scholarly journals Pheochromocytoma due to a novel SDHD variant presenting as unilateral visual loss

2021 ◽  
Vol 2021 ◽  
Author(s):  
Clare Miller ◽  
Agnieszka Pazderska ◽  
John Reynolds ◽  
Patricia Gou ◽  
Barbara Dunne ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Organ Damage ◽  
Secondary Hypertension ◽  
Cystoid Macular Oedema ◽  
List Type ◽  
Next Generation ◽  
Novel Variants ◽  
High Heritability ◽  
Learning Points ◽  
Generation Sequencing

Summary A 53-year-old female presented to a tertiary ophthalmology referral centre complaining of unilateral painless loss of vision. Subsequent assessment revealed malignant hypertension causing right-sided cystoid macular oedema. During the course of secondary hypertension workup, she was diagnosed with a 7.8 cm phaeochromocytoma which was resected. Testing for a panel of all predisposing phaeochromocytoma-causing variants using next-generation sequencing resulted in the diagnosis of a novel SDHD variant. Learning points Screening for secondary causes of hypertension is indicated when there is evidence of hypertension-mediated end-organ damage (1). Testing for a predisposing variant should be considered in all patients with phaeochromocytoma or paraganglioma due to the high heritability rate and prevalence of somatic variants (2, 3, 4). Novel variants are commonly uncovered in the Succinate Dehydrogenase (SDH) subunit; proving pathogenicity is a complex, time-consuming process and one challenge of next-generation sequencing (3). SDHB immunohistochemistry as a tool for demonstrating pathogenicity is associated with reduced sensitivity when assessing SDHD variants (5, 6).

scholarly journals Next-generation sequencing reveals three novel variants in Polish patients with Usher syndrome

Klinika Oczna ◽  
2018 ◽  
Vol 2018 (4) ◽  
pp. 189-194
Author(s):  
Anna Wawrocka ◽  
Joanna Walczak-Sztulpa ◽  
Anna Skorczyk-Werner ◽  
Łukasz Kuszel ◽  
Magdalena Socha ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Usher Syndrome ◽  
Next Generation ◽  
Novel Variants ◽  
Generation Sequencing

Molecular genetic diagnosis by next-generation sequencing in a cohort of Mexican patients with haemophilia and report of novel variants

2020 ◽  
Vol 83 ◽  
pp. 102423 ◽  
Author(s):  
Laura Villarreal-Martínez ◽  
Marisol Ibarra-Ramirez ◽  
Geovana Calvo-Anguiano ◽  
José de Jesús Lugo-Trampe ◽  
Hilda Luna-Záizar ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Next Generation ◽  
Novel Variants ◽  
Molecular Genetic Diagnosis ◽  
Generation Sequencing ◽  
Mexican Patients

scholarly journals A universal primer-independent next-generation sequencing approach for investigations of norovirus outbreaks and novel variants

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Jannik Fonager ◽  
Marc Stegger ◽  
Lasse Dam Rasmussen ◽  
Mille Weismann Poulsen ◽  
Jesper Rønn ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Next Generation ◽  
Universal Primer ◽  
Novel Variants ◽  
Generation Sequencing

scholarly journals αIIbβ3 variants defined by next-generation sequencing: Predicting variants likely to cause Glanzmann thrombasthenia

2015 ◽  
Vol 112 (15) ◽  
pp. E1898-E1907 ◽  
Author(s):  
Lorena Buitrago ◽  
Augusto Rendon ◽  
Yupu Liang ◽  
Ilenia Simeoni ◽  
Ana Negri ◽  
...  
Keyword(s):  
Amino Acids ◽  
Next Generation Sequencing ◽  
Hek293 Cells ◽  
Next Generation ◽  
Glanzmann Thrombasthenia ◽  
Missense Variants ◽  
Sorting Intolerant From Tolerant ◽  
Fibrinogen Binding ◽  
Novel Variants ◽  
Generation Sequencing

Next-generation sequencing is transforming our understanding of human genetic variation but assessing the functional impact of novel variants presents challenges. We analyzed missense variants in the integrin αIIbβ3 receptor subunit genes ITGA2B and ITGB3 identified by whole-exome or -genome sequencing in the ThromboGenomics project, comprising ∼32,000 alleles from 16,108 individuals. We analyzed the results in comparison with 111 missense variants in these genes previously reported as being associated with Glanzmann thrombasthenia (GT), 20 associated with alloimmune thrombocytopenia, and 5 associated with aniso/macrothrombocytopenia. We identified 114 novel missense variants in ITGA2B (affecting ∼11% of the amino acids) and 68 novel missense variants in ITGB3 (affecting ∼9% of the amino acids). Of the variants, 96% had minor allele frequencies (MAF) < 0.1%, indicating their rarity. Based on sequence conservation, MAF, and location on a complete model of αIIbβ3, we selected three novel variants that affect amino acids previously associated with GT for expression in HEK293 cells. αIIb P176H and β3 C547G severely reduced αIIbβ3 expression, whereas αIIb P943A partially reduced αIIbβ3 expression and had no effect on fibrinogen binding. We used receiver operating characteristic curves of combined annotation-dependent depletion, Polyphen 2-HDIV, and sorting intolerant from tolerant to estimate the percentage of novel variants likely to be deleterious. At optimal cut-off values, which had 69–98% sensitivity in detecting GT mutations, between 27% and 71% of the novel αIIb or β3 missense variants were predicted to be deleterious. Our data have implications for understanding the evolutionary pressure on αIIbβ3 and highlight the challenges in predicting the clinical significance of novel missense variants.

scholarly journals 112 Axonal polyneuropathy with onset in young adulthood due to TUBB3 mutation

2019 ◽  
Vol 90 (e7) ◽  
pp. A36.2-A36
Author(s):  
Po Sheng Yang ◽  
Kimberley K Forrest ◽  
Ian B Wilson
Keyword(s):  
Next Generation Sequencing ◽  
Axonal Neuropathy ◽  
Extraocular Muscles ◽  
Diagnostic Process ◽  
List Type ◽  
Next Generation ◽  
Sensorimotor Polyneuropathy ◽  
Axonal Polyneuropathy ◽  
Congenital Fibrosis ◽  
Generation Sequencing

IntroductionThe TUBB3 gene encodes the protein Beta-tubulin isotype III, a component of the microtubule cytoskeleton. Mutations in this gene have been associated with axonal polyneuropathy, however usually associated with congenital fibrosis of the extraocular muscles (CFOEM) and other abnormalities of cerebral development.1 2 We report a case of isolated neuropathy associated with a TUBB3 mutation.MethodsCase report - clinical information and next generation sequencing results were obtained.ResultsA 64 year old man presented with a severe, progressive, length dependent sensorimotor polyneuropathy which commenced in his late twenties. There was no clinical involvement of the extraocular muscles and cognition was normal. Family history was limited, but there were no other members affected.The patient had previously been extensively investigated including sural nerve biopsy, which confirmed axonal neuropathy without a specific diagnosis. Intravenous immunoglobulins and steroids had been trialled without benefit.A neuromuscular gene panel utilising next generation sequencing was performed and demonstrated heterozygosity for a variant of the TUBB3 gene (D417N substitution).Case series describing TUBB3 mutations show a large heterogeneity in phenotypic expression depending on the amino acid substitution.2–4 There is also heterogeneity in patients with D417N mutations, although a small number have been reported to develop a polyneuropathy without CFOEM1.ConclusionsThis case strengthens previous reports that TUBB3 mutation can be associated with a pure, axonal, sensorimotor polyneuropathy and highlights the use of next generation sequencing in streamlining the diagnostic process.ReferenceTischfield M, et al. Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. Cell 2010;140(1):pp.74–87.Ncbi.nlm.nih.gov. (2019). Congenital fibrosis of the extraocular muscles - Conditions - GTR - NCBI. [online] Available at: https://www.ncbi.nlm.nih.gov/gtr/conditions/CN043677/ [Accessed 14 Feb. 2019].Omim.org. (2019). OMIM Entry - * 602661 - TUBULIN, BETA-3; TUBB3. [online] Available at: https://www.omim.org/entry/602661 [Accessed 14 Feb. 2019].Krupa, K. and Bekiesinska-Figatowska, M. (2013). Congenital and Acquired Abnormalities of the Corpus Callosum: A Pictorial Essay. BioMed Research International, 2013, pp.1–14.

The utility of next-generation sequencing technologies in diagnosis of Mendelian mitochondrial diseases and reflections on clinical spectrum

2021 ◽  
Vol 34 (4) ◽  
pp. 417-430
Author(s):  
Melis Kose ◽  
Esra Isik ◽  
Ayça Aykut ◽  
Asude Durmaz ◽  
Engin Kose ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Exome Sequencing ◽  
Diagnostic Process ◽  
Unknown Etiology ◽  
Next Generation ◽  
Related Gene ◽  
Targeted Exome Sequencing ◽  
Novel Variants ◽  
Gene Defects ◽  
Generation Sequencing

Abstract Objectives Diagnostic process of mitochondrial disorders (MD) is challenging because of the clinical variability and genetic heterogeneity of these conditions. Next-Generation Sequencing (NGS) technology offers a high-throughput platform for nuclear MD. Methods We included 59 of 72 patients that undergone WES and targeted exome sequencing panel suspected to have potential PMDs. Patients who were included in the analysis considering the possible PMD were reviewed retrospectively and scored according to the Mitochondrial Disease Criteria Scale. Results Sixty-one percent of the patients were diagnosed with whole-exome sequencing (WES) (36/59) and 15% with targeted exome sequencing (TES) (9/59). Patients with MD-related gene defects were included in the mito group, patients without MD-related gene defects were included in the nonmito group, and patients in whom no etiological cause could be identified were included in the unknown etiology group. In 11 out of 36 patients diagnosed with WES, a TES panel was applied prior to WES. In 47 probands in 39 genes (SURF1, SDHAF1, MTO1, FBXL4, SLC25A12, GLRX5, C19oRF12, NDUFAF6, DARS2, BOLA3, SLC19A3, SCO1, HIBCH, PDHA1, PDHAX, PC, ETFA, TRMU, TUFM, NDUFS6, WWOX, UBCD TREX1, ATL1, VAC14, GFAP, PLA2G6, TPRKB, ATP8A2, PEX13, IGHMBP2, LAMB2, LPIN1, GFPT1, CLN5, DOLK) (20 mito group, 19 nonmito group) 59 variants (31 mito group, 18 nonmito group) were detected. Seven novel variants in the mito group (SLC25A12, GLRX5, DARS2, SCO1, PC, ETFA, NDUFS6), nine novel variants in the nonmito group (IVD, GCDH, COG4, VAC14, GFAP, PLA2G6, ATP8A2, PEX13, LPIN1) were detected. Conclusions We explored the feasibility of identifying pathogenic alleles using WES and TES in MD. Our results show that WES is the primary method of choice in the diagnosis of MD until at least all genes responsible for PMD are found and are highly effective in facilitating the diagnosis process.

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