scholarly journals Genetic predisposition to neural crest-derived tumors: revisiting the role of KIF1B

2020 ◽  
Vol 9 (10) ◽  
pp. 1042-1050
Author(s):  
Catherine Cardot Bauters ◽  
Emmanuelle Leteurtre ◽  
Bruno Carnaille ◽  
Christine Do Cao ◽  
Stéphanie Espiard ◽  
...  
Keyword(s):  
Germline Variant ◽  
Whole Exome ◽  
Familial Cancers ◽  
Heterozygous Variant ◽  
Unknown Significance ◽  
Next Generation Sequencing Ngs ◽  
Design And Methods ◽  
Generation Sequencing

Objective We previously described a family in which predisposition to pheochromocytoma (PCC) segregates with a germline heterozygous KIF1B nucleotide variant (c.4442G>A, p.Ser1481Asn) in three generations. During the clinical follow-up, one proband’s brother, negative for the KIF1B nucleotide variant, developed a bilateral PCC at 31 years. This prompted us to reconsider the genetic analysis. Design and methods Germline DNA was analyzed by next-generation sequencing (NGS) using a multi-gene panel plus MLPA or by whole exome sequencing (WES). Tumor-derived DNA was analyzed by SnapShot, Sanger sequencing or NGS to identify loss-of-heterozygosity (LOH) or additional somatic mutations. Results A germline heterozygous variant of unknown significance in MAX (c.145T>C, p.Ser49Pro) was identified in the proband’s brother. Loss of the wild-type MAX allele occurred in his PCCs thus demonstrating that this variant was responsible for the bilateral PCC in this patient. The proband and her affected grandfather also carried the MAX variant but no second hit could be found at the somatic level. No other pathogenic mutations were detected in 36 genes predisposing to familial PCC/PGL or familial cancers by WES of the proband germline. Germline variants detected in other genes, TFAP2E and TMEM214, may contribute to the multiple tumors of the proband. Conclusion In this family, the heritability of PCC is linked to the MAX germline variant and not to the KIF1B germline variant which, however, may have contributed to the occurrence of neuroblastoma (NB) in the proband.

scholarly journals Next-generation sequencing approach to hyperCKemia

2019 ◽  
Vol 5 (5) ◽  
pp. e352 ◽  
Author(s):  
Anna Rubegni ◽  
Alessandro Malandrini ◽  
Claudia Dosi ◽  
Guja Astrea ◽  
Jacopo Baldacci ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Molecular Diagnosis ◽  
Diagnostic Yield ◽  
Clinical Neurology ◽  
Next Generation ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

ObjectiveNext-generation sequencing (NGS) was applied in molecularly undiagnosed asymptomatic or paucisymptomatic hyperCKemia to investigate whether this technique might allow detection of the genetic basis of the condition.MethodsSixty-six patients with undiagnosed asymptomatic or paucisymptomatic hyperCKemia, referred to tertiary neuromuscular centers over an approximately 2-year period, were analyzed using a customized, targeted sequencing panel able to investigate the coding exons and flanking intronic regions of 78 genes associated with limb-girdle muscular dystrophies, rhabdomyolysis, and metabolic and distal myopathies.ResultsA molecular diagnosis was reached in 33 cases, corresponding to a positive diagnostic yield of 50%. Variants of unknown significance were found in 17 patients (26%), whereas 16 cases (24%) remained molecularly undefined. The major features of the diagnosed cases were mild proximal muscle weakness (found in 27%) and myalgia (in 24%). Fourteen patients with a molecular diagnosis and mild myopathic features on muscle biopsy remained asymptomatic at a 24-month follow-up.ConclusionsThis study of patients with undiagnosed hyperCKemia, highlighting the advantages of NGS used as a first-tier diagnostic approach in genetically heterogeneous conditions, illustrates the ongoing evolution of molecular diagnosis in the field of clinical neurology. Isolated hyperCKemia can be the sole feature alerting to a progressive muscular disorder requiring careful surveillance.

scholarly journals CSF3R T618I, SETBP1 G870S, SRSF2 P95H, and ASXL1 Q780* tetramutation co-contribute to myeloblast transformation in a chronic neutrophilic leukemia

2021 ◽  
Author(s):  
Yi Qian ◽  
Yan Chen ◽  
Xiaoming Li
Keyword(s):  
Alpha Interferon ◽  
Past Medical History ◽  
Variant Allele Frequency ◽  
Significant Past Medical History ◽  
Chronic Neutrophilic Leukemia ◽  
Hypercellular Marrow ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Stat Pathway

AbstractChronic neutrophilic leukemia (CNL) is a rare but serious myeloid malignancy. In a review of reported cases for WHO-defined CNL, CSF3R mutation is found in about 90% cases and confirmed as the molecular basis of CNL. Concurrent mutations are observed in CSF3R-mutated CNL patients, including ASXL1, SETBP1, SRSF2, JAK2, CALR, TET2, NRAS, U2AF1, and CBL. Both ASXL1 and SETBP1 mutations in CNL have been associated with a poor prognosis, whereas, SRSF2 mutation was undetermined. Our patient was a 77-year-old man and had no significant past medical history and symptoms with leukocytosis. Bone marrow (BM) aspirate and biopsy revealed a markedly hypercellular marrow with prominent left-shifted granulopoiesis. Next-generation sequencing (NGS) of DNA from the BM aspirate of a panel of 28 genes, known to be pathogenic in MDS/MPN, detected mutations in CSF3R, SETBP1, and SRSF2, and a diagnosis of CNL was made. The patient did not use a JAK-STAT pathway inhibitor (ruxolitinib) but started on hydroxyurea and alpha-interferon and developed pruritus after 4 months of diagnosis and nasal hemorrhage 1 month later. Then, the patient was diagnosed with CNL with AML transformation and developed intracranial hemorrhage and died. We repeated NGS and found that three additional mutations were detected: ASXL1, PRKDC, MYOM2; variant allele frequency (VAF) of the prior mutations in CSF3R, SETBP1, and SRSF2 increased. The concurrence of CSF3RT618I, ASXL1, SETBP1, and SRSF2 mutation may be a mutationally detrimental combination and contribute to disease progression and AML transformation, as well as the nonspecific treatment of hydroxyurea and alpha-interferon, but the significance and role of PRKDC and MYOM2 mutations were not undetermined.

scholarly journals Tubuloglomerular Disease With Cone-Shaped Epiphyses Associated With Hypomorphic Variant and a Novel p.Cys14Arg in the TTC21B Gene: A Case Report

2021 ◽  
Vol 9 ◽  
Author(s):  
Martin Bezdíčka ◽  
Dana Zemková ◽  
Sylva Skálová ◽  
Eva Hovorková ◽  
Miroslav Podhola ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Kidney Development ◽  
Kidney Biopsy ◽  
Intraflagellar Transport ◽  
X Ray ◽  
Heterozygous Variant ◽  
Renal Tubular ◽  
Nephrotic Range Proteinuria ◽  
Generation Sequencing

Monogenic nephrotic syndrome (NS) is associated with a resistance to initial glucocorticoid therapy and causative variants, which may be found in several genes influencing podocyte stability and kidney development. The TTC21B gene, which encodes the retrograde intraflagellar transport protein IFT139, is found mostly in association with ciliopathies in humans. The role of this protein in podocyte cytoskeleton stability was confirmed later and the mutated TTC21B also may be associated with proteinuric diseases, such as nephrotic syndrome. Our patient manifested as an infant with brachydactyly, nephrotic-range proteinuria, and renal tubular acidosis, and a kidney biopsy revealed focal segmental glomerulosclerosis (FSGS). Multiple phalangeal cone-shaped epiphyses of the hand were seen on X-ray. Next-generation sequencing revealed the well-described p.Pro209Leu heterozygous variant and a novel heterozygous p.Cys14Arg variant in the TTC21B gene. Our finding confirmed that the causative variants in the TTC21B gene may contribute to a spectrum of clinical features, such as glomerular proteinuric disease with tubulointerstitial involvement and skeletal abnormalities.

scholarly journals Profibrotic circulating proteins and risk of early progressive renal decline in Type 2 Diabetes patients with and without albuminuria

2020 ◽  
Author(s):  
Katsuhito Ihara ◽  
Jan Skupien ◽  
Hiroki Kobayashi ◽  
Zaipul I. Md Dom ◽  
Jonathan M. Wilson ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Core Domain ◽  
Fibrotic Process ◽  
Baseline Levels ◽  
Design And Methods ◽  
Circulating Levels ◽  
Index Combination

<b>OBJECTIVE</b>: The role of fibrosis in early progressive renal decline in type 2 diabetes is unknown. Circulating WFDC2 (WAP four-disulfide core domain protein 2) and MMP-7 (Matrilysin) are postulated to be biomarkers of renal fibrosis. This study examined an association of circulating levels of these proteins with early progressive renal decline. <p><b>RESEARCH DESIGN AND METHODS</b>: Individuals with type 2 diabetes enrolled in the Joslin Kidney Study with eGFR ≥60 ml/min/1.73m<sup>2</sup> were followed for 6-12 years to ascertain fast early progressive renal decline defined as eGFR loss ≥5 ml/min/1.73m<sup>2</sup>/year. </p> <p><b>RESULTS</b>: A total of 1,181 individuals were studied: 681 without and 500 with albuminuria. Median eGFR and ACR at baseline were 97 ml/min/1.73m<sup>2</sup> and 24 mg/g, respectively. During follow-up, 152 individuals experienced fast early progressive renal decline: 6.9% in those with normoalbuminuria and 21% with albuminuria. In both subgroups risk of renal decline increased with increasing baseline levels of WFDC2 (p <0.0001) and MMP-7 (p <0.0001). After adjustment for relevant clinical characteristics and known biomarkers, an increase by one quartile in the Fibrosis Index (combination of levels of WFDC2 and MMP-7) was associated with higher risk of renal decline (OR 1.63; 95% CI 1.30-2.04). The association was similar and statistically significant among patients with and without albuminuria. </p> <p><b>CONCLUSIONS: </b>Elevation of circulating profibrotic proteins is associated with the development of early progressive renal decline in type 2 diabetes. This association is independent from albuminuria status and points to the importance of the fibrotic process in development of early renal decline. </p>

scholarly journals Methylmalonic Acidemia with Novel MUT Gene Mutations

2017 ◽  
Vol 2017 ◽  
pp. 1-2
Author(s):  
Inusha Panigrahi ◽  
Savita Bhunwal ◽  
Harish Varma ◽  
Simranjeet Singh
Keyword(s):  
Sanger Sequencing ◽  
Gene Mutations ◽  
Methylmalonic Acidemia ◽  
Feeding Problems ◽  
Novel Variants ◽  
Mut Gene ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Poor Weight Gain

A 5-year-old boy presented with recurrent episodes of fever, feeding problems, lethargy, from the age of 11 months, and poor weight gain. He was admitted and evaluated for metabolic causes and diagnosed as having methylmalonic acidemia (MMA). He was treated with vit B12 and carnitine supplements and has been on follow-up for the last 3 years. Mutation analysis by next generation sequencing (NGS), supplemented with Sanger sequencing, revealed two novel variants in the MUT gene responsible for MMA in exon 5 and exon 3, respectively. Recently he developed dystonic movements including orofacial dyskinesia. With advent of NGS, judicious use of NGS with Sanger sequencing can help identify causative possibly pathogenic mutations.

Role of Ancillary Techniques in Biliary Cytopathology Specimens

2019 ◽  
Vol 64 (1-2) ◽  
pp. 175-181 ◽  
Author(s):  
Lester Layfield
Keyword(s):  
Mutational Analysis ◽  
Diagnostic Sensitivity ◽  
Individual Gene ◽  
Duct Systems ◽  
Brushing Cytology ◽  
Standard Of Practice ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Biliary brushing cytology has become the standard of practice for the investigation of strictures of the biliary and pancreatic duct systems. The methodology however has a limitation in that it has low diagnostic sensitivity when only cytologic evaluation is used. A number of testing methodologies have been applied to brushing specimens in an attempt to improve overall sensitivity without loss of specificity. These have included DNA ploidy analysis, immunocytochemistry, individual gene mutational analysis, fluorescence in-situ hybridization (FISH), and next generation sequencing (NGS). Currently, FISH coupled with routine cytology appears to be the method of choice for improving diagnostic sensitivity. NGS shows significant promise for improvement of diagnostic sensitivity.

scholarly journals Next Generation Sequencing Identifies Five Novel Mutations in Lebanese Patients with Bardet–Biedl and Usher Syndromes

Genes ◽  
2019 ◽  
Vol 10 (12) ◽  
pp. 1047 ◽  
Author(s):  
Lama Jaffal ◽  
Wissam H Joumaa ◽  
Alexandre Assi ◽  
Charles Helou ◽  
George Cherfan ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Usher Syndrome ◽  
Bioinformatic Analysis ◽  
Next Generation ◽  
Novel Mutations ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Targeted Ngs ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Aim: To identify disease-causing mutations in four Lebanese families: three families with Bardet–Biedl and one family with Usher syndrome (BBS and USH respectively), using next generation sequencing (NGS). Methods: We applied targeted NGS in two families and whole exome sequencing (WES) in two other families. Pathogenicity of candidate mutations was evaluated according to frequency, conservation, in silico prediction tools, segregation with disease, and compatibility with inheritance pattern. The presence of pathogenic variants was confirmed via Sanger sequencing followed by segregation analysis. Results: Most likely disease-causing mutations were identified in all included patients. In BBS patients, we found (M1): c.2258A > T, p. (Glu753Val) in BBS9, (M2): c.68T > C; p. (Leu23Pro) in ARL6, (M3): c.265_266delTT; p. (Leu89Valfs*11) and (M4): c.880T > G; p. (Tyr294Asp) in BBS12. A previously known variant (M5): c.551A > G; p. (Asp184Ser) was also detected in BBS5. In the USH patient, we found (M6): c.188A > C, p. (Tyr63Ser) in CLRN1. M2, M3, M4, and M6 were novel. All of the candidate mutations were shown to be likely disease-causing through our bioinformatic analysis. They also segregated with the corresponding phenotype in available family members. Conclusion: This study expanded the mutational spectrum and showed the genetic diversity of BBS and USH. It also spotlighted the efficiency of NGS techniques in revealing mutations underlying clinically and genetically heterogeneous disorders.

X-Linked Hyper IgM Syndrome Manifesting as Recurrent Pneumocystis jirovecii Pneumonia: A Case Report

2020 ◽  
Vol 66 (6) ◽  
pp. 648-654
Author(s):  
Sai Hu Huang ◽  
Xiang Ying Meng ◽  
Zhen Jiang Bai ◽  
Ying Li ◽  
Shui Yan Wu
Keyword(s):  
Severe Pneumonia ◽  
Pneumocystis Jirovecii ◽  
Pneumocystis Jirovecii Pneumonia ◽  
Whole Exome ◽  
Hyper Igm ◽  
Reading Counts ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Exon 10 ◽  
Gene Exon

Abstract We reported a Chinese boy with X-linked hyper IgM (XHIGM) syndrome, manifesting as recurrent and severe pneumonia caused by Pneumocystis jirovecii. His parents were healthy and unrelated. In August 2018, the 5-month-old boy manifested as cough and dyspnea, and then in July 2019, he was admitted because of the same symptoms. Immunological results of the two admissions both showed low IgG, low IgA, normal IgM and high levels of 1,3-β-D-glucan (BDG). Using next-generation sequencing (NGS), great reading counts of P. jirovecii were identified from the deep sputum in both admissions. Caspofungin combined with trimethoprim-sulfamethoxazole were used to anti-infection, and he recovered quickly. Whole-exome sequencing was performed for this family because of immune suppression, the disease-causing gene (exon 10–22 of CD40L) deletion for XHIGM syndrome was identified. NGS is beneficial for etiology diagnosis. Pneumocystis jirovecii pneumonia as an opportunistic infection could be recurrent in patients with XHIGM syndrome.

scholarly journals Whole-exome sequencing and its impact in hereditary hearing loss

2015 ◽  
Vol 97 ◽  
Author(s):  
TAHIR ATIK ◽  
GUNEY BADEMCI ◽  
OSCAR DIAZ-HORTA ◽  
SUSAN H. BLANTON ◽  
MUSTAFA TEKIN
Keyword(s):  
Hearing Loss ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Hereditary Deafness ◽  
Whole Exome ◽  
Human Genes ◽  
Genetic Revolution ◽  
Recent Developments ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

SummaryNext-generation sequencing (NGS) technologies have played a central role in the genetic revolution. These technologies, especially whole-exome sequencing, have become the primary tool of geneticists to identify the causative DNA variants in Mendelian disorders, including hereditary deafness. Current research estimates that 1% of all human genes have a function in hearing. To date, mutations in over 80 genes have been reported to cause nonsyndromic hearing loss (NSHL). Strikingly, more than a quarter of all known genes related to NSHL were discovered in the past 5 years via NGS technologies. In this article, we review recent developments in the usage of NGS for hereditary deafness, with an emphasis on whole-exome sequencing.

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