scholarly journals Genotype–Phenotype Associations in 72 Adults with Suspected ALPL-Associated Hypophosphatasia

2020 ◽  
Author(s):  
Nico Maximilian Jandl ◽  
Tobias Schmidt ◽  
Tim Rolvien ◽  
Julian Stürznickel ◽  
Konstantin Chrysostomou ◽  
...  
Keyword(s):  
Inborn Error ◽  
Rare Variants ◽  
Clinical Symptoms ◽  
Positive Family History ◽  
Gene Sequencing ◽  
Genetics And Genomics ◽  
Specific Symptoms ◽  
Rare Inborn Error ◽  
Bone Complications

AbstractHypophosphatasia (HPP) is a rare inborn error of metabolism due to a decreased activity of tissue nonspecific alkaline phosphatase (TNSALP). As the onset and severity of HPP are heterogenous, it can be challenging to determine the pathogenicity of detected rare ALPL variants in symptomatic patients. We aimed to characterize patients with rare ALPL variants to propose which patients can be diagnosed with adult HPP. We included 72 patients with (1) clinical symptoms of adult HPP or positive family history and (2) low TNSALP activity and/or high pyridoxal 5′-phosphate (PLP) levels, who underwent ALPL gene sequencing. The patients were analyzed and divided into three groups depending on ALPL variant pathogenicity according to the classification of the American College of Medical Genetics and Genomics (ACMG). Reported pathogenic (n = 34 patients), rare (n = 17) and common (n = 21) ALPL variants only were found. Muscular complaints were the most frequent symptoms (> 80%), followed by bone affection (> 50%). Tooth involvement was significantly more common in patients with pathogenic or rare ALPL variants. Seven rare variants could be classified as likely pathogenic (ACMG class 4) of which five have not yet been described. Inconclusive genetic findings and less specific symptoms make diagnosis difficult in cases where adult HPP is not obvious. As not every pathogenic or rare ALPL variant leads to a manifestation of HPP, only patients with bone complications and at least one additional complication concerning teeth, muscle, central nervous and mental system, repeated low TNSALP activity and high PLP levels should be diagnosed as adult HPP if rare ALPL gene variants of ACMG class 4 or higher support the diagnosis.

scholarly journals Rare Variants Associated with Arrhythmogenic Cardiomyopathy: Reclassification Five Years Later

2021 ◽  
Vol 11 (3) ◽  
pp. 162 ◽  
Author(s):  
Marta Vallverdú-Prats ◽  
Mireia Alcalde ◽  
Georgia Sarquella-Brugada ◽  
Sergi Cesar ◽  
Elena Arbelo ◽  
...  
Keyword(s):  
Rare Variant ◽  
Rare Variants ◽  
Medical Genetics ◽  
Definite Diagnosis ◽  
Arrhythmogenic Cardiomyopathy ◽  
Genetic Interpretation ◽  
Genetics And Genomics

Genetic interpretation of rare variants associated with arrhythmogenic cardiomyopathy (ACM) is essential due to their diagnostic implications. New data may relabel previous variant classifications, but how often reanalysis is necessary remains undefined. Five years ago, 39 rare ACM-related variants were identified in patients with features of cardiomyopathy. These variants were classified following the American College of Medical Genetics and Genomics’ guidelines. In the present study, we reevaluated these rare variants including novel available data. All cases carried one rare variant classified as being of ambiguous significance (82.05%) or likely pathogenic (17.95%) in 2016. In our comprehensive reanalysis, the classification of 30.77% of these variants changed, mainly due to updated global frequencies. As in 2016, nowadays most variants were classified as having an uncertain role (64.1%), but the proportion of variants with an uncertain role was significantly decreased (17.95%). The percentage of rare variants classified as potentially deleterious increased from 17.95% to 23.07%. Moreover, 83.33% of reclassified variants gained certainty. We propose that periodic genetic reanalysis of all rare variants associated with arrhythmogenic cardiomyopathy should be undertaken at least once every five years. Defining the roles of rare variants may help clinicians obtain a definite diagnosis.

scholarly journals Classification of CHD7 Rare Variants in Chinese Congenital Hypogonadotropic Hypogonadism Patients and Analysis of Their Clinical Characteristics

2022 ◽  
Vol 12 ◽  
Author(s):  
Bang Sun ◽  
Xi Wang ◽  
Jiangfeng Mao ◽  
Zhiyuan Zhao ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Clinical Characteristics ◽  
Rare Variants ◽  
Hypogonadotropic Hypogonadism ◽  
Charge Syndrome ◽  
Phenotype Correlation ◽  
Congenital Hypogonadotropic Hypogonadism ◽  
Uncertain Significance ◽  
Genetics And Genomics

Purpose:CHD7 rare variants can cause congenital hypogonadotropic hypogonadism (CHH) and CHARGE syndrome. We aimed to summarize the genotype and phenotype characteristics of CHH patients with CHD7 rare variants.Methods: Rare sequencing variants (RSVs) were detected by Sanger sequencing in a series of 327 CHH patients and were interpreted and grouped according to the American College of Medical Genetics and Genomics (ACMG) guideline. Detailed phenotyping and genotype-phenotype correlation were analyzed.Results: The RSV detection rate was 11.01% (36/327) in the CHH patients. We identified 30 RSVs and 19 of them were novel. Following ACMG criteria, three variants were pathogenic (P), 4 were likely pathogenic (LP), 3 were of uncertain significance with paradoxical evidence (US1), and 20 were of uncertain significance without enough evidence (US2). All patients (4/4, 100%) with P or LP variants manifested extragonadal symptoms.Conclusion: Addition of 19 novel CHD7 variants expanded the spectrum of variants, and pathogenic or likely pathogenic RSVs were more likely to cause syndromic CHH. For CHH patients carrying CHD7 RSVs, detailed genotyping and phenotyping can facilitate clinical diagnosis and therapy.

Scrub typhus (Orientia tsutsugamushi), A rapidly spreading epidemic in Chennai - A standalone lab experience

2016 ◽  
Vol 5 (09) ◽  
pp. 4896
Author(s):  
Sripriya C.S.* ◽  
Shanthi B. ◽  
Arockia Doss S. ◽  
Antonie Raj I. ◽  
Mohana Priya
Keyword(s):  
Scrub Typhus ◽  
Clinical Symptoms ◽  
Clinical Manifestations ◽  
Febrile Illness ◽  
Orientia Tsutsugamushi ◽  
The Past ◽  
Igm Elisa ◽  
The Mean ◽  
Specific Symptoms ◽  
Symptoms And Signs

Scrub typhus (Orientia tsutsugamushi), is a strict intracellular bacterium which is reported to be a recent threat to parts of southern India. There is re-emergence of scrub typhus during the past few years in Chennai. Scrub typhus is an acute febrile illness which generally causes non-specific symptoms and signs. The clinical manifestations of this disease range from sub-clinical disease to organ failure to fatal disease. This study documents our laboratory experience in diagnosis of scrub typhus in patients with fever and suspected clinical symptoms of scrub typhus infection for a period of two years from April 2014 to April 2016 using immunochromatography and IgM ELISA methods. The study was conducted on 648 patients out of whom 188 patients were found to be positive for scrub typhus. Results also showed that pediatric (0 -12 years) and young adults (20 – 39 years) were more exposed to scrub typhus infection and female patients were more infected compared to male. The study also showed that the rate of infection was higher between September to February which also suggested that the infection rate is proportional to the climatic condition. Statistical analysis showed that the mean age of the patients in this study was 37.6, standard deviation was 18.97, CV % was 50.45. 

scholarly journals Diagnostic exome-based preconception carrier testing in consanguineous couples: results from the first 100 couples in clinical practice

2021 ◽  
Author(s):  
Suzanne C. E. H. Sallevelt ◽  
Alexander P. A. Stegmann ◽  
Bart de Koning ◽  
Crool Velter ◽  
Anja Steyls ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Rare Variants ◽  
Clinical Care ◽  
Carrier Testing ◽  
Carrier Status ◽  
Routine Diagnostics ◽  
Affected Offspring ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Genetics And Genomics

Abstract Purpose Consanguineous couples are at increased risk of being heterozygous for the same autosomal recessive (AR) disorder(s), with a 25% risk of affected offspring as a consequence. Until recently, comprehensive preconception carrier testing (PCT) for AR disorders was unavailable in routine diagnostics. Here we developed and implemented such a test in routine clinical care. Methods We performed exome sequencing (ES) for 100 consanguineous couples. For each couple, rare variants that could give rise to biallelic variants in offspring were selected. These variants were subsequently filtered against a gene panel consisting of ~2,000 genes associated with known AR disorders (OMIM-based). Remaining variants were classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, after which only likely pathogenic and pathogenic (class IV/V) variants, present in both partners, were reported. Results In 28 of 100 tested consanguineous couples (28%), likely pathogenic and pathogenic variants not previously known in the couple or their family were reported conferring 25% risk of affected offspring. Conclusion ES-based PCT provides a powerful diagnostic tool to identify AR disease carrier status in consanguineous couples. Outcomes provided significant reproductive choices for a higher proportion of these couples than previous tests.

scholarly journals Clinical and genetic spectrum of glycogen storage disease in Iranian population using targeted gene sequencing

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zahra Beyzaei ◽  
Fatih Ezgu ◽  
Bita Geramizadeh ◽  
Mohammad Hadi Imanieh ◽  
Mahmood Haghighat ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Molecular Genetic ◽  
Gene Sequencing ◽  
Glycogen Storage ◽  
Loss Of Function ◽  
Retrospective Case ◽  
Complex Disorders ◽  
Glycogen Storage Diseases ◽  
Targeted Gene Sequencing ◽  
Retrospective Case Study

AbstractGlycogen storage diseases (GSDs) are known as complex disorders with overlapping manifestations. These features also preclude a specific clinical diagnosis, requiring more accurate paraclinical tests. To evaluate the patients with particular diagnosis features characterizing GSD, an observational retrospective case study was designed by performing a targeted gene sequencing (TGS) for accurate subtyping. A total of the 15 pediatric patients were admitted to our hospital and referred for molecular genetic testing using TGS. Eight genes namely SLC37A4, AGL, GBE1, PYGL, PHKB, PGAM2, and PRKAG2 were detected to be responsible for the onset of the clinical symptoms. A total number of 15 variants were identified i.e. mostly loss-of-function (LoF) variants, of which 10 variants were novel. Finally, diagnosis of GSD types Ib, III, IV, VI, IXb, IXc, X, and GSD of the heart, lethal congenital was made in 13 out of the 14 patients. Notably, GSD-IX and GSD of the heart-lethal congenital (i.e. PRKAG2 deficiency) patients have been reported in Iran for the first time which shown the development of liver cirrhosis with novel variants. These results showed that TGS, in combination with clinical, biochemical, and pathological hallmarks, could provide accurate and high-throughput results for diagnosing and sub-typing GSD and related diseases.

scholarly journals Rare Variants in Autophagy and Non-Autophagy Genes in Late-Onset Pompe Disease: Suggestions of Their Disease-Modifying Role in Two Italian Families

2021 ◽  
Vol 22 (7) ◽  
pp. 3625
Author(s):  
Filomena Napolitano ◽  
Giorgia Bruno ◽  
Chiara Terracciano ◽  
Giuseppina Franzese ◽  
Nicole Piera Palomba ◽  
...  
Keyword(s):  
Pompe Disease ◽  
Rare Variants ◽  
Clinical Symptoms ◽  
Late Onset ◽  
Respiratory Muscles ◽  
Autosomal Recessive Disorder ◽  
Compound Heterozygous ◽  
Enzyme Replacement ◽  
Whole Exome ◽  
Clinical Pictures

Pompe disease is an autosomal recessive disorder caused by a deficiency in the enzyme acid alpha-glucosidase. The late-onset form of Pompe disease (LOPD) is characterized by a slowly progressing proximal muscle weakness, often involving respiratory muscles. In LOPD, the levels of GAA enzyme activity and the severity of the clinical pictures may be highly variable among individuals, even in those who harbour the same combination of GAA mutations. The result is an unpredictable genotype–phenotype correlation. The purpose of this study was to identify the genetic factors responsible for the progression, severity and drug response in LOPD. We report here on a detailed clinical, morphological and genetic study, including a whole exome sequencing (WES) analysis of 11 adult LOPD siblings belonging to two Italian families carrying compound heterozygous GAA mutations. We disclosed a heterogeneous pattern of myopathic impairment, associated, among others, with cardiac defects, intracranial vessels abnormality, osteoporosis, vitamin D deficiency, obesity and adverse response to enzyme replacement therapy (ERT). We identified deleterious variants in the genes involved in autophagy, immunity and bone metabolism, which contributed to the severity of the clinical symptoms observed in the LOPD patients. This study emphasizes the multisystem nature of LOPD and highlights the polygenic nature of the complex phenotype disclosed in these patients.

370 Pure Primary Small Cell Carcinoma of the Prostate: A Rare Entity

2021 ◽  
Vol 108 (Supplement_2) ◽  
Author(s):  
C Desai ◽  
A Bhojwani ◽  
J Parkin
Keyword(s):  
Cell Carcinoma ◽  
Small Cell Carcinoma ◽  
Clinical Symptoms ◽  
Positive Family History ◽  
Malignant Neoplasm ◽  
Small Cell ◽  
Whole Body ◽  
Carcinoma Of The Prostate ◽  
Patient Reported ◽  
Prostate Cancers

Abstract Introduction We report a case of small cell carcinoma of the prostate (SCCP) which is a rare, high-grade malignant neoplasm accounting for 1% of all prostate cancers (CPa). Case Presentation A 56-year-old male patient initially presented to primary care with a six-month history of frequency, nocturia and pain in the perineal region when seated. A positive family-history for CPa was noted, serum PSA was 11.58, and a rectal examination found a large, irregular mass. He was treated with antibiotics for possible prostatitis and referred to the colorectal team. MRI rectum confirmed a mass between the prostate and rectum, which was found to be pure SCCP on biopsy. Whole-body scanning found multiple lung and pelvic metastases. The patient was commenced on six cycles of Etoposide and Carboplatin therapy. The patient reported that his pelvic discomfort has improved following the first cycle. Conclusions SCCP metastasizes early and therefore the clinical presentation is often in an advanced stage. It is noted that there is limited value of serum PSA for SCCP diagnosis. Instead, pathological examinations and MRI rectum are vital. In terms of treatment, chemotherapy provides relief of the clinical symptoms and its use is in in accordance with the 2016 National Comprehensive Cancer Network guidelines.

scholarly journals Midventricular takotsubo syndrome: different dyskinesia location leading to a different electrocardiogram?

2021 ◽  
Vol 10 (Supplement_1) ◽  
Author(s):  
M Padilla Lopez ◽  
A Duran Cambra ◽  
M Vidal Burdeus ◽  
L Rodriguez Sotelo ◽  
J Sanchez Vega ◽  
...  
Keyword(s):  
Acute Phase ◽  
Clinical Symptoms ◽  
Takotsubo Syndrome ◽  
St Segment Elevation ◽  
Funding Sources ◽  
Wave Inversion ◽  
St Segment ◽  
Electrocardiogram Ecg ◽  
Study Inclusion

Abstract Funding Acknowledgements Type of funding sources: None. Background Takotsubo syndrome (TKS) is characterized by the appearance of apical reversible dyskinesia in its typical form. Electrocardiogram (ECG) in the acute phase (<12 from symptom onset) generally shows anterior ST segment elevation. Nonetheless, other atypical forms of TKS have been described depending on the location of the dyskinetic segments, such as, mid-ventricular, basal and focal forms. Considering the different segments involved in these atypical forms, it seems reasonable to consider that ST changes in acute phase ECG could be different. Purpose To compare ECG in the acute phase of typical TKS versus mid-ventricular TKS, as it was the more frequent form of atypical TKS in our registry. Methods Patients included in the prospective TKS registry of our center according to the Mayo Clinic diagnostic criteria, with the first ECG performed less than 12 hours from the symptoms onset were reviewed. All cardiac left ventriculographies were reviewed to ensure a correct classification of the different types of TKS. Results A total of 297 patients were included in our local registry. 80 patients met our study inclusion criteria. 56 ECGs of typical apical TKS were compared to 24 ECGs of atypical midventricular TKS. There were no differences between the baseline characteristics in both groups, except for mid-ventricular TKS, that was more frequently triggered by physical stressor. Regarding the ECG analysis, the main difference found in our serie was related to ST-segment deviation (Table 1). While ST-segment elevation was more common in typical TKS than in atypical TKS (73% vs 50%), ST-segment depression (generally in inferior leads) was observed in 54% of patients with atypical TKS and in no patient with typical TKS (figure 1). Conclusion The different location of dyskinesia between typical TKS and mid-ventricular TKS is associated to significant differences in the ECG obtained in the first hours after the onset of the clinical symptoms. The presence of ST-segment depression is highly suggestive of mid-ventricular TKS. ECG characteristicsTypical (n = 56)Midventricular (n = 24)pSTe > 1mm, no (%)41 (73)12 (50)0,044STd >0,5 mm, no (%)013 (54)< 0,001T wave inversion, no (%)12 (21)4 (17)0,626Q wave, no (%)22 ( 39)12 (50)0,374cQT, mean (SD)445 (54)438 (37)0,578QRS low voltages*, n (%)9 ( 16)1 (4)0,328STe ST-segment elevation, STd: ST-segment depression, cQT: corrected QT interval *Voltages <5mm in all limb leads or <10mm in all precordial leads Abstract Figure. 12-lead ECG and left ventriculography

scholarly journals A new pipeline for structural characterization and classification of RNA-Seq microbiome data

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Sebastian Racedo ◽  
Ivan Portnoy ◽  
Jorge I. Vélez ◽  
Homero San-Juan-Vergara ◽  
Marco Sanjuan ◽  
...  
Keyword(s):  
Classification Accuracy ◽  
High Throughput Sequencing ◽  
Compositional Data ◽  
Graphical Representation ◽  
Synthetic Data ◽  
Gene Sequencing ◽  
Rrna Gene ◽  
Interaction Patterns ◽  
Simulation Experiments

Abstract Background High-throughput sequencing enables the analysis of the composition of numerous biological systems, such as microbial communities. The identification of dependencies within these systems requires the analysis and assimilation of the underlying interaction patterns between all the variables that make up that system. However, this task poses a challenge when considering the compositional nature of the data coming from DNA-sequencing experiments because traditional interaction metrics (e.g., correlation) produce unreliable results when analyzing relative fractions instead of absolute abundances. The compositionality-associated challenges extend to the classification task, as it usually involves the characterization of the interactions between the principal descriptive variables of the datasets. The classification of new samples/patients into binary categories corresponding to dissimilar biological settings or phenotypes (e.g., control and cases) could help researchers in the development of treatments/drugs. Results Here, we develop and exemplify a new approach, applicable to compositional data, for the classification of new samples into two groups with different biological settings. We propose a new metric to characterize and quantify the overall correlation structure deviation between these groups and a technique for dimensionality reduction to facilitate graphical representation. We conduct simulation experiments with synthetic data to assess the proposed method’s classification accuracy. Moreover, we illustrate the performance of the proposed approach using Operational Taxonomic Unit (OTU) count tables obtained through 16S rRNA gene sequencing data from two microbiota experiments. Also, compare our method’s performance with that of two state-of-the-art methods. Conclusions Simulation experiments show that our method achieves a classification accuracy equal to or greater than 98% when using synthetic data. Finally, our method outperforms the other classification methods with real datasets from gene sequencing experiments.

Mixed Infection of Tick-borne Haemo-parasites in Water Buffalo and Associated Pathological Responses and Treatment

2021 ◽  
Author(s):  
Pankaj Kumar ◽  
Prabhas Kumar ◽  
Rama Krishna Roy ◽  
Rashmi Rekha Kumari ◽  
Abhay Kumar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Clinical Symptoms ◽  
Water Buffaloes ◽  
High Prevalence ◽  
Tick Borne Disease ◽  
Associated Risk Factors ◽  
Good Productivity ◽  
And Oxidative Stress ◽  
Production Losses

Background: Water buffaloes are important milch species of tropical and subtropical countries. In general, they are considered to more resistant to diseases compared to crossbred cattle. However, a recent problem of tick-borne diseases in the water buffaloes by the field veterinarians and farmers causing production losses was observed. The study was conducted to explore the spectrum of tick-borne diseases (TBDs) infections in buffaloes and analyze the associated risk factors. Methods: Acute-phase response, cytokine and oxidative stress in infected buffaloes with TBDs were evaluated and compared with the negative buffaloes (control) to elucidate their role in pathogenesis and outcome of infection. The study was undertaken in 107 tick-infested water buffaloes. The conventional Giemsa stained blood smear (GSBS) based confirmation and classification of infection of haemo-parasites were made. The statistical model was used to understand their relevance with TBDs. Conclusion: Tick-borne disease in water buffaloes must be looked upon seriously to maintain good productivity. The buffaloes are often accompanied by low and un-yielding clinical symptoms due to associated co-infections of haemo-parasites. Our study showed that the buffaloes had a high prevalence (47.66%) of haemo-parasites transmitted by the ticks associated with co-infections and a low level of parasitemia. Most buffaloes responded symptomatically with the different modalities administered. Production parameter was not restored post 15 days of treatment. Oxidative stress is one of the important mechanisms of production losses in infected buffaloes.

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