Two novel variants and follow-up findings in four children with Bloom syndrome from two families

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Busra Kasap ◽  
Filiz Guclu-Geyik ◽  
Dilek Uludag Alkaya ◽  
Güven Cetin ◽  
Beyhan Tuysuz
Keyword(s):  
Bloom Syndrome ◽  
Novel Variants

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.

scholarly journals Ataxia and hypogonadotropic hypogonadism with intrafamilial variability caused by RNF216 mutation

2016 ◽  
Vol 8 (2) ◽  
Author(s):  
Mohammed Alqwaifly ◽  
Saeed Bohlega
Keyword(s):  
Splice Site ◽  
Autosomal Recessive ◽  
Hypogonadotropic Hypogonadism ◽  
Distinct Phenotype ◽  
Splicing Variant ◽  
Autosomal Recessive Cerebellar Ataxia ◽  
Whole Exome ◽  
Novel Variants ◽  
Intrafamilial Variability

Gordon Holmes syndrome (GHS) is a distinct phenotype of autosomal recessive cerebellar ataxia, characterized by ataxia, dementia, reproductive defects and hypogonadism; it has been recently found to be associated with <em>RNF216</em> mutation. We performed whole-exome sequencing and filtered the resulting novel variants by the coordinates of the shared autozygome. We identified a novel splicing variant in <em>RNF216</em> that is likely to abolish the canonical splice site at the junction of exon/intron 13 (NM_207111.3:c.2061G&gt;A). We herein report two patients with GHS caused by a novel <em>RNF216</em> mutation as the first follow up report on <em>RNF216</em>-related GHS, and <em>show</em> interfamilial variability of phenotype supporting the previously reported RNF216-related cases.

scholarly journals Infantile fibrosarcoma with TPM3-NTRK1 fusion in a boy with Bloom syndrome

2020 ◽  
Author(s):  
Sue M. Huson ◽  
Timo Staab ◽  
Marta Pereira ◽  
Heather Ward ◽  
Roberto Paredes ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Chromosomal Instability ◽  
Fusion Transcript ◽  
Bloom Syndrome ◽  
Sequence Variants ◽  
Infantile Fibrosarcoma ◽  
Pathogenic Variants ◽  
Long Term Follow Up

AbstractBloom syndrome (BS) is a genomic and chromosomal instability disorder with prodigious cancer predisposition caused by pathogenic variants in BLM. We report the clinical and genetic details of a boy who first presented with infantile fibrosarcoma (IFS) at the age of 6 months and subsequently was diagnosed with BS at the age of 9 years. Molecular analysis identified the pathogenic germline BLM sequence variants (c.1642C>T and c.2207_2212delinsTAGATTC). This is the first report of IFS related to BS, for which we show that both BLM alleles are maintained in the tumor and demonstrate a TPM3-NTKR1 fusion transcript in the IFS. Our communication emphasizes the importance of long-term follow up after treatment for pediatric neoplastic conditions, as clues to important genetic entities might manifest later, and the identification of a heritable tumor predisposition often leads to changes in patient surveillance and management.

scholarly journals Clinical and Molecular Characterization of Achromatopsia Patients: A Longitudinal Study

2021 ◽  
Vol 22 (4) ◽  
pp. 1681
Author(s):  
Raffaella Brunetti-Pierri ◽  
Marianthi Karali ◽  
Paolo Melillo ◽  
Valentina Di Iorio ◽  
Antonella De Benedictis ◽  
...  
Keyword(s):  
Progressive Disease ◽  
Structural Integrity ◽  
Genetic Disorder ◽  
Molecular Genetic ◽  
Gene Replacement ◽  
Novel Variants ◽  
Reduced Light ◽  
Italian Cohort

Achromatopsia (ACHM) is a rare genetic disorder of infantile onset affecting cone photoreceptors. To determine the extent of progressive retinal changes in achromatopsia, we performed a detailed longitudinal phenotyping and genetic characterization of an Italian cohort comprising 21 ACHM patients (17 unrelated families). Molecular genetic testing identified biallelic pathogenic mutations in known ACHM genes, including four novel variants. At baseline, the patients presented a reduced best corrected visual acuity (BCVA), reduced macular sensitivity (MS), normal dark-adapted electroretinogram (ERG) responses and undetectable or severely reduced light-adapted ERG. The longitudinal analysis of 16 patients (mean follow-up: 5.4 ± 1.0 years) showed a significant decline of BCVA (0.012 logMAR/year) and MS (−0.16 dB/year). Light-adapted and flicker ERG responses decreased below noise level in three and two patients, respectively. Only two patients (12.5%) progressed to a worst OCT grading during the follow-up. Our findings corroborate the notion that ACHM is a progressive disease in terms of BCVA, MS and ERG responses, and affects slowly the structural integrity of the retina. These observations can serve towards the development of guidelines for patient selection and intervention timing in forthcoming gene replacement therapies.

Congenital Myasthenic Syndrome From a Single Center: Phenotypic and Genotypic features

2021 ◽  
pp. 088307382098775
Author(s):  
Devin E. Prior ◽  
Partha S. Ghosh
Keyword(s):  
Genetic Variants ◽  
Chart Review ◽  
Genetic Disorders ◽  
Retrospective Chart Review ◽  
Congenital Myasthenic Syndrome ◽  
Significant Delay ◽  
Prompt Treatment ◽  
Novel Variants ◽  
Myasthenic Syndrome

Background: Congenital myasthenic syndrome is a group of rare genetic disorders affecting transmission across the neuromuscular junction. Patients present with variable ocular, bulbar, respiratory, and extremity weakness that may respond to symptomatic therapies. Methods: We identified 18 patients with congenital myasthenic syndrome from a pediatric neuromuscular center over a decade. Through a retrospective chart review, we characterize demographic profile, clinical features, genetic variants, treatment, and follow-up of these patients. Results: Patients had the following genetic subtypes: CHRNE (6), CHAT (2), MUSK (2), DOK7 (2), COLQ (1), RAPSN (1), PREPL (1), GFPT1 (1), CHRBB1 (1), and CHRNA1 (1). The phenotype varied based on the genetic variants, though most patients have generalized fatigable weakness affecting ocular, bulbar, and extremity muscles. There was a significant delay in the diagnosis of this condition from the onset of symptoms. Although most patients improved with pyridostigmine, some subtypes showed worsening with pyridostigmine and others benefited from albuterol, ephedrine, or 3,4-diaminopyridine treatment. Conclusion: Increasing recognition of this rare syndrome will lead to early diagnosis and prompt treatment. Prompt utilization of genetic testing will identify novel variants and the expanding phenotype of this condition.

scholarly journals Novel combined variants of WT1 and TET2 in a refractory and recurrent AML patient

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Qiang Ma ◽  
Yixian Guo ◽  
Xiaoxi Lan ◽  
Guoxiang Wang ◽  
Wanling Sun
Keyword(s):  
Complete Remission ◽  
Myeloid Leukemia ◽  
Wilms Tumor ◽  
Potential Effect ◽  
Early Recurrence ◽  
Hematopoietic Stem ◽  
Case Presentation ◽  
Novel Variants ◽  
Hematopoietic Disorders

Abstract Background Somatic mutations in Wilms' tumor 1 (WT1) and tet methylcytosine dioxygenase 2 (TET2) genes were separately perceived as contributors to hematopoietic disorders and usually thought to have a mutually exclusive effect in acute myeloid leukemia (AML). However, we found novel WT1 and TET2 variants persistently co-existed in a refractory and recurrent AML patient with t(9;11)(p21.3;q23.3); KMT2A-MLLT3, and were only detectable genetic alteration in early recurrence. Hence, these two novel variants were further investigated in patient’s family, and the potential effect on disease progression was evaluated at follow-up. Case presentation A 27-year-old male was diagnosed with AML, having t(9;11)(p21.3;q23.3); KMT2A-MLLT3, accompanied by WT1 (NM_024426.6:exon7:c.1109G>C:p.Arg370Pro) and TET2 (NM_001127208.3:exon11:c.5530G>A:p.Asp1844Asn) variants. After two cycles of induction chemotherapy, complete remission was achieved. A consolidation treatment was then completed. However, the evaluation of the bone marrow revealed that early recurrence, WT1 (p.Arg370Pro) and TET2 (p.Asp1844Asn) variants still detectable, instead of KMT2A-MLLT3. Subsequently, these two variants were proved to be germline variants, which inherited from father and mother respectively. And the patient's elder brother also carried TET2 (p.Asp1844Asn) variant. A sequential allogeneic HLA-matched sible hematopoietic stem cell transplantation (allo-HSCT) was carried out, and the donor is the patient's elder brother, the original two variants of patient were replaced by the donor-derived TET2 (p.Asp1844Asn) variant after allo-HSCT; the patient has remained in complete remission with regular follow-up. Conclusions In brief, it is firstly reported that WT1 p.Arg370Pro and TET2 p.Asp1844Asn variants co-existed in a refractory and recurrent AML patient by inheritance. These two variants of the patient were replaced with donor-derived TET2 p.Asp1844Asn after allo-HSCT, and the patient has remained in complete remission with regular follow-up.

Follow-up GWAS study for novel variants associated with early-onset prostate cancer in Romania

2018 ◽  
Vol 17 (12) ◽  
pp. e2641
Author(s):  
D.G. Rosoga ◽  
P. Iordache ◽  
A.S.C. Rascu ◽  
D.G. Radavoi ◽  
D.L. Badescu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Early Onset ◽  
Gwas Study ◽  
Novel Variants

scholarly journals Long Term Follow-Up of Polish Patients with Isovaleric Aciduria. Clinical and Molecular Delineation of Isovaleric Aciduria

Diagnostics ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 738
Author(s):  
Edyta Szymańska ◽  
Aleksandra Jezela-Stanek ◽  
Anna Bogdańska ◽  
Dariusz Rokicki ◽  
Ewa Ehmke vel Emczyńska-Seliga ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Autosomal Recessive ◽  
Clinical State ◽  
Neurological Outcomes ◽  
Pathogenic Variants ◽  
Novel Variants ◽  
Long Term Follow Up ◽  
Isovaleric Aciduria

Isovaleric acidemia (IVA) is an autosomal recessive leucine inborn error of metabolism caused by isovaleryl-CoA dehydrogenase deficiency. The disease has various courses, from severe ones manifesting in newborns to the intermittent form with first manifestation in children and adults. The aim of this study was to analyze clinical and neurological outcomes in Polish patients with IVA. Ten patients diagnosed and treated in The Children’s Memorial Health Institute were included in the study. The diagnosis was based on tandem MS (increased level of C5 acylcarnitine) and urine GCMS (increased isovalerylglycine, and 3-hydroxyisovaleric acid). Molecular analysis was performed in seven patients (70%) leading to the detection of pathogenic variants in the IVD gene in all of them. A retrospective analysis of patients’ medical records included: demographics, symptoms at diagnosis, medical management, and biochemical and clinical outcomes following therapy. The median follow-up time (median; Q1–Q2) was 2.5 years (1.5–9.0) for newborn screening (NBS) and family screening (FS) children, and 17 years (5.0–20) for symptomatic patients. Five patients were in a good clinical state, four children presented mild neurological symptoms, and one—severely delayed child. In the IVD gene, five known and two novel variants (p.466C>G, c.1132G>A) were identified. Molecular analysis was performed in seven patients leading to identification of biallelic pathogenic variants in the IVD gene in all of them. We can conclude that long-term clinical and neurological outcomes of patients with IVA were satisfactory as a result of an early diagnosis and proper management. Although early treatment did not prevent decompensations, they were milder in these patients.

Genotype/Phenotype Analysis in 67 Chinese Patients with Gitelman's Syndrome

2016 ◽  
Vol 44 (2) ◽  
pp. 159-168 ◽  
Author(s):  
Ting Liu ◽  
Cui Wang ◽  
Jingru Lu ◽  
Xiangzhong Zhao ◽  
Yanhua Lang ◽  
...  
Keyword(s):  
Fractional Excretion ◽  
Chinese Patients ◽  
Gitelman's Syndrome ◽  
Abnormal Glucose Metabolism ◽  
Renal Tubular Disorder ◽  
Novel Variants ◽  
Phenotype Analysis ◽  
Male Patients ◽  
Renal Tubular

Background: Gitelman's syndrome (GS) is an autosomal recessive renal tubular disorder, which is caused by the mutations in SLC12A3. This study was designed to analyze the characteristics of the genotype and phenotype, and follow-up in the largest group of Chinese patients with GS. Methods: Sixty-seven patients with GS underwent SLCl2A3 analysis, and their clinical characteristics and biochemical findings as well as follow-up were reviewed, aiming to achieve a better description of GS. Additionally, the association of genotype and phenotype was explored. Results: Forty-one different mutations were identified within these 67 GS patients, including 11 novel mutations and 5 recurrent ones. Typical hypocalciuria and hypomagnesemia were not found in 6 (9%) and 8 (11.9%) patients, respectively. Male patients and those harboring severe mutations in both alleles had significant higher urinary fractional excretion (FE) of potassium, magnesium and chlorine. In addition, there were 2 patients who had chronic kidney disease (estimated glomerular filtration rate <60 ml/min/1.73 m2) and 32 patients with abnormal glucose metabolism. Conclusions: We identified 41 mutations related to GS, containing 11 novel variants and 5 high-frequency ones, which should facilitate earlier and more accurate diagnosis of GS. FE of electrolytes in urine may be more sensitive in the phenotype evaluation and differential diagnosis than corresponding serum electrolytes. Hypokalemia and hypomagnesemia in GS were difficult to correct; however, spironolactone might be helpful for hypokalemia to some degree. Compared with normal people, patients with GS were at higher risk of developing type 2 diabetes.

Therapy and prevention for mental health: What if mental diseases are mostly not brain disorders?

2019 ◽  
Vol 42 ◽  
Author(s):  
John P. A. Ioannidis
Keyword(s):  
Mental Health ◽  
Mental Disease ◽  
Brain Disorders ◽  
Social Stressors ◽  
Labor Education ◽  
Mental Diseases ◽  
Long Term Follow Up ◽  
Political Decisions

AbstractNeurobiology-based interventions for mental diseases and searches for useful biomarkers of treatment response have largely failed. Clinical trials should assess interventions related to environmental and social stressors, with long-term follow-up; social rather than biological endpoints; personalized outcomes; and suitable cluster, adaptive, and n-of-1 designs. Labor, education, financial, and other social/political decisions should be evaluated for their impacts on mental disease.

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