scholarly journals Clinical Application of Whole Exome Sequencing to Identify Rare but Remediable Neurologic Disorders

2020 ◽  
Vol 9 (11) ◽  
pp. 3724
Author(s):  
Min-Jee Kim ◽  
Mi-Sun Yum ◽  
Go Hun Seo ◽  
Yena Lee ◽  
Han Na Jang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Diagnosis ◽  
Intractable Epilepsy ◽  
Episodic Ataxia ◽  
Treatment Modalities ◽  
Congenital Myasthenic Syndrome ◽  
Early Application ◽  
Whole Exome ◽  
Neurologic Disorders

Background: The aim of this study was to describe the application of whole exome sequencing (WES) in the accurate genetic diagnosis and personalized treatment of extremely rare neurogenetic disorders. Methods: From 2017 to 2019, children with neurodevelopmental symptoms were evaluated using WES in the pediatric neurology clinic and medical genetics center. The clinical presentation, laboratory findings including the genetic results from WES, and diagnosis-based treatment and outcomes of the four patients are discussed. Results: A total of 376 children with neurodevelopmental symptom were evaluated by WES, and four patients (1.1%) were diagnosed with treatable neurologic disorders. Patient 1 (Pt 1) showed global muscle hypotonia, dysmorphic facial features, and multiple anomalies beginning in the perinatal period. Pt 1 was diagnosed with congenital myasthenic syndrome 22 of PREPL deficiency. Pt 2 presented with hypotonia and developmental arrest and was diagnosed with autosomal recessive dopa-responsive dystonia due to TH deficiency. Pt 3, who suffered from intractable epilepsy and progressive cognitive decline, was diagnosed with epileptic encephalopathy 47 with a heterozygous FGF12 mutation. Pt 4 presented with motor delay and episodic ataxia and was diagnosed with episodic ataxia type II (heterozygous CACNA1A mutation). The patients’ major neurologic symptoms were remarkably relieved with pyridostigmine (Pt 1), levodopa (Pt 2), sodium channel blocker (Pt 3), and acetazolamide (Pt 4), and most patients regained developmental milestones in the follow-up period (0.4 to 3 years). Conclusions: The early application of WES helps in the identification of extremely rare genetic diseases, for which effective treatment modalities exist. Ultimately, WES resulted in optimal clinical outcomes of affected 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 Novel MYO15A variants are associated with hearing loss in the two Iranian pedigrees

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Somayeh Khatami ◽  
Masomeh Askari ◽  
Fatemeh Bahreini ◽  
Morteza Hashemzadeh-Chaleshtori ◽  
Saeed Hematian ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Diagnosis ◽  
Clinical Genetic ◽  
Large Size ◽  
Whole Exome ◽  
Novel Variants ◽  
Syndromic Hearing Loss ◽  
Traditional Approaches

Abstract Background Clinical genetic diagnosis of non-syndromic hearing loss (NSHL) is quite challenging. With regard to its high heterogeneity as well as large size of some genes, it is also really difficult to detect causative mutations using traditional approaches. One of the recent technologies called whole-exome sequencing (WES) has been thus developed in this domain to remove the limitations of conventional methods. Methods This study was a report on a research study of two unrelated pedigrees with multiple affected cases of hearing loss (HL). Accordingly, clinical evaluations and genetic analysis were performed in both families. Results The results of WES data analysis to uncover autosomal recessive non-syndromic hearing loss (ARNSHL) disease-causing variants was reported in the present study. Initial analysis identified two novel variants of MYO15A i.e. c.T6442A:p.W2148R and c.10504dupT:p.C3502Lfs*15 correspondingly which were later confirmed by Sanger validations and segregation analyses. According to online prediction tools, both identified variants seemed to have damaging effects. Conclusion In this study, whole exome sequencing were used as a first approach strategy to identify the two novel variants in MYO15A in two Iranian families with ARNSHL.

scholarly journals Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency

2016 ◽  
Vol 7 ◽  
Author(s):  
Patrick Maffucci ◽  
Charles A. Filion ◽  
Bertrand Boisson ◽  
Yuval Itan ◽  
Lei Shang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Common Variable Immunodeficiency ◽  
Genetic Diagnosis ◽  
Whole Exome ◽  
Common Variable

scholarly journals Whole-exome sequencing in an individual with severe global developmental delay and intractable epilepsy identifies a novel, de novoGRIN2Amutation

Epilepsia ◽  
2014 ◽  
Vol 55 (7) ◽  
pp. e75-e79 ◽  
Author(s):  
Sunita Venkateswaran ◽  
Ken A. Myers ◽  
Amanda C. Smith ◽  
Chandree L. Beaulieu ◽  
Jeremy A. Schwartzentruber ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
Intractable Epilepsy ◽  
Global Developmental Delay ◽  
Whole Exome

Identification of Two Novel Mutations in PKHD1 Gene from Two Families with Polycystic Kidney Disease by Whole Exome Sequencing

2021 ◽  
Vol 22 ◽  
Author(s):  
Masoud Heidari ◽  
Hamid Gharshasbi ◽  
Alireza Isazadeh ◽  
Morteza Soleyman-Nejad ◽  
Mohammad Hossein Taskhiri ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Exome Sequencing ◽  
Polycystic Kidney Disease ◽  
Whole Exome Sequencing ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Genetic Alterations ◽  
Polycystic Kidney ◽  
Novel Mutations ◽  
Whole Exome

Background:: Polycystic kidney disease (PKD) is an autosomal recessive disorder resulting from mutations in the PKHD1 gene on chromosome 6 (6p12), a large gene spanning 470 kb of genomic DNA. Objective: The aim of the present study was to report newly identified mutations in the PKHD1 gene in two Iranian families with PKD. Materials and Methods: Genetic alterations of a 3-month-old boy and a 27-year-old girl with PKD were evaluated using whole-exome sequencing. The PCR direct sequencing was performed to analyse the co-segregation of the variants with the disease in the family. Finally, the molecular function of the identified novel mutations was evaluated by in silico study. Results: In the 3 month-old boy, a novel homozygous frameshift mutation was detected in the PKHD1 gene, which can cause PKD. Moreover, we identified three novel heterozygous missense mutations in ATIC, VPS13B, and TP53RK genes. In the 27-year-old woman, with two recurrent abortions history and two infant mortalities at early weeks due to metabolic and/or renal disease, we detected a novel missense mutation on PKHD1 gene and a novel mutation in ETFDH gene. Conclusion: In general, we have identified two novel mutations in the PKHD1 gene. These molecular findings can help accurately correlate genotype and phenotype in families with such disease in order to reduce patient births through preoperative genetic diagnosis or better management of disorders.

scholarly journals Not Only Diagnostic Yield: Whole-Exome Sequencing in Infantile Cardiomyopathies Impacts on Clinical and Family Management

2021 ◽  
Vol 9 (1) ◽  
pp. 2
Author(s):  
Laura Pezzoli ◽  
Lidia Pezzani ◽  
Ezio Bonanomi ◽  
Chiara Marrone ◽  
Agnese Scatigno ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Molecular Diagnosis ◽  
Clinical Management ◽  
Genetic Diagnosis ◽  
Family Management ◽  
Whole Exome ◽  
Time To Diagnosis ◽  
The Mean ◽  
Mean Time

Whole-exome sequencing (WES) is a powerful and comprehensive tool for the genetic diagnosis of rare diseases, but few reports describe its timely application and clinical impact on infantile cardiomyopathies (CM). We conducted a retrospective analysis of patients with infantile CMs who had trio (proband and parents)-WES to determine whether results contributed to clinical management in urgent and non-urgent settings. Twenty-nine out of 42 enrolled patients (69.0%) received a definitive molecular diagnosis. The mean time-to-diagnosis was 9.7 days in urgent settings, and 17 out of 24 patients (70.8%) obtained an etiological classification. In non-urgent settings, the mean time-to-diagnosis was 225 days, and 12 out of 18 patients (66.7%) had a molecular diagnosis. In 37 out of 42 patients (88.1%), the genetic findings contributed to clinical management, including heart transplantation, palliative care, or medical treatment, independent of the patient’s critical condition. All 29 patients and families with a definitive diagnosis received specific counseling about recurrence risk, and in seven (24.1%) cases, the result facilitated diagnosis in parents or siblings. In conclusion, genetic diagnosis significantly contributes to patients’ clinical and family management, and trio-WES should be performed promptly to be an essential part of care in infantile cardiomyopathy, maximizing its clinical utility.

scholarly journals Searching for the missing genetic determinants of hereditary breast cancer risk by whole-exome sequencing of BRCA-negative patients: new candidate genes USP39, SLIT3, CREB3

2021 ◽  
Vol 67 (1) ◽  
pp. 111-116
Author(s):  
Kirill Zagorodnev ◽  
Aleksandr Romanko ◽  
Uliy Gorgul ◽  
Aleksandr Ivantsov ◽  
Anna Sokolenko ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Exome Sequencing ◽  
Candidate Genes ◽  
Whole Exome Sequencing ◽  
Hereditary Breast Cancer ◽  
Germ Line ◽  
Genetic Diagnosis ◽  
Clinical Signs ◽  
Causative Mutation ◽  
Whole Exome

The search for the new hereditary mutations and a precise molecular genetic diagnosis that determines the causative mutation in each specific case of hereditary breast cancer (BC) is a clinically important task since it helps to define the personal therapeutic approach and increase the effectiveness of preventive measures. Using whole-exome sequencing (WES) we analyzed the full spectrum of hereditary variations in 49 Russian patients with clinical signs of a hereditary disease which allowed us to compile a list of 229 candidate probably pathogenic germ-line variants. Then, the selected candidate mutations were validated by Sanger sequencing and molecular-epidemiological studies, the predisposing roles of three oncologically relevant mutations (USP39 c.*208G>C, SLIT3 p.Arg154Cys, and CREB3 p.Lys157Glu) were confirmed. Our candidate genes are first mentioned in connection with the hereditary risk of BC. The final proofs of the causative roles of these variants could be obtained through functional tests as well as via the analysis of the mutations segregation in BC families.

Utility of Whole Exome Sequencing for Genetic Diagnosis of Previously Undiagnosed Pediatric Neurology Patients

2016 ◽  
Vol 31 (14) ◽  
pp. 1534-1539 ◽  
Author(s):  
Maya Kuperberg ◽  
Dorit Lev ◽  
Lubov Blumkin ◽  
Ayelet Zerem ◽  
Mira Ginsberg ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Autosomal Recessive ◽  
Genetic Diagnosis ◽  
Clinical Feature ◽  
Causative Gene ◽  
High Detection Rate ◽  
Whole Exome ◽  
Neurological Patients ◽  
Low Costs

Whole exome sequencing enables scanning a large number of genes for relatively low costs. The authors investigate its use for previously undiagnosed pediatric neurological patients. This retrospective cohort study performed whole exome sequencing on 57 patients of “Magen” neurogenetic clinics, with unknown diagnoses despite previous workup. The authors report on clinical features, causative genes, and treatment modifications and provide an analysis of whole exome sequencing utility per primary clinical feature. A causative gene was identified in 49.1% of patients, of which 17 had an autosomal dominant mutation, 9 autosomal recessive, and 2 X-linked. The highest rate of positive diagnosis was found for patients with developmental delay, ataxia, or suspected neuromuscular disease. Whole exome sequencing warranted a definitive change of treatment for 5 patients. Genetic databases were updated accordingly. In conclusion, whole exome sequencing is useful in obtaining a high detection rate for previously undiagnosed disorders. Use of this technique could affect diagnosis, treatment, and prognostics for both patients and relatives.

scholarly journals Delineation of molecular findings by whole exome sequencing for suspected cases of paediatric-onset mitochondrial diseases in the Southern Chinese population

2020 ◽  
Author(s):  
Mandy Ho-Yin Tsang ◽  
Anna Ka-Yee Kwong ◽  
Kate Lok-San Chan ◽  
Jasmine Lee-Fong Fung ◽  
Mullin Ho-Chung Yu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Chinese Population ◽  
Founder Mutation ◽  
Diagnostic Yield ◽  
Genetic Diagnosis ◽  
Mitochondrial Diseases ◽  
Chinese Patients ◽  
Southern Chinese ◽  
Whole Exome

Abstract BackgroundMitochondrial diseases (MDs) are a group of clinically and genetically heterogeneous disorders characterized by defects in oxidative phosphorylation. Since clinical phenotypes of MDs may be non-specific, genetic diagnosis is crucial for guiding disease management. In the current study, whole-exome sequencing (WES) was performed for our paediatric-onset MD cohort of a Southern Chinese origin, with the aim of identifying key disease-causing variants in the Chinese patients with MDs.MethodsWe recruited Chinese patients who had paediatric-onset MDs and a minimum mitochondrial disease criteria (MDC) score of 3. Patients with positive target gene or mitochondrial DNA sequencing results were excluded. WES was performed, variants with population frequency ≤1% were analysed for pathogenicity on the basis of the American College of Medical Genetics and Genomics guidelines.ResultsSixty-six patients with pre-biopsy MDC scores of 3–8 were recruited. The overall diagnostic yield was 35% (23/66). Eleven patients (17%) were found to have mutations in MD-related genes, with COQ4 having the highest mutation rate owing to the Chinese-specific founder mutation (4/66, 6%). Twelve patients (12/66, 18%) had mutations in non-MD-related genes: ATP1A3 (n=3, two were siblings), ALDH5A1 , ARX , FA2H , KCNT1 , LDHD , NEFL , NKX2-2 , TBCK , and WAC.ConclusionsWe confirmed that the COQ4 :c.370G>A, p.(Gly124Ser) variant was a recurrent founder mutation among the Southern Chinese population. Screening for this mutation should therefore be considered while diagnosing Chinese patients suspected to have MDs. Furthermore, WES has proven to be useful in detecting variants in patients suspected to have MDs because it helps to obtain an unbiased and precise genetic diagnosis for these diseases, which are genetically heterogeneous.

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