The SEeMORE strategy: single-tube electrophoresis analysis-based genotyping to detect monogenic diseases rapidly and effectively from conception until birth

2017 ◽  
Vol 56 (1) ◽  
Author(s):  
Federica Cariati ◽  
Maria Savarese ◽  
Valeria D’Argenio ◽  
Francesco Salvatore ◽  
Rossella Tomaiuolo
Keyword(s):  
Prenatal Diagnosis ◽  
Molecular Diagnosis ◽  
Biological Sample ◽  
Genetic Diagnosis ◽  
Disease Type ◽  
Molecular Diagnostic ◽  
Monogenic Disease ◽  
Laboratory Practice ◽  
Single Tube ◽  
Monogenic Diseases

AbstractBackground:The development of technologies that detect monogenic diseases in embryonic and fetal samples are opening novel diagnostic possibilities for preimplantation genetic diagnosis (PGD) and prenatal diagnosis (PND) thereby changing laboratory practice. Molecular diagnostic laboratories use different workflows for PND depending on the disease, type of biological sample, the presence of one or more known mutations, and the availability of the proband. Paternity verification and contamination analysis are also performed. The aim of this study was to test the efficacy of a single workflow designed to optimize the molecular diagnosis of monogenic disease in families at-risk of transmitting a genetic alteration.Methods:We used this strategy, which we designated “SEeMORE strategy” (Results:The results obtained with the SEeMORE strategy concurred with those obtained with traditional PND. In addition, this strategy has several advantages: (i) use of one or a few cells; (ii) reduction of the procedure to 1 day; and (iii) a reduction of at least 2–3-fold of the analytic cost.Conclusions:The SEeMORE strategy is effective for the molecular diagnosis of monogenic diseases, irrespective of the amount of starting material and of the disease mutation, and can be used for PND and PGD.

Steroid hormone profiles and molecular diagnostic tools in pediatric patients with non-CAH primary adrenal insufficiency

2022 ◽  
Author(s):  
Tuba Seven Menevse ◽  
Yasemin Kendir Demirkol ◽  
Busra Gurpinar Tosun ◽  
Elvan Bayramoglu ◽  
Melek Yildiz ◽  
...  
Keyword(s):  
Adrenal Insufficiency ◽  
Molecular Diagnosis ◽  
High Throughput Sequencing ◽  
Steroid Hormone ◽  
Genetic Diagnosis ◽  
Molecular Diagnostic ◽  
Diagnostic Tools ◽  
Unknown Etiology ◽  
Control Group ◽  
Primary Adrenal Insufficiency

Abstract Background There is a significant challenge of attributing specific diagnoses to patients with primary adrenal insufficiency of unknown etiology other than congenital adrenal hyperplasia (non-CAH PAI). Specific diagnoses per se may guide personalized treatment or may illuminate pathophysiology. Objective Investigation of the efficacy of steroid hormone profiles and high-throughput sequencing methods in establishing the etiology in non-CAH PAI of unknown origin. Design Paediatric patients with non-CAH PAI whose etiology could not be established by clinical and biochemical characteristics were enrolled. Genetic analysis was performed using targetedgene panel sequencing (TPS) and whole-exome sequencing (WES). Plasma adrenal steroids were quantified by liquid chromatography-mass spectrometry and compared to that of controls. Setting Eighteen pediatric endocrinology clinics. Patients Forty-one patients (17 females, median age: 3 months, range: 0-8 years) with non-CAH PAI of unknown etiology. Results A genetic diagnosis was obtained in 29 (70.7%) patients by TPS. Further molecular diagnosis could not be achieved by WES. Compared to healthy control group, patients showed lower steroid concentrations, most significantly in cortisone, cortisol, and corticosterone (p<0.0001, area under the ROC curve: 0.96, 0.88, 0.87, respectively). Plasma cortisol<4 ng/mL, cortisone<11 ng/mL, and corticosterone<0.11 ng/mL had >95% specificity to ensure the diagnosis of non-CAH PAI of unknown etiology. Conclusion Steroid hormone profiles are highly sensitive for the diagnosis of non-CAH PAI of unknown etiology, while they are unlikely to point out a specific molecular diagnosis. TPS is an optimal approach in the molecular diagnosis of these patients with high efficacy, while little additional benefit is expected from WES.

scholarly journals Discovering Monogenic Patients with a Confirmed Molecular Diagnosis in Millions of Clinical Notes with MonoMiner

2021 ◽  
Author(s):  
David Wei Wu ◽  
Jon A Bernstein ◽  
Gill Bejerano
Keyword(s):  
Molecular Diagnosis ◽  
Language Processing ◽  
Clinical Care ◽  
Disease Diagnosis ◽  
Monogenic Disease ◽  
Free Text ◽  
Causal Gene ◽  
Hospital System ◽  
Clinical Notes ◽  
Monogenic Diseases

Purpose: Cohort building is a powerful foundation for improving clinical care, performing research, clinical trial recruitment, and many other applications. We set out to build a cohort of all patients with monogenic conditions who have received a definitive causal gene diagnosis in a 3 million patient hospital system. Methods: We define a subset of half (4,461) of OMIM curated diseases for which at least one monogenic causal gene is definitively known. We then introduce MonoMiner, a natural language processing framework to identify molecularly confirmed monogenic patients from free-text clinical notes. Results: We show that ICD-10-CM codes cover only a fraction of known monogenic diseases, and even where available, code-based patient retrieval offers 0.12 precision. Searching by causal gene symbol offers great recall but an even worse 0.09 precision. MonoMiner achieves 7-9 times higher precision (0.82), with 0.88 precision on disease diagnosis alone, tagging 4,259 patients with 560 monogenic diseases and 534 causal genes, at 0.48 recall. Conclusion: MonoMiner enables the discovery of a large, high-precision cohort of monogenic disease patients with an established molecular diagnosis, empowering numerous downstream uses. Because it relies only on clinical notes, MonoMiner is highly portable, and its approach is adaptable to other domains and languages.

scholarly journals Current state of preimplantation genetic diagnosis

2012 ◽  
Vol 61 (3) ◽  
pp. 75-82
Author(s):  
Julija Artemevna Loginova ◽  
Olga Gavrilovna Chiryaeva
Keyword(s):  
Prenatal Diagnosis ◽  
Assisted Reproductive Technology ◽  
Preimplantation Genetic Diagnosis ◽  
Molecular Diagnosis ◽  
Single Cells ◽  
Genetic Diagnosis ◽  
Reproductive Technology ◽  
Preimplantation Diagnosis ◽  
Experimental Procedure ◽  
Current State

Preimplantation genetic diagnosis was first reported 20 years ago. During this time the range of possibilities of assisted reproductive technology has expanded and the possibility of molecular diagnosis of single cells greatly increased. Preimplantation diagnosis has evolved from an experimental procedure to an efficient form of Prenatal Diagnosis, which broadened the indications for Prenatal Diagnosis and can be applied at the earliest stage. This review shows the current state of preimplantation genetic diagnosis and describes its capabilities

scholarly journals Prevalence of monogenic disease in paediatric patients with a predominant respiratory phenotype

2021 ◽  
pp. archdischild-2021-322058
Author(s):  
Dan Dai ◽  
Mei Mei ◽  
Liyuan Hu ◽  
Yun Cao ◽  
Xiaochuan Wang ◽  
...  
Keyword(s):  
Lung Disease ◽  
Exome Sequencing ◽  
Respiratory Infections ◽  
Management Strategies ◽  
Genetic Diagnosis ◽  
Clinical Manifestations ◽  
Monogenic Disease ◽  
Prognostic Information ◽  
Paediatric Patients ◽  
Monogenic Diseases

ObjectiveThis study aimed to investigate the prevalence and clinical characteristics of monogenic disease in paediatric patients with a predominant respiratory phenotype.MethodsExome sequencing was performed in a cohort of 971 children with a predominant respiratory phenotype and suspected genetic aetiology. A total of 140 positive cases were divided into subgroups based on recruitment age and the primary biological system(s) involved.ResultsThere were 140 (14.4%) patients with a positive molecular diagnosis, and their primary clinical manifestations were respiratory distress (12.9%, 18 of 140), respiratory failure (12.9%, 18 of 140) and recurrent/persistent lower respiratory infections (66.4%, 93 of 140). Primary immunodeficiency (49.3%), multisystem malformations/syndromes (17.9%), and genetic lung disease (16.4%) were the three most common genetic causes in the cohort, and they varied among the age subgroups. A total of 72 (51.4%) patients had changes in medical management strategies after genetic diagnosis, and the rate in those with genetic lung disease (82.6%, 19 of 23) was far higher than that in patients with genetic disease with lung involvement (45.3%, 53 of 117) (p=0.001).ConclusionOur findings demonstrate that exome sequencing is a valuable diagnostic tool for monogenic diseases in children with a predominant respiratory phenotype, and the genetic spectrum varies with age. Taken together, genetic diagnoses provide invaluable clinical and prognostic information that may also facilitate the development of precision medicine for paediatric patients.

scholarly journals The Increasing Impact of Translational Research in the Molecular Diagnostics of Neuromuscular Diseases

2021 ◽  
Vol 22 (8) ◽  
pp. 4274
Author(s):  
Dèlia Yubero ◽  
Daniel Natera-de Benito ◽  
Jordi Pijuan ◽  
Judith Armstrong ◽  
Loreto Martorell ◽  
...  
Keyword(s):  
Molecular Diagnosis ◽  
Clinical Symptoms ◽  
Neuromuscular Diseases ◽  
Genomic Analysis ◽  
Molecular Diagnostic ◽  
Diagnostic Process ◽  
Targeted Analysis ◽  
Whole Exome ◽  
Referral Hospitals ◽  
Uncertain Significance

The diagnosis of neuromuscular diseases (NMDs) has been progressively evolving from the grouping of clinical symptoms and signs towards the molecular definition. Optimal clinical, biochemical, electrophysiological, electrophysiological, and histopathological characterization is very helpful to achieve molecular diagnosis, which is essential for establishing prognosis, treatment and genetic counselling. Currently, the genetic approach includes both the gene-targeted analysis in specific clinically recognizable diseases, as well as genomic analysis based on next-generation sequencing, analyzing either the clinical exome/genome or the whole exome or genome. However, as of today, there are still many patients in whom the causative genetic variant cannot be definitely established and variants of uncertain significance are often found. In this review, we address these drawbacks by incorporating two additional biological omics approaches into the molecular diagnostic process of NMDs. First, functional genomics by introducing experimental cell and molecular biology to analyze and validate the variant for its biological effect in an in-house translational diagnostic program, and second, incorporating a multi-omics approach including RNA-seq, metabolomics, and proteomics in the molecular diagnosis of neuromuscular disease. Both translational diagnostics programs and omics are being implemented as part of the diagnostic process in academic centers and referral hospitals and, therefore, an increase in the proportion of neuromuscular patients with a molecular diagnosis is expected. This improvement in the process and diagnostic performance of patients will allow solving aspects of their health problems in a precise way and will allow them and their families to take a step forward in their lives.

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