scholarly journals Neurofibromatosis genetic testing: cohort study

2020 ◽  
pp. 10-11
Author(s):  
К.О. Карандашева ◽  
М.С. Пащенко ◽  
К.И. Аношкин ◽  
Е.Б. Кузнецова ◽  
А.С. Танас ◽  
...  
Keyword(s):  
Cohort Study ◽  
Genetic Testing ◽  
Sanger Sequencing ◽  
Clinical Signs ◽  
Neurofibromatosis Type ◽  
Pathogenic Mutation ◽  
Parallel Sequencing ◽  
Dependent Probe

Исследование проведено на материале ДНК периферической крови 1000 пациентов с клиническими признаками нейрофиброматоза 1-го типа или нейрофиброматоза 2-го типа. Молекулярно-диагностический комплекс включал высокопроизводительное параллельное секвенирование, мультиплексную амплификацию лигированных зондов, секвенирование по Сэнгеру. Клинический диагноз был подтвержден в 70,2% случаев, мутации в генах NF1 и NF2 были выявлены у 672 и 30 пациентов соответственно. The study was conducted of DNA from peripheral blood of 1000 patients with clinical signs of neurofibromatosis type 1 or neurofibromatosis type 2. The genetic testing included massive parallel sequencing, multiplex ligation-dependent probe amplification, Sanger sequencing. The pathogenic mutation was identified in 70.2% of the cases, affecting NF1 and NF2 genes in 672 and 30 cases, respectively.

scholarly journals Paragangliomas/Pheochromocytomas: Clinically Oriented Genetic Testing

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Rute Martins ◽  
Maria João Bugalho
Keyword(s):  
Genetic Testing ◽  
Somatic Mutations ◽  
Parasympathetic Nervous System ◽  
Multiple Endocrine Neoplasia Type ◽  
Neurofibromatosis Type ◽  
Clinical Aspects ◽  
Von Hippel Lindau

Paragangliomas are rare neuroendocrine tumors that arise in the sympathetic or parasympathetic nervous system. Sympathetic paragangliomas are mainly found in the adrenal medulla (designated pheochromocytomas) but may also have a thoracic, abdominal, or pelvic localization. Parasympathetic paragangliomas are generally located at the head or neck. Knowledge concerning the familial forms of paragangliomas has greatly improved in recent years. Additionally to the genes involved in the classical syndromic forms:VHLgene (von Hippel-Lindau),RETgene (Multiple Endocrine Neoplasia type 2), andNF1gene (Neurofibromatosis type 1), 10 novel genes have so far been implicated in the occurrence of paragangliomas/pheochromocytomas:SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, EGLN1, HIF2A,andKIF1B. It is currently accepted that about 35% of the paragangliomas cases are due to germline mutations in one of these genes. Furthermore, somatic mutations ofRET, VHL, NF1, MAX, HIF2A,andH-RAScan also be detected. The identification of the mutation responsible for the paraganglioma/pheochromocytoma phenotype in a patient may be crucial in determining the treatment and allowing specific follow-up guidelines, ultimately leading to a better prognosis. Herein, we summarize the most relevant aspects regarding the genetics and clinical aspects of the syndromic and nonsyndromic forms of pheochromocytoma/paraganglioma aiming to provide an algorithm for genetic testing.

scholarly journals Somatic mosaicism in neurofibromatosis type 1

2019 ◽  
pp. 28-36
Author(s):  
К.О. Карандашева ◽  
М.С. Пащенко ◽  
Н.А. Дёмина ◽  
И.А. Акимова ◽  
О.Н. Макиенко ◽  
...  
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Genetic Variants ◽  
Sanger Sequencing ◽  
Molecular Genetic ◽  
Somatic Mosaicism ◽  
Neurofibromatosis Type ◽  
Pathogenic Mutation ◽  
Alternative Methods ◽  
Heteroduplex Analysis

Актуальность. Нейрофиброматоз первого типа является одним из наиболее распространенных моногенных заболеваний. Этиологическим фактором его развития является патогенная мутация в гене NF1. Однако у части пациентов не удается достичь молекулярно-генетического подтверждения клинического диагноза. Мы полагаем, что в некоторых случаях это может быть обусловлено соматическим мозаицизмом с малой долей клеток, несущих патогенный аллель, в анализируемом образце биологического материала. Аллели с низкой представленностью отсеиваются общепринятыми фильтрами программного обеспечения при поиске генетических вариантов методом высокопроизводительного параллельного секвенирования (ВПС) и/или не детектируются визуально за счет слияния с фоновым шумом при анализе результатов секвенирования по Сэнгеру. Цель. Поиск патогенных мозаичных генетических вариантов у пациентов с нейрофиброматозом первого типа без выявленных стандартными методами герминальных мутаций в гене NF1. Материалы и методы. Исследование проведено на материале ДНК лимфоцитов периферической крови 275 пациентов, объединенных клиническим диагнозом нейрофиброматоз первого типа и отсутствием герминальных мутаций в генах NF1 и NF2 по результатам стандартных лабораторных исследований. Поиск точковых мутаций осуществляли методом ВПС на платформе Ion Torrent. Дизайн панели праймеров включал экзоны, прилегающие к ним интронные сегменты (20-70 п.н.), а также 3’UTR и 5’UTR генов NF1 и NF2. Исключение протяженных делеций в NF1 и NF2 осуществляли методом MLPA. С целью поиска мозаичных генетических вариантов был разработан и проведен углубленный анализ данных ВПС, основанный на биоинформатических и статистических подходах. Для верификации выявленных мозаичных патогенных генетических вариантов использовали секвенирование ДНК по Сэнгеру и гетеродуплексный анализ. Результаты. Патогенные соматические мутации в гене NF1 выявлены в 12 из 275 образцов (4,4%) ДНК больных, у которых были исключены герминальные мутации. В 8 образцах наличие мутантного аллеля было подтверждено альтернативными методами. Выводы. ДНК-диагностика доминантно наследуемых заболеваний требует особых подходов, учитывающих явление соматического мозаицизма. Предложенный метод позволяет выявить генетические варианты, представленные с малой аллельной частотой, без увеличения глубины секвенирования исследуемого образца и может быть применен для ретроспективного анализа данных ВПС с целью повышения качества ДНК-диагностики. Background. Neurofibromatosis type 1 is one of the most common monogenic disorders. A pathogenic mutation in NF1 is the etiological factor of neurofibromatosis type 1. Nevertheless, not all patients receive molecular genetic verification of the clinical diagnosis. We believe that this may be due to a somatic mosaicism with a small fraction of pathogenic allele, which is neglected by the NGS analysis software and/or is undetectable by Sanger sequencing due to noisy background. Objective. To detect pathogenic mosaic mutations in cases of neurofibromatosis type 1 without germline genetic variants. Material and methods. Two hundred seventy five peripheral blood lymphocyte DNA samples from patients with NF1 and without germline mutation were retrospectively analyzed. DNA samples were sequenced with Ion PGM and Ion S5 NGS systems. Gene panel design included NF1 and NF2 genes: exons, adjacent intron segments (20-70 b.p.), 3’UTRs and 5’UTRs. Samples were also tested using MLPA in order to exclude deletions in NF1 and NF2. We developed and implemented the pipeline to search mosaic cases using bioinformatics approaches. All newly detected mutations were evaluated by Sanger sequencing and by heteroduplex analysis. Result. We have identified new pathogenic mutations in NF1 for 12 patients (4.4%) and verified 8 of them using alternative methods. Conclusion. Dominant disorders, like neurofibromatosis type 1, require a detailed bioinformatic analysis of NGS results with respect to somatic mosaicism. Our approach makes it possible to identify genetic variants with low representation of a pathogenic allele without increasing the sequencing depth of the sample under study and can be used for retrospective analysis of NGS data in order to improve the quality of DNA diagnostics.

scholarly journals EXPRESS: Pulmonary Hypertension Associated With Neurofibromatosis Type 2

2021 ◽  
pp. 204589402110295
Author(s):  
Hirohisa Taniguchi ◽  
Tomoya Takashima ◽  
Ly Tu ◽  
Raphaël Thuillet ◽  
Asuka Furukawa ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Neurofibromatosis Type ◽  
Pulmonary Vascular Remodeling ◽  
Life Threatening ◽  
History Of ◽  
Pulmonary Arterial ◽  
First Time

Although precapillary pulmonary hypertension (PH) is a rare but severe complication of patients with neurofibromatosis type 1 (NF1), its association with NF2 remains unknown. Herein, we report a case of a 44-year-old woman who was initially diagnosed with idiopathic pulmonary arterial hypertension (IPAH) and treated with PAH-specific combination therapy. However, a careful assessment for a relevant family history of the disease and genetic testing reveal that this patient had a mutation in the NF2 gene. Using immunofluorescence and Western blotting, we demonstrated a decrease in endothelial NF2 protein in lungs from IPAH patients compared to control lungs, suggesting a potential role of NF2 in PAH development. To our knowledge, this is the first time that precapillary PH has been described in a patient with NF2. The altered endothelial NF2 expression pattern in PAH lungs should stimulate work to better understand how NF2 is contributing to the pulmonary vascular remodeling associated to these severe life-threatening conditions.

scholarly journals Severe COVID-19 in people with type 1 and type 2 diabetes in Sweden: A nationwide retrospective cohort study

2021 ◽  
Vol 4 ◽  
pp. 100105
Author(s):  
Aidin Rawshani ◽  
Elin Allansson Kjölhede ◽  
Araz Rawshani ◽  
Naveed Sattar ◽  
Katarina Eeg-Olofsson ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cohort Study ◽  
Retrospective Cohort Study ◽  
Retrospective Cohort

Higher glucose variability in type 1 than in type 2 diabetes patients admitted to the intensive care unit: A retrospective cohort study

2017 ◽  
Vol 38 ◽  
pp. 300-303 ◽  
Author(s):  
Marjolein K. Sechterberger ◽  
Sigrid C.J. van Steen ◽  
Esther M.N. Boerboom ◽  
Peter H.J. van der Voort ◽  
Rob J. Bosman ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Intensive Care Unit ◽  
Cohort Study ◽  
Intensive Care ◽  
Retrospective Cohort Study ◽  
Retrospective Cohort ◽  
Glucose Variability ◽  
Diabetes Patients

Current status and recommendations for imaging in neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis

2019 ◽  
Vol 49 (2) ◽  
pp. 199-219 ◽  
Author(s):  
Shivani Ahlawat ◽  
Jaishri O. Blakeley ◽  
Shannon Langmead ◽  
Allan J. Belzberg ◽  
Laura M. Fayad
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Neurofibromatosis Type 2 ◽  
Current Status ◽  
Type 1 Neurofibromatosis

scholarly journals Plantar fasciitis in patients with type 1 and type 2 diabetes: A contemporary cohort study

2019 ◽  
Vol 33 (10) ◽  
pp. 107399 ◽  
Author(s):  
Sari J. Priesand ◽  
Brian M. Schmidt ◽  
Lynn Ang ◽  
James S. Wrobel ◽  
Michael Munson ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cohort Study ◽  
Plantar Fasciitis

Sporadic vestibular schwannoma: a molecular testing summary

2020 ◽  
pp. jmedgenet-2020-107022
Author(s):  
Katherine V Sadler ◽  
Naomi L Bowers ◽  
Claire Hartley ◽  
Philip T Smith ◽  
Simon Tobi ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Vestibular Schwannoma ◽  
Dna Analysis ◽  
Genomic Medicine ◽  
Familial Risk ◽  
Neurofibromatosis Type ◽  
Molecular Testing ◽  
Pathogenic Variants ◽  
Patient Subgroups

ObjectivesCases of sporadic vestibular schwannoma (sVS) have a low rate of association with germline pathogenic variants. However, some individuals with sVS can represent undetected cases of neurofibromatosis type 2 (NF2) or schwannomatosis. Earlier identification of patients with these syndromes can facilitate more accurate familial risk prediction and prognosis.MethodsCases of sVS were ascertained from a local register at the Manchester Centre for Genomic Medicine. Genetic analysis was conducted in NF2 on blood samples for all patients, and tumour DNA samples when available. LZTR1 and SMARCB1 screening was also performed in patient subgroups.ResultsAge at genetic testing for vestibular schwannoma (VS) presentation was younger in comparison with previous literature, a bias resulting from updated genetic testing recommendations. Mosaic or constitutional germline NF2 variants were confirmed in 2% of patients. Pathogenic germline variants in LZTR1 were found in 3% of all tested patients, with a higher rate of 5% in patients <30 years. No pathogenic SMARCB1 variants were identified within the cohort. Considering all individuals who received tumour DNA analysis, 69% of patients were found to possess two somatic pathogenic NF2 variants, including those with germline LZTR1 pathogenic variants.ConclusionsUndiagnosed schwannoma predisposition may account for a significant minority of apparently sVS cases, especially at lower presentation ages. Loss of NF2 function is a common event in VS tumours and may represent a targetable common pathway in VS tumourigenesis. These data also support the multi-hit mechanism of LZTR1-associated VS tumourigenesis.

Sign in / Sign up

Export Citation Format

Share Document