scholarly journals Powerful use of automated prioritization of candidate variants in genetic hearing loss with extreme etiologic heterogeneity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
So Young Kim ◽  
Seungmin Lee ◽  
Go Hun Seo ◽  
Bong Jik Kim ◽  
Doo Yi Oh ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Molecular Diagnosis ◽  
Diagnostic Yield ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Variant Prioritization ◽  
Manual Analysis ◽  
Genetic Hearing Loss ◽  
Etiologic Heterogeneity ◽  
Molecular Genetic Diagnosis

AbstractVariant prioritization of exome sequencing (ES) data for molecular diagnosis of sensorineural hearing loss (SNHL) with extreme etiologic heterogeneity poses a significant challenge. This study used an automated variant prioritization system (“EVIDENCE”) to analyze SNHL patient data and assess its diagnostic accuracy. We performed ES of 263 probands manifesting mild to moderate or higher degrees of SNHL. Candidate variants were classified according to the 2015 American College of Medical Genetics guidelines, and we compared the accuracy, call rates, and efficiency of variant prioritizations performed manually by humans or using EVIDENCE. In our in silico panel, 21 synthetic cases were successfully analyzed by EVIDENCE. In our cohort, the ES diagnostic yield for SNHL by manual analysis was 50.19% (132/263) and 50.95% (134/263) by EVIDENCE. EVIDENCE processed ES data 24-fold faster than humans, and the concordant call rate between humans and EVIDENCE was 97.72% (257/263). Additionally, EVIDENCE outperformed human accuracy, especially at discovering causative variants of rare syndromic deafness, whereas flexible interpretations that required predefined specific genotype–phenotype correlations were possible only by manual prioritization. The automated variant prioritization system remarkably facilitated the molecular diagnosis of hearing loss with high accuracy and efficiency, fostering the popularization of molecular genetic diagnosis of SNHL.

Non-syndromic hearing loss: clinical and diagnostic challenges

2020 ◽  
Vol 32 (2) ◽  
pp. 117-129
Author(s):  
Barbara Vona ◽  
Julia Doll ◽  
Michaela A. H. Hofrichter ◽  
Thomas Haaf
Keyword(s):  
Hearing Loss ◽  
Diagnostic Yield ◽  
Molecular Genetic ◽  
Diagnostic Testing ◽  
Genetic Diagnosis ◽  
Treatment Modalities ◽  
Hereditary Hearing Loss ◽  
Planning Decisions ◽  
Preclinical Trials ◽  
Syndromic Hearing Loss

Abstract Hereditary hearing loss is clinically and genetically heterogeneous. There are presently over 120 genes that have been associated with non-syndromic hearing loss and many more that are associated with syndromic forms. Despite an increasing number of genes that have been implemented into routine molecular genetic diagnostic testing, the diagnostic yield from European patient cohorts with hereditary hearing loss remains around the 50 % mark. This attests to the many gaps of knowledge the field is currently working toward resolving. It can be expected that many more genes await identification. However, it can also be expected, for example, that the mutational signatures of the known genes are still unclear, especially variants in non-coding or regulatory regions influencing gene expression. This review summarizes several challenges in the clinical and diagnostic setting for hereditary hearing loss with emphasis on syndromes that mimic non-syndromic forms of hearing loss in young children and other factors that heavily influence diagnostic rates. A molecular genetic diagnosis for patients with hearing loss opens several additional avenues, such as patient tailored selection of the best currently available treatment modalities, an understanding of the prognosis, and supporting family planning decisions. In the near future, a genetic diagnosis may enable patients to engage in preclinical trials for the development of therapeutics.

scholarly journals Whole-Exome Sequencing Enables a Precision Medicine Approach for Kidney Transplant Recipients

2019 ◽  
Vol 30 (2) ◽  
pp. 201-215 ◽  
Author(s):  
Nina Mann ◽  
Daniela A. Braun ◽  
Kassaundra Amann ◽  
Weizhen Tan ◽  
Shirlee Shril ◽  
...  
Keyword(s):  
Diagnostic Yield ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Renal Transplant Recipients ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Whole Exome ◽  
Pediatric Renal Transplant ◽  
Molecular Genetic Diagnosis ◽  
Pediatric Renal Transplant Recipients

BackgroundWhole-exome sequencing (WES) finds a CKD-related mutation in approximately 20% of patients presenting with CKD before 25 years of age. Although provision of a molecular diagnosis could have important implications for clinical management, evidence is lacking on the diagnostic yield and clinical utility of WES for pediatric renal transplant recipients.MethodsTo determine the diagnostic yield of WES in pediatric kidney transplant recipients, we recruited 104 patients who had received a transplant at Boston Children’s Hospital from 2007 through 2017, performed WES, and analyzed results for likely deleterious variants in approximately 400 genes known to cause CKD.ResultsBy WES, we identified a genetic cause of CKD in 34 out of 104 (32.7%) transplant recipients. The likelihood of detecting a molecular genetic diagnosis was highest for patients with urinary stone disease (three out of three individuals), followed by renal cystic ciliopathies (seven out of nine individuals), steroid-resistant nephrotic syndrome (nine out of 21 individuals), congenital anomalies of the kidney and urinary tract (ten out of 55 individuals), and chronic glomerulonephritis (one out of seven individuals). WES also yielded a molecular diagnosis for four out of nine individuals with ESRD of unknown etiology. The WES-related molecular genetic diagnosis had implications for clinical care for five patients.ConclusionsNearly one third of pediatric renal transplant recipients had a genetic cause of their kidney disease identified by WES. Knowledge of this genetic information can help guide management of both transplant patients and potential living related donors.

scholarly journals A genome sequencing program for novel undiagnosed diseases

2015 ◽  
Vol 17 (12) ◽  
pp. 995-1001 ◽  
Author(s):  
Cinnamon S. Bloss ◽  
Ashley A. Scott-Van Zeeland ◽  
Sarah E. Topol ◽  
Burcu F. Darst ◽  
Debra L. Boeldt ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
Molecular Diagnosis ◽  
Genetic Disorder ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Clinical Information ◽  
Case Review ◽  
Novel Gene ◽  
A Genome ◽  
Molecular Genetic Diagnosis

Abstract Purpose: The Scripps Idiopathic Diseases of Man (IDIOM) study aims to discover novel gene–disease relationships and provide molecular genetic diagnosis and treatment guidance for individuals with novel diseases using genome sequencing integrated with clinical assessment and multidisciplinary case review. Here we describe the operational protocol and initial results of the IDIOM study. Methods: A total of 121 cases underwent first-tier review by the principal investigators to determine whether the primary inclusion criteria were satisfied, 59 (48.8%) underwent second-tier review by our clinician–scientist review panel, and 17 patients (14.0%) and their family members were enrolled. Results: 60% of cases resulted in a plausible molecular diagnosis, and 18% of cases resulted in a confirmed molecular diagnosis. Two of three confirmed cases led to the identification of novel gene–disease relationships. In the third confirmed case a previously described but unrecognized disease was revealed. In all three confirmed cases a new clinical management strategy was initiated based on the genetic findings. Conclusion: Genome sequencing provides tangible clinical benefit for individuals with idiopathic genetic disease, not only in the context of molecular genetic diagnosis of known rare conditions but also in cases where prior clinical information regarding a new genetic disorder is lacking. Genet Med 17 12, 995–1001.

Clinical and genetic investigation of 136 Japanese patients with congenital hypothyroidism

2020 ◽  
Vol 33 (6) ◽  
pp. 691-701 ◽  
Author(s):  
Tatsushi Tanaka ◽  
Kohei Aoyama ◽  
Atsushi Suzuki ◽  
Shinji Saitoh ◽  
Haruo Mizuno
Keyword(s):  
Congenital Hypothyroidism ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Japanese Patients ◽  
Thyroid Stimulating Hormone ◽  
Allelic Variant ◽  
Genetic Investigation ◽  
Pathogenic Variants ◽  
Recessive Genes ◽  
Molecular Genetic Diagnosis

AbstractObjectivesCongenital hypothyroidism (CH) is the most common congenital endocrine disorder. Recent advances in genetic testing have revealed its causative mutations in some CH patients. However, the underlying etiology remains unknown in most patients. This study aimed to perform clinical and genetic investigation in Japanese CH patients to uncover genotype-phenotype correlations.MethodsWe enrolled 136 Japanese patients with transient or permanent CH between April 2015 and March 2017, and performed next-generation sequencing of 19 genes implicated in CH.ResultsWe identified potentially pathogenic bi-allelic variants in DUOX2, TSHR, and TPO in 19, 5, and 1 patient, respectively (autosomal recessive), and a potentially pathogenic mono-allelic variant in NKX2-1 (autosomal dominant) in 1 patient. Molecular genetic diagnosis was highly suggested in 26 patients (19%) from 23 families. We also detected a potentially pathogenic mono-allelic variant in five recessive genes (DUOX2, TSHR, TG, DUOXA2, and TPO) in 31 unrelated patients (23%), although the pathogenicity of these variants remains inconclusive. Patients with bi-allelic DUOX2 variants showed a more severe clinical presentation in infancy than those with bi-allelic TSHR variants. However, this trend reversed beyond infancy. There were no statistical differences in initial thyroid stimulating hormone, free thyroxine, thyroglobulin, and levothyroxine dose as of March 2017 between patients with bi-allelic and mono-allelic DUOX2 variants.ConclusionsThe prevalence of potentially-pathogenic variants in Japanese CH patients was similar to that found by previous reports. Our study demonstrates a genotype-phenotype correlation in Japanese CH patients.

Mitochondrial encephalopathies: molecular genetic diagnosis from blood samples

The Lancet ◽  
1991 ◽  
Vol 337 (8753) ◽  
pp. 1311-1313 ◽  
Author(s):  
S.R. Hammans ◽  
M.G. Sweeney ◽  
M. Brockington ◽  
J.A. Morgan-Hughes ◽  
A.E. Harding
Keyword(s):  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Blood Samples ◽  
Molecular Genetic Diagnosis

scholarly journals Clinician's modern approaches to molecular genetic diagnosis of glioblastomas

2021 ◽  
Vol 67 (1) ◽  
pp. 13-19
Author(s):  
Turna Ashkhatcava ◽  
Marina Tatarinova ◽  
Lali Kogoniya ◽  
David Naskhletashvili ◽  
Vadim Zhukov
Keyword(s):  
Braf Mutation ◽  
Molecular Mechanisms ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Braf V600e ◽  
Poor Prognostic Factor ◽  
Molecular Genetic Diagnosis ◽  
The Brain ◽  
Tert Mutation ◽  
Primary Glioblastomas

The article is devoted to the issue of molecular genetic diagnosis of cerebral glioblastomas. Despite significant advances in neurooncology, little progress has been made in prolonging the life of patients with cerebral glioblastoma, and a significant part of the effectiveness of treatment depends on the recognition of two prognostic biomarkers: mutations of the isocitrate dehydrogenase (IDH) promoter and  the methylation of the O6-methylguanine methyl transferase (MGMT) promoter. The article summarizes the data of world and domestic clinical studies, allowing to supplement the histological characteristics of primary glioblastomas with genetic markers: the presence of the TERT mutation, EFGR amplification, loss of PTEN function, LOH 10q, and the presence of the BRAF mutation. It should be noted that the amplification of EGFR, causing resistance to apoptotic stimuli and alkylating chemotherapy with Temozolomide, attracts much attention as a therapeutic target. The frequency of occurrence of the TERT mutation is 90% of all tumors of various genesis, most often the TERT mutation is found in oligodendroglioma or primary glioblastoma. Loss of heterozygosity in the region of localization of the PTEN gene is observed in many types of sporadic tumors, including more than 40% of glioblastomas. Mutations in this gene are found in tumors of the brain, endometrium, prostate, kidney, and mammary gland. The presence of a PTEN mutation is a poor prognostic factor. LOH 22q is much more common in secondary glioblastomas (82%) than in primary glioblastomas (41%). Among brain tumors, the BRAF mutation is most common with pleomorphic xanastrocytoma (60-70%).The BRAF V600E mutation was found in epithelioid glioblastoma, which is a rare and aggressive type of glioblastoma, characterized by an unfavorable prognosis (about 6 months) and frequent leptomeningeal spread. Thus, knowledge of the molecular mechanisms of carcinogenesis will enable a personalized approach to treatment with glioblastomas of the brain.

scholarly journals Molecular Genetic Diagnosis of von Hippel-Lindau Disease: Analysis of Five Japanese Families

1996 ◽  
Vol 87 (5) ◽  
pp. 423-428 ◽  
Author(s):  
Hiroshi Kanno ◽  
Taro Shuin ◽  
Keiichi Kondo ◽  
Susumu Ito ◽  
Masahiko Hosaka ◽  
...  
Keyword(s):  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Molecular Genetic Diagnosis ◽  
Disease Analysis
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