scholarly journals Clinical activity of FOLFIRI plus cetuximab in elderly patients (pts) according to extended gene mutation status by Next Generation Sequencing (NGS) in the CAPRI- GOIM trial

2016 ◽  
Vol 27 ◽  
pp. iv39
Author(s):  
E. Maiello ◽  
E. Martinelli ◽  
C. Cardone ◽  
T. Troiani ◽  
N. Normanno ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Elderly Patients ◽  
Gene Mutation ◽  
Clinical Activity ◽  
Next Generation ◽  
Mutation Status ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

scholarly journals Novel SCNN1A Gene Splicing-site Mutation Causing Autosomal Recessive Pseudohypoaldosteronism type 1 (PHA1) in two Italian Patients Belonging to the Same Small Town

2021 ◽  
Author(s):  
Gregorio Serra ◽  
Vincenzo Antona ◽  
Maria Michela D’Alessandro ◽  
Maria Cristina Maggio ◽  
Vincenzo Verde ◽  
...  
Keyword(s):  
Metabolic Acidosis ◽  
Next Generation Sequencing ◽  
Family History ◽  
Gene Mutation ◽  
Small Town ◽  
Next Generation ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Pseudohypoaldosteronism Type

Abstract IntroductionPseudohypoaldosteronism type 1 (PHA1) is a rare genetic disease due to the peripheral resistance to aldosterone. Its clinical spectrum includes neonatal salt loss syndrome with hyponatremia and hypochloraemia, hyperkalemia, metabolic acidosis and increased plasmatic levels of aldosterone. Two genetically distinct forms of disease, renal and systemic, have been described, showing a wide clinical expressivity. Mutations in the genes encoding for the subunits of the epithelial sodium channels (ENaC) are responsible for generalized PHA1. Patients’ presentationWe hereby report on two Italian patients with generalized PHA1, coming from the same small town in the center of Sicily. The first patient is a male child, born from the first pregnancy of healthy consanguineous Sicilian parents. A novel SCNN1A (sodium channel epithelial subunit alpha) gene mutation, inherited from both heterozygous parents, was identified by next generation sequencing (NGS) in the homozygous child (and later, also in the heterozygous maternal aunt). A more detailed family history disclosed a possible related twenty-year-old girl, belonging to the same Sicilian small town, with referred neonatal salt loss syndrome associated to hyperkalemia, and subsequent normal growth and neurodevelopment. This second patient had a PHA1 clinical diagnosis when she was about one year old. The genetic investigation was, then, extended to her and to her family, revealing the same mutation in the homozygous girl and in the heterozygous parents.ConclusionsThe neonatologist should consider PHA1 diagnosis in newborns showing hyponatremia, hyperkalemia and metabolic acidosis, after the exclusion of a salting-loss form of adrenogenital syndrome. The increased plasmatic levels of aldosterone and aldosterone/renin ratio, associated to a poor response to steroid administration, confirmed the diagnosis in the first present patient. An accurate family history may be decisive to identify the clinical picture. A multidisciplinary approach and close follow-up evaluations are requested, in view of optimal management, adequate growth and development of patients. Next generation sequencing (NGS) techniques allowed the identification of the SCNN1A gene mutation either in both patients or in other heterozygous family members, enabling also primary prevention of disease. Our report may broaden the knowledge of the genetic and molecular bases of PHA1, improving its clinical characterization and providing useful indications for the treatment of patients. Clinical approach must be personalized, also in relation to long-term survival and potential multiorgan complications.

Refining Triage to Polycythaemia Vera or Primary Myelofibrosis Based on Targeted Molecular Profiling By Clinical Next Generation Sequencing

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4076-4076
Author(s):  
Song Jinming ◽  
Mohammad Omar Hussaini ◽  
Haipeng Shao ◽  
Eric Padron ◽  
Jeffrey E Lancet ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Next Generation Sequencing ◽  
Gene Mutation ◽  
Research Funding ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Next Generation ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Potential Biomarkers

Abstract Background: Primary myelofibrosis (PMF) and polycythemia vera (PV) are myeloproliferative neoplasms (MPN) that can both share a similar bone marrow morphology with panmyelosis and fibrosis, posing a diagnostic challenge, particularly when the differential is between cellular phase of PMF and PV, or fibrotic PMF and post-PV myelofibrosis. Despite advances in genomic analysis, limited information is known regarding their differences in genetic profile/signature. It has been well known that constitutive tyrosine kinase activation due to JAK2 V617F mutation is seen in both PV and PMF. MPL and CALR mutations do segregate with PMF but may not be found in all cases. Accordingly, we analyzed next generation sequencing (NGS) data to look for potential biomarkers that may further aid in distinguishing these two entities. Design: The IRB approved study intended to recruit patients with diagnosis of PMF and PV who have myeloid gene mutation profiles available. Clinical information and molecular data from both a CLIA certified reference laboratory and our institution from May 2011 to June 2015 were retrieved. Cases with other myeloid neoplasms were excluded. The gene mutation profiles by Next Generation sequencing (NGS) and conventional karyotyping were acquired and compared. Clinicopathologic features including disease progression, degree of fibrosis in bone marrow, percentage of blasts, bone marrow cellularity, and circulating blood count (CBC) are correlated. Student t-test was used for numerical variables and Chi square (x2) test was used for categorical variables. Results: Of the 62 patients qualified in the study, 36 patients were diagnosed with PMF (Age 68.5 ± 12.2, M:F ratio of 1:1) and 26 patients with PV (Age 66.5 ± 11.9, M:F ratio of 1.6). The majority of patients (34/36 PMF and 26/26 PV) showed persistent disease with only two PMF patients progressing to acute myeloid leukemia (AML). In accordance with prior reports, JAK2 V617F mutation was more prevalent in PV (23/26, 88%) than in PMF (17/36, 47%)(p<0.05), while MPL mutation was found in PMF (5/36, 14%) but not in PV (0/26) (p<0.001). Overall, PMF patients tended to have more non JAK2 mutations (mean = 1.6 ± 1) than PV patients (mean= 0.54 ± 0.65) (p = 0.005), even though the PV patients tended to have a longer history of disease. Interestingly, ASXL1 mutations (mainly frame-shift, reportedly pathologic) appear to be more prevalent in PMF (28%) than in PV (8%) patients (p = 0.058). SRSF2 mutations were found in 14% of PMF patients but absent in all 26 PV patients (p=0.068). Mutations in a subset of other analyzed genes (TET2, EZH2, IDH2, and CUX1) were also more frequent in PMF than in PV patients (25% vs 15%, 8% vs 0%, 8% vs 0%, and 6% vs 0%, respectively), but not statistically significant due to limited number of cases. The highest number of mutations (n=4) was in a case of PMF that progressed to AML, suggesting a 'dosage' effect of driver mutations on outcomes similar to that described in MDS. The other patient that progressed from PMF to AML harbored JAK2, ASXL1, SRSF2 mutations along with del(20q). ASXL1 mutation was associated with del(20q) in 4/62 cases, all of which were PMF patients including the case that has progressed to AML. JAK2 mutation was associated with del(20q) in 7 out of the 62 cases, 6 (86%) of which were PMF patients. No gene mutations were uniquely associated with degree of fibrosis, blast count, cellularity, white blood cell counts, hemoglobin, or platelet counts. Conclusion: Our results indicate that PMF patients tend to have more non JAK2 mutations (e.g., ASXL1, SRSF2) than PV. Furthermore, the mutations, including JAK2 mutations, are more likely to be associated with del(20q) in PMF patients. Our findings provide insight into the genetic landscape of PMF and PV and offer potential biomarkers that may be helpful to distinguish between these entities, thus benefiting patient stratification for clinical practice. Disclosures Lancet: Seattle Genetics: Consultancy; Pfizer: Research Funding; Boehringer-Ingelheim: Consultancy; Kalo-Bios: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Research Funding. Komrokji:Celgene: Consultancy, Research Funding; Incite: Consultancy; Novartis: Speakers Bureau; GSK: Research Funding.

scholarly journals Novel SCNN1A gene splicing-site mutation causing autosomal recessive pseudohypoaldosteronism type 1 (PHA1) in two Italian patients belonging to the same small town

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Gregorio Serra ◽  
Vincenzo Antona ◽  
Maria Michela D’Alessandro ◽  
Maria Cristina Maggio ◽  
Vincenzo Verde ◽  
...  
Keyword(s):  
Metabolic Acidosis ◽  
Next Generation Sequencing ◽  
Family History ◽  
Gene Mutation ◽  
Small Town ◽  
Next Generation ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Pseudohypoaldosteronism Type

Abstract Introduction Pseudohypoaldosteronism type 1 (PHA1) is a rare genetic disease due to the peripheral resistance to aldosterone. Its clinical spectrum includes neonatal salt loss syndrome with hyponatremia and hypochloraemia, hyperkalemia, metabolic acidosis and increased plasmatic levels of aldosterone. Two genetically distinct forms of disease, renal and systemic, have been described, showing a wide clinical expressivity. Mutations in the genes encoding for the subunits of the epithelial sodium channels (ENaC) are responsible for generalized PHA1. Patients’ presentation We hereby report on two Italian patients with generalized PHA1, coming from the same small town in the center of Sicily. The first patient is a male child, born from the first pregnancy of healthy consanguineous Sicilian parents. A novel SCNN1A (sodium channel epithelial subunit alpha) gene mutation, inherited from both heterozygous parents, was identified by next generation sequencing (NGS) in the homozygous child (and later, also in the heterozygous maternal aunt). A more detailed family history disclosed a possible related twenty-year-old girl, belonging to the same Sicilian small town, with referred neonatal salt loss syndrome associated to hyperkalemia, and subsequent normal growth and neurodevelopment. This second patient had a PHA1 clinical diagnosis when she was about 1 year old. The genetic investigation was, then, extended to her and to her family, revealing the same mutation in the homozygous girl and in the heterozygous parents. Conclusions The neonatologist should consider PHA1 diagnosis in newborns showing hyponatremia, hyperkalemia and metabolic acidosis, after the exclusion of a salting-loss form of adrenogenital syndrome. The increased plasmatic levels of aldosterone and aldosterone/renin ratio, associated to a poor response to steroid administration, confirmed the diagnosis in the first present patient. An accurate family history may be decisive to identify the clinical picture. A multidisciplinary approach and close follow-up evaluations are requested, in view of optimal management, adequate growth and development of patients. Next generation sequencing (NGS) techniques allowed the identification of the SCNN1A gene mutation either in both patients or in other heterozygous family members, enabling also primary prevention of disease. Our report may broaden the knowledge of the genetic and molecular bases of PHA1, improving its clinical characterization and providing useful indications for the treatment of patients. Clinical approach must be personalized, also in relation to long-term survival and potential multiorgan complications.

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