scholarly journals A Novel Germline c.1267T>A MEN1 Mutation in MEN1 Family—from Phenotype to Gene and Back

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1382
Author(s):  
Wojciech Gierlikowski ◽  
Agata Skwarek-Szewczyk ◽  
Michał Popow
Keyword(s):  
Genetic Testing ◽  
Primary Hyperparathyroidism ◽  
Family Members ◽  
Heterozygous Mutation ◽  
Gastroenteropancreatic Neuroendocrine Tumors ◽  
Endocrine Disorder ◽  
Radiological Features ◽  
Gene Panels ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Primary hyperparathyroidism is a relatively common endocrine disorder, which may be hereditary. This report describes clinical, biochemical, radiographic, and genetic findings, the latter obtained using next generation sequencing (NGS), in three consanguineous patients. Gene panels in NGS consisted of 5 or 70 genes, including MEN1 and RET. The first patient suffered from recurrent primary hyperparathyroidism. Primary hyperparathyroidism and pituitary microadenomas were afterwards diagnosed in two of her daughters. No clinical nor radiological features of gastroenteropancreatic neuroendocrine tumors were found. All three family members were heterozygous for MEN1 NM_130799: c.1267T>A transversion, which is predicted to result in substitution of tryptophan with arginine in position 423. Additionally, the first patient was also a carrier of RET NM_020975: c.1946C>T missense mutation, which was not present in two other family members. We describe a family with a novel heterozygous mutation (NM_130799: c.1267T>A) in MEN1 gene and postulate that it leads to MEN1 syndrome. The study underlies the importance of genetic testing in primary hyperparathyroidism in personalizing patients’ care.

scholarly journals Novel PAX6 variant in a family with ophthalmologic, pancreatic, and olfactory features

2021 ◽  
pp. mcs.a006149
Author(s):  
Kristen Lee Buehne ◽  
Sarah Hart ◽  
Bradley Williams ◽  
Jennifer L Cohen
Keyword(s):  
Genetic Testing ◽  
Next Generation Sequencing ◽  
Family Members ◽  
Clinical Findings ◽  
Young Age ◽  
Next Generation ◽  
Congenital Cataracts ◽  
Novel Variant ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Variants in the PAX6 gene have been associated with ophthalmologic, neurologic, and pancreatic differences. We report on a proband, mother, and affected brother who presented with congenital cataracts and glaucoma at a young age. Non-ocular findings are also reported among these family members. After a congenital cataracts next generation sequencing (NGS) gene panel was found to be non-diagnostic in 2016, a more expanded panel in 2020 revealed a novel variant: c.178T>A; p.Tyr60Asn in exon 6 of the PAX6 gene in the proband. The variant is also present in the affected mother and affected brother; it is absent in an unaffected brother. The clinical findings of these three relatives, in conjunction with their genetic testing and the associated PAX6 features reported in the literature, suggest that this novel familial variant may be an underlying etiology for these individuals' ophthalmologic, pancreatic, and olfactory symptoms.

P–551 Blastocyst cohort size is not associated with embryo aneuploidy: comprehensive multi-centre data from current preimplantation genetic testing cycles

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
R Vassena ◽  
A Lorenzon ◽  
A L Lopes ◽  
D Sakkas ◽  
A Korkidakis ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Maternal Age ◽  
Age Groups ◽  
Ovarian Response ◽  
Cohort Size ◽  
Preimplantation Genetic Testing ◽  
Indirect Measure ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Euploid Embryo

Abstract Study question Does blastocyst cohort size impact aneuploidy rates, evaluated by next generation sequencing (NGS)? Summary answer Embryo aneuploidy rates were independent of blastocyst cohort size across all patient ages. What is known already The effects of ovarian response on oocyte and embryo quality remain controversial. Several studies have proposed that a high response to ovarian stimulation may negatively impact oocyte competence. Alternatively, irrespective of maternal age, a poor ovarian response may potentially compromise embryo quality. Using blastocyst cohort size as an indirect measure of ovarian response, previous studies applying array comparative genomic hybridisation (aCGH) have demonstrated that the number of embryos available for biopsy does not impact embryo aneuploidy rates. Nevertheless, these findings remain to be confirmed in a comprehensive cohort, using current approaches for preimplantation genetic testing for aneuploidies (PGT-A). Study design, size, duration Retrospective, international, cohort study of 3998 patients from 16 clinics undergoing PGT-A from 2016–2020. We evaluated 11665 blastocysts, tested using trophectoderm (TE) biopsy and next generation sequencing (NGS). To eliminate bias of multiple treatments, we considered only the first PGT-A cycle for all patients. Both autologous and donation cycles were included in the analysis. Cycles were excluded if they utilised preimplantation genetic testing for monogenic disorders (PGT-M) or preimplantation genetic testing for structural rearrangements (PGT-SR). Participants/materials, setting, methods We evaluated aneuploidy and mosaicism rates, as well as the proportion of patients who had at least one euploid embryo suitable for transfer. Findings were stratified according to SART-defined maternal age groups, <35 (n = 698/2622 patients/blastocysts), 35–37 (n = 988/3141 patients/blastoycsts), 38–40 (n = 1447/3939 patients/blastocysts), 41–42 (653/1562 patients/blastocysts) and >42 (212/401 patients/blastocysts) and blastoycst cohort size (1–2, 3–5, 6–9 and 10 or more biopsied blastocysts). Main results and the role of chance The mean maternal age was 37.0±3.7. The overall embryo aneuploidy rate was 50.6% (5904/11665), while mosaicism was established in 4.0% (469/11665) of blastocysts. As expected, the proportion of aneuploid embryos increased steadily with advancing maternal age (31.8%, 41.5%, 58.4%, 71.2%, 87.8%; p < 0.0001), while mosaicism rates did not vary significantly (p = 0.2). Within each age group, we observed no association between the number of blastocysts biopsied and aneuploidy or mosaicism rates. However, as previously suggested, the chance of having at least one euploid embryo increased linearly with the number of embryos biopsied. We observed that young patients (<35) with 1–2 blastocysts had a 70.4% of having at least one embryo suitable for transfer, which increased to 96.4% and 99.2% with 3–5 and 6–9 blastocysts, respectively. Similar trends were observed in the 36–38 and 39–40 age groups. Patients in the 40–41 age group had a significantly lower chance of having a suitable embryo for transfer. Nevertheless, the chance increased from 27.2% with 1–2 embryos to 61.2% with 3–5 blastocysts. Patients with >10 embryos had at least one euploid embryo in 100% of cases, across all ages. Albeit, the numbers of patients within this category was low, and decreased significantly with advancing maternal age. Limitations, reasons for caution While blastocyst cohort size is considered to be an indirect measure of ovarian reserve, the number of oocytes retrieved was not evaluated. Our study only included the first PGT-A cycle for all patients. Subsequent, alterations in stimulation protocols may have resulted in an improved response in some patients. Wider implications of the findings: The comprehensive nature of the study, based on current PGT-A approaches and a large number of cycles across 16 centres increases clinical confidence in the notion that ovarian response is independent of embryo aneuploidy. Importantly, our findings may serve as a valuable clinical resource to guide patient counselling strategies. Trial registration number NA

scholarly journals Applications of Next Generation Sequencing to the Analysis of Familial Breast/Ovarian Cancer

2020 ◽  
Vol 9 (1) ◽  
pp. 1
Author(s):  
Veronica Zelli ◽  
Chiara Compagnoni ◽  
Katia Cannita ◽  
Roberta Capelli ◽  
Carlo Capalbo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Next Generation Sequencing ◽  
Next Generation ◽  
Brca1 And Brca2 ◽  
Familial Predisposition ◽  
Cancer Pathogenesis ◽  
Or Gene ◽  
Gene Panels ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Next generation sequencing (NGS) provides a powerful tool in the field of medical genetics, allowing one to perform multi-gene analysis and to sequence entire exomes (WES), transcriptomes or genomes (WGS). The generated high-throughput data are particularly suitable for enhancing the understanding of the genetic bases of complex, multi-gene diseases, such as cancer. Among the various types of tumors, those with a familial predisposition are of great interest for the isolation of novel genes or gene variants, detectable at the germline level and involved in cancer pathogenesis. The identification of novel genetic factors would have great translational value, helping clinicians in defining risk and prevention strategies. In this regard, it is known that the majority of breast/ovarian cases with familial predisposition, lacking variants in the highly penetrant BRCA1 and BRCA2 genes (non-BRCA), remains unexplained, although several less penetrant genes (e.g., ATM, PALB2) have been identified. In this scenario, NGS technologies offer a powerful tool for the discovery of novel factors involved in familial breast/ovarian cancer. In this review, we summarize and discuss the state of the art applications of NGS gene panels, WES and WGS in the context of familial breast/ovarian cancer.

scholarly journals Next-Generation Sequencing Improves Diagnosis, Prognosis and Clinical Management of Myeloid Neoplasms

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1364 ◽  
Author(s):  
Diego Carbonell ◽  
Julia Suárez-González ◽  
María Chicano ◽  
Cristina Andrés-Zayas ◽  
Juan Carlos Triviño ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Copy Number Variants ◽  
Genetic Alterations ◽  
Next Generation ◽  
Pathogenic Variants ◽  
Myeloid Neoplasms ◽  
Diagnostic Samples ◽  
Gene Panels ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Molecular diagnosis of myeloid neoplasms (MN) is based on the detection of multiple genetic alterations using various techniques. Next-generation sequencing (NGS) has been proved as a useful method for analyzing many genes simultaneously. In this context, we analyzed diagnostic samples from 121 patients affected by MN and ten relapse samples from a subset of acute myeloid leukemia patients using two enrichment-capture NGS gene panels. Pathogenicity classification of variants was enhanced by the development and application of a custom onco-hematology score. A total of 278 pathogenic variants were detected in 84% of patients. For structural alterations, 82% of those identified by cytogenetics were detected by NGS, 25 of 31 copy number variants and three out of three translocations. The detection of variants using NGS changed the diagnosis of seven patients and the prognosis of 15 patients and enabled us to identify 44 suitable candidates for clinical trials. Regarding AML, six of the ten relapsed patients lost or gained variants, comparing with diagnostic samples. In conclusion, the use of NGS panels in MN improves genetic characterization of the disease compared with conventional methods, thus demonstrating its potential clinical utility in routine clinical testing. This approach leads to better-adjusted treatments for each patient.

scholarly journals Primary hyperparathyroidism in young patients in Russia: high frequency of hyperparathyroidism-jaw tumor syndrome

2017 ◽  
Vol 6 (8) ◽  
pp. 557-565 ◽  
Author(s):  
Elizaveta Mamedova ◽  
Natalya Mokrysheva ◽  
Evgeny Vasilyev ◽  
Vasily Petrov ◽  
Ekaterina Pigarova ◽  
...  
Keyword(s):  
Primary Hyperparathyroidism ◽  
High Frequency ◽  
Multiple Endocrine Neoplasia Type ◽  
Young Patients ◽  
Parathyroid Adenomas ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Germline Sequence ◽  
Dependent Probe

Background Primary hyperparathyroidism (PHPT) is a relatively rare disorder among children, adolescents and young adults. Its development at an early age is suspicious for hereditary causes, though the need for routine genetic testing remains controversial. Objective To identify and describe hereditary forms of PHPT in patients with manifestation of the disease under 40 years of age. Design We enrolled 65 patients with PHPT diagnosed before 40 years of age. Ten of them had MEN1 mutation, and PHPT in them was the first manifestation of multiple endocrine neoplasia type 1 syndrome. Methods The other fifty-five patients underwent next-generation sequencing (NGS) of a custom-designed panel of genes, associated with PHPT (MEN1, CASR, CDC73, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2C, CDKN2D). In cases suspicious for gross CDC73 deletions multiplex ligation-dependent probe amplification was performed. Results NGS revealed six pathogenic or likely pathogenic germline sequence variants: four in CDC73 c.271C>T (p.Arg91*), c.496C>T (p.Gln166*), c.685A>T (p.Arg229*) and c.787C>T (p.Arg263Cys); one in CASR c.3145G>T (p.Glu1049*) and one in MEN1 c.784-9G>A. In two patients, MLPA confirmed gross CDC73 deletions. In total, 44 sporadic and 21 hereditary PHPT cases were identified. Parathyroid carcinomas and atypical parathyroid adenomas were present in 8/65 of young patients, in whom CDC73 mutations were found in 5/8. Conclusions Hereditary forms of PHPT can be identified in up to 1/3 of young patients with manifestation of the disease at <40 years of age. Parathyroid carcinomas or atypical parathyroid adenomas in young patients are frequently associated with CDC73 mutations.

scholarly journals Is the $1000 Genome as Near as We Think? A Cost Analysis of Next-Generation Sequencing

2016 ◽  
Vol 62 (11) ◽  
pp. 1458-1464 ◽  
Author(s):  
Kirsten J M van Nimwegen ◽  
Ronald A van Soest ◽  
Joris A Veltman ◽  
Marcel R Nelen ◽  
Gert Jan van der Wilt ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Sensitivity Analyses ◽  
Clinical Settings ◽  
Next Generation ◽  
Capital Costs ◽  
Whole Exome ◽  
Cost Calculations ◽  
Gene Panels ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Abstract BACKGROUND The substantial technological advancements in next-generation sequencing (NGS), combined with dropping costs, have allowed for a swift diffusion of NGS applications in clinical settings. Although several commercial parties report to have broken the $1000 barrier for sequencing an entire human genome, a valid cost overview for NGS is currently lacking. This study provides a complete, transparent and up-to-date overview of the total costs of different NGS applications. METHODS Cost calculations for targeted gene panels (TGP), whole exome sequencing (WES) and whole genome sequencing (WGS) were based on the Illumina NextSeq500, HiSeq4000, and HiSeqX5 platforms, respectively. To anticipate future developments, sensitivity analyses are performed. RESULTS Per-sample costs were €1669 for WGS, € 792 for WES and €333 for TGP. To reach the coveted $1000 genome, not only is the long-term and efficient use of the sequencing equipment needed, but also large reductions in capital costs and especially consumable costs are also required. CONCLUSIONS WES and TGP are considerably lower-cost alternatives to WGS. However, this does not imply that these NGS approaches should be preferred in clinical practice, since this should be based on the tradeoff between costs and the expected clinical utility of the approach chosen. The results of the present study contribute to the evaluation of such tradeoffs.

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