ◽  
Jianguang Ji
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Family History ◽  
Alcohol Use ◽  
Attention Deficit ◽  
De Novo ◽  
Alcohol Use Disorders ◽  
De Novo Mutations ◽  
Parental History ◽  
Hyperactivity Disorder ◽  
History Of

Recent studies suggest de novo mutations may involve the pathogenesis of autism and attention-deficit/hyperactivity disorder (ADHD). Based on the evidence that excessive alcohol consumption may be associated with an increased rate of de novo mutations in germ cells (sperms or eggs), we examine here whether the risks of autism and ADHD are increased among individuals with a family history of alcohol use disorders (AUDs). The standardized incidence ratios (SIRs) of autism and ADHD among individuals with a biological parental history of AUDs were 1.39 (95% CI 1.34–1.44) and 2.19 (95% CI 2.15–2.23), respectively, compared to individuals without an affected parent. Among offspring whose parents were diagnosed with AUDs before their birth, the corresponding risks were 1.46 (95% CI 1.36–1.58) and 2.70 (95% CI 2.59–2.81), respectively. Our study calls for extra surveillance for children with a family history of AUDs, and further studies examining the underlying mechanisms are needed.

DNM1 Gene and Its Related Epileptic Phenotypes

2021 ◽  
Author(s):  
Milena Motta ◽  
Maria Chiara Consentino ◽  
Alessandra Fontana ◽  
Laura Sciuto ◽  
Raffaele Falsaperla ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Wide Spectrum ◽  
Intractable Epilepsy ◽  
Gene Mutations ◽  
Infantile Spasms ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
De Novo Mutations ◽  
Negative Effect

AbstractThe phenotypic variety associated to mutations in dynamin 1 (DNM1), codifying the presynaptic protein DNM1 has been increasingly reported, mainly related to encephalopathy with intractable epilepsy; currently, it is known the phenotype related to DNM1 gene mutations is relatively homogeneous with developmental delay, hypotonia, and epilepsy characterized by infantile spasms and possible progression to Lennox-Gastaut syndrome. By examining all the papers published until 2020 (18 articles), we compared data from 30 patients (extrapolated from 5 papers) with DNM1 mutations, identifying 26 patients with de novo mutations in DNM1. Nine patients (33.3%) reported the recurrent mutation p.Arg237Trp. A usual phenotype observed comprises severe to deep developmental delay and muscular hypotonia in all patients with epilepsy beginning with infantile spasms, which often evolved into Lennox-Gastaut syndrome. Data about GTPase or central domains mutations, and existing structural modeling and functional suggest a dominant negative effect on DMN1 function. Generally genetic epilepsies consist of a wide spectrum of clinical features, unlike that, DNM1-related CNS impairment phenotype is quite uniform. In up to one third of patients it has been found variant p.Arg237Trp, which is one of the most frequent variant detected in epileptic encephalopathies. The understanding of DNM1 function opens up the chance that this gene would become a new therapeutic target for epilepsies.

scholarly journals Advantages of high throughput parallel sequencing in detecting somatic mosaicism in sporadic retinoblastoma

2020 ◽  
pp. 6-7
Author(s):  
Е.А. Алексеева ◽  
О.В. Бабенко ◽  
В.М. Козлова ◽  
Т.Л. Ушакова ◽  
Т.П. Казубская ◽  
...  
Keyword(s):  
Family History ◽  
High Throughput ◽  
De Novo ◽  
Somatic Mosaicism ◽  
Allelic Frequency ◽  
De Novo Mutations ◽  
Rb1 Gene ◽  
Parallel Sequencing ◽  
Pathogenic Variants

Почти 80% случаев наследственной ретинобластомы не имеют семейного анамнеза и возникают в результате мутаций de novo в гене RB1. Методом высокопроизводительного параллельного секвенирования (ВПС) проведено молекулярно-генетическое обследование 208 неродственных больных со спорадической РБ, среди которых 145 пациентов с унилатеральной формой заболевания и 63 - с билатеральной. В группе пациентов с билатеральной РБ молекулярные изменения в гене RB1 обнаружены в 90,5% (57/63) случаев. У 4,8% (3/63) пациентов определен мозаичный вариант мутации в гене RB1. В группе пациентов с унилатеральной РБ молекулярные изменения в гене RB1 выявлены в 17,9% (26/145) случаев. Среди исследованных пациентов соматический мозаицизм выявлен в 9,0% (13/165) случаев. Применение ВПС позволяет точно определять аллельную частоту вариантов, что делает поиск соматического мозаицизма эффективным. Almost 80% of cases of hereditary retinoblastoma do not have a family history and arise as a result of de novo mutations in the RB1 gene. An NGS test was performed on 208 unrelated patients with sporadic RB, including 145 patients with a unilateral form and 63 patients with a bilateral one. In the group of patients with bilateral RB, pathogenic variants in the RB1 gene were detected in 90.5% (57/63) cases. In 4.8% (3/63) of patients, a mosaic variants were determined. In the group of patients with unilateral RB, changes in the RB1 gene were detected in 17.9% (26/145) cases. Among the examined patients, somatic mosaicism was detected in 9.0% (13/165) cases. NGS allows us to determine the allelic frequency of variants, which makes the search for somatic mosaicism effective.

scholarly journals Presence of De Novo Mutations in Autosomal Dominant Polycystic Kidney Disease Patients Without Family History

2008 ◽  
Vol 52 (6) ◽  
pp. 1042-1050 ◽  
Author(s):  
Berenice Reed ◽  
Kim McFann ◽  
William J. Kimberling ◽  
York Pei ◽  
Patricia A. Gabow ◽  
...  
Keyword(s):  
Family History ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
De Novo ◽  
De Novo Mutations ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney
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