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 Exome sequencing in paediatric patients with movement disorders

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Anna Ka-Yee Kwong ◽  
Mandy Ho-Yin Tsang ◽  
Jasmine Lee-Fong Fung ◽  
Christopher Chun-Yu Mak ◽  
Kate Lok-San Chan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Movement Disorders ◽  
Rare Variants ◽  
Diagnostic Yield ◽  
Neurological Diseases ◽  
Genetic Diagnosis ◽  
Potential Treatment ◽  
Paediatric Patients ◽  
Whole Exome

Abstract Background Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis. Results We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation. Conclusions A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management. The study highlights the potential of implementing precision medicine in the patients.

scholarly journals Clinical exome sequencing is a powerful tool in the diagnostic flow of monogenic kidney diseases: an Italian experience

2020 ◽  
Author(s):  
Tiziana Vaisitti ◽  
Monica Sorbini ◽  
Martina Callegari ◽  
Silvia Kalantari ◽  
Valeria Bracciamà ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Exome Sequencing ◽  
Ad Hoc ◽  
Kidney Diseases ◽  
Positive Family History ◽  
Genetic Diagnosis ◽  
In Silico Analysis ◽  
Monogenic Disease ◽  
Cooperative Effort ◽  
Clinical Exome Sequencing

Abstract Background A considerable minority of patients on waiting lists for kidney transplantation either have no diagnosis (and fall into the subset of undiagnosed cases) because kidney biopsy was not performed or histological findings were non-specific, or do not fall into any well-defined clinical category. Some of these patients might be affected by a previously unrecognised monogenic disease. Methods Through a multidisciplinary cooperative effort, we built an analytical pipeline to identify patients with chronic kidney disease (CKD) with a clinical suspicion of a monogenic condition or without a well-defined diagnosis. Following the stringent phenotypical and clinical characterization required by the flowchart, candidates meeting these criteria were further investigated by clinical exome sequencing followed by in silico analysis of 225 kidney-disease-related genes. Results By using an ad hoc web-based platform, we enrolled 160 patients from 13 different Nephrology and Genetics Units located across the Piedmont region over 15 months. A preliminary “remote” evaluation based on well-defined inclusion criteria allowed us to define eligibility for NGS analysis. Among the 138 recruited patients, 52 (37.7%) were children and 86 (62.3%) were adults. Up to 48% of them had a positive family history for kidney disease. Overall, applying this workflow led to the identification of genetic variants potentially explaining the phenotype in 78 (56.5%) cases. Conclusions These results underline the importance of clinical exome sequencing as a versatile and highly useful, non-invasive tool for genetic diagnosis of kidney diseases. Identifying patients who can benefit from targeted therapies, and improving the management of organ transplantation are further expected applications.

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.

scholarly journals Exome Sequencing in Paediatric Patients with Movement Disorders with Treatment Possibilities

2020 ◽  
Author(s):  
Anna Ka-Yee Kwong ◽  
Mandy Ho-Yin Tsang ◽  
Jasmine Lee-Fong Fung ◽  
Christopher Chun-Yu Mak ◽  
Kate Lok-San Chan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Movement Disorders ◽  
Rare Variants ◽  
Diagnostic Yield ◽  
Neurological Diseases ◽  
Genetic Diagnosis ◽  
Paediatric Patients ◽  
Whole Exome ◽  
Prediction Of Prognosis

Abstract Background: Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis. Results: We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential targeted treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation. Conclusion: A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management using targeted therapies. The study highlights the potential of implementing precision medicine in the patients.

scholarly journals Allergic Bronchopulmonary Aspergillosis in Children with Cystic Fibrosis: An Update on the Newest Diagnostic Tools and Therapeutic Approaches

Pathogens ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 716
Author(s):  
Claudia Lattanzi ◽  
Giulia Messina ◽  
Valentina Fainardi ◽  
Maria Candida Tripodi ◽  
Giovanna Pisi ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Diagnostic Criteria ◽  
Respiratory Infections ◽  
Fungal Infections ◽  
Early Recognition ◽  
Allergic Bronchopulmonary Aspergillosis ◽  
Clinical Manifestations ◽  
Diagnostic Tools ◽  
The Impact

Cystic fibrosis (CF), the most common autosomal-recessive genetic disease in the Caucasian population, is characterized by frequent respiratory infections and progressive lung disease. Fungal species are commonly found in patients with CF, and among them, Aspergillus fumigatus is the most frequently isolated. While bacteria, particularly Pseudomonas aeruginosa, have a well-established negative effect on CF lung disease, the impact of fungal infections remains unclear. In patients with CF, inhalation of Aspergillus conidia can cause allergic bronchopulmonary aspergillosis (ABPA), a Th2-mediated lung disease that can contribute to disease progression. Clinical features, diagnostic criteria and treatment of ABPA are still a matter of debate. Given the consequences of a late ABPA diagnosis or the risk of ABPA overdiagnosis, it is imperative that the diagnostic criteria guidelines are reviewed and standardized. Along with traditional criteria, radiological features are emerging as tools for further classification as well as novel immunological tests. Corticosteroids, itraconazole and voriconazole continue to be the bedrock of ABPA therapy, but other molecules, such as posaconazole, vitamin D, recombinant INF-γ and Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators, have been showing positive results. However, few studies have been conducted recruiting CF patients, and more research is needed to improve the prevention and the classification of clinical manifestations as well as to personalize treatment. Early recognition and early treatment of fungal infections may be fundamental to prevent progression of CF disease. The aim of this narrative review is to give an update on ABPA in children with CF.

The Promise of Whole-exome Sequencing for Prenatal Genetic Diagnosis

2020 ◽  
Vol 17 (1) ◽  
pp. 25-31
Author(s):  
Jiun Kang
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Disorders ◽  
Genetic Diagnosis ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Prognostic Information ◽  
Prenatal Genetic Diagnosis ◽  
Whole Exome ◽  
Nextgeneration Sequencing

Prenatal genetic diagnosis provides information for pregnancy and perinatal decision- making and management. Cytogenetic testing methods, including chromosomal microarray analysis and gene panels, have evolved to become a part of routine laboratory testing, providing valuable diagnostic and prognostic information for prenatal diagnoses. Despite this progress, however, cytogenetic analyses are limited by their resolution and diagnosis is only possible in around 40% of the dysmorphic fetuses. The advent of nextgeneration sequencing (NGS), whole-genome sequencing or whole-exome sequencing has revolutionized prenatal diagnosis and fetal medicine. These technologies have improved the identification of genetic disorders in fetuses with structural abnormalities and provide valuable diagnostic and prognostic information for the detection of genomic defects. Here, the potential future of prenatal genetic diagnosis, including a move toward NGS technologies, is discussed.

scholarly journals Common Variable Immunodeficiency with Genetic Defects Identified by Whole Exome Sequencing

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Ran Li ◽  
Yali Zheng ◽  
Yuqian Li ◽  
Rongbao Zhang ◽  
Fang Wang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Common Variable Immunodeficiency ◽  
Respiratory Infections ◽  
Genetic Diagnosis ◽  
Genetic Defects ◽  
Compound Heterozygous ◽  
Recurrent Respiratory Infections ◽  
Whole Exome ◽  
Common Variable

Common variable immunodeficiency (CVID) belongs to the primary immunodeficiency disorders (PIDs), presenting a profound heterogeneity in phenotype and genotype, with monogenic or complex causes. Recurrent respiratory infections are the most common clinical manifestations. CVID patients can also develop various autoimmune and lymphoproliferative complications. Genetic testing such as whole exome sequencing (WES) can be utilized to investigate likely genetic defects, helping for better clinical management. We described the clinical phenotypes of three sporadic cases of CVID, who developed recurrent respiratory infections with different autoimmune and lymphoproliferative complications. WES was applied to screen disease-causing or disease-associated mutations. Two patients were identified to have monogenic disorders, with compound heterozygous mutations in LRBA for one patient and a frameshift insertion in NFKB1 for another. The third patient was identified to be a complex form of CVID. Two novel mutations were identified, respectively, in LRBA and NFKB1. A combination of clinical and genetic diagnosis can be more extensively utilized in the clinical practice due to the complexity and heterogeneity of CVID.

scholarly journals Rapid Whole-Exome Sequencing as a Diagnostic Tool in a Neonatal/Pediatric Intensive Care Unit

2020 ◽  
Vol 9 (7) ◽  
pp. 2220
Author(s):  
Robert Śmigiel ◽  
Mateusz Biela ◽  
Krzysztof Szmyd ◽  
Michal Błoch ◽  
Elżbieta Szmida ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Tool ◽  
Diagnostic Yield ◽  
Genetic Disorder ◽  
Genetic Diagnosis ◽  
Monogenic Disease ◽  
Whole Exome

Genetic disorders are the leading cause of infant morbidity and mortality. Due to the large number of genetic diseases, molecular and phenotype heterogeneity and often severe course, these diseases remain undiagnosed. In infants with a suspected acute monogenic disease, rapid whole-exome sequencing (R-WES) can be successfully performed. R-WES (singletons) was performed in 18 unrelated infants with a severe and/or progressing disease with the suspicion of genetic origin hospitalized in an Intensive Care Unit (ICU). Blood samples were also collected from the parents. The results from the R-WES were available after 5–14 days. A conclusive genetic diagnosis was obtained in 13 children, corresponding to an overall diagnostic yield of 72.2%. For nine patients, R-WES was used as a first-tier test. Eight patients were diagnosed with inborn errors of metabolism, mainly mitochondrial diseases. In two patients, the disease was possibly caused by variants in genes which so far have not been associated with human disease (NARS1 and DCAF5). R-WES proved to be an effective diagnostic tool for critically ill infants in ICUs suspected of having a genetic disorder. It also should be considered as a first-tier test after precise clinical description. The quickly obtained diagnosis impacts patient’s medical management, and families can receive genetic counseling.

Sign in / Sign up

Export Citation Format

Share Document