Whole exome sequencing using Ion Proton system enables reliable genetic diagnosis of inherited retinal dystrophies

Abstract Inherited retinal dystrophies (IRDs), displaying pronounced genetic and clinical heterogeneity, comprise of a broad range of diseases characterized by progressive retinal cell death and gradual loss of vision. By the combined use of whole exome sequencing (WES), SNP-array and WES-based homozygosity mapping, as well as directed DNA sequencing (Sanger), we have identified nine pathogenic variants in six genes (ABCA4, RPE65, MERTK, USH2A, SPATA7, TULP1) in 10 consanguineous Iranian families. Six of the nine identified variants were novel, including a putative founder mutation in ABCA4 (c.3260A>G, p.Glu1087Gly), detected in two families from Northeastern Iran. Our findings provide additional information to the molecular pathology of IRDs in Iran, hopefully contributing to better genetic counselling and patient management in the respective families from this country.

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Whole exome sequencing reveals putatively novel associations in retinopathies and drusen formation

European Journal of Human Genetics ◽

10.1038/s41431-021-00872-3 ◽

2021 ◽

Author(s):

Lance P. Doucette ◽

Nicole C. L. Noel ◽

Yi Zhai ◽

Manlong Xu ◽

Oana Caluseriu ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Research Setting ◽

Genetic Etiology ◽

Inherited Retinal Dystrophies ◽

Retinal Dystrophies ◽

Clinical Investigations ◽

Whole Exome ◽

Disease Associated Genes ◽

Novel Associations

AbstractInherited retinal dystrophies (IRDs) affect 1 in 3000 individuals worldwide and are genetically heterogeneous, with over 270 identified genes and loci; however, there are still many identified disorders with no current genetic etiology. Whole exome sequencing (WES) provides a hypothesis-free first examination of IRD patients in either a clinical or research setting to identify the genetic cause of disease. We present a study of IRD in ten families from Alberta, Canada, through the lens of novel gene discovery. We identify the genetic etiology of IRDs in three of the families to be variants in known disease-associated genes, previously missed by clinical investigations. In addition, we identify two potentially novel associations: LRP1 in early-onset drusen formation and UBE2U in a multi-system condition presenting with retinoschisis, cataracts, learning disabilities, and developmental delay. We also describe interesting results in our unsolved cases to provide further information to other investigators of these blinding conditions.

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Exome sequencing in paediatric patients with movement disorders

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01688-6 ◽

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.

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Novel MYO15A variants are associated with hearing loss in the two Iranian pedigrees

BMC Medical Genetics ◽

10.1186/s12881-020-01168-x ◽

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.

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Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency

Frontiers in Immunology ◽

10.3389/fimmu.2016.00220 ◽

2016 ◽

Vol 7 ◽

Cited By ~ 117

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

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

Current Genomics ◽

10.2174/1389202922666210219111810 ◽

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.

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

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd9010002 ◽

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.

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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

Problems in oncology ◽

10.37469/0507-3758-2021-67-1-111-116 ◽

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.

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