scholarly journals An automatic diagnostic system for pediatric genetic disorders developed by linking genotype and phenotype information

2021 ◽  
Author(s):  
Xinran Dong ◽  
Bingbing Wu ◽  
Huijun Wang ◽  
Lin Yang ◽  
Xiang Chen ◽  
...  
Keyword(s):  
Clinical Phenotype ◽  
Genetic Disorders ◽  
Quantitative Description ◽  
Genetic Diagnosis ◽  
Diagnostic System ◽  
Causal Gene ◽  
Bayes Model ◽  
Phenotype Data ◽  
Precision Recall Curve ◽  
Pediatric Disorders

Background: Quantitatively describe the phenotype spectrum of pediatric disorders has remarkable power to assist genetic diagnosis. Here, we developed a matrix which provide this quantitative description of genomic-phenotypic association and constructed an automatic system to assist the diagnose of pediatric genetic disorders. Results: 20,580 patients with genetic diagnostic conclusions from the Children's Hospital of Fudan University during 2015 to 2019 were reviewed. Based on that, a phenotype spectrum matrix -- cGPS (clinical Gene's Preferential Synopsis) -- was designed by Naive Bayes model to quantitatively describe genes' contribution to clinical phenotype categories. Further, for patients who have both genomic and phenotype data, we designed a ConsistencyScore based on cGPS. ConsistencyScore aimed to figure out genes that were more likely to be the genetic causal of the patient's phenotype and to prioritize the causal gene among all candidates. When using the ConsistencyScore in each sample to predict the causal gene for patients, the AUC could reach 0.975 for ROC (95% CI 0.972-0.976 and 0.575 for precision-recall curve (95% CI 0.541-0.604). Further, the performance of ConsistencyScore was evaluated on another cohort with 2,323 patients, which could rank the causal gene of the patient as the first for 75.00% (95% CI 70.95%-79.07%) of the 296 positively genetic diagnosed patients. The causal gene of 97.64% (95% CI 95.95%-99.32%) patients could be ranked within top 10 by ConsistencyScore, which is much higher than existing algorithms (p <0.001). Conclusions: cGPS and ConsistencyScore offer useful tools to prioritize disease-causing genes for pediatric disorders and show great potential in clinical applications.

scholarly journals Diagnosis of ‘possible’ mitochondrial disease: an existential crisis

2019 ◽  
Vol 56 (3) ◽  
pp. 123-130 ◽  
Author(s):  
Sumit Parikh ◽  
Amel Karaa ◽  
Amy Goldstein ◽  
Enrico Silvio Bertini ◽  
Patrick F Chinnery ◽  
...  
Keyword(s):  
Mitochondrial Disease ◽  
Clinical Phenotype ◽  
Genetic Disorders ◽  
Genetic Diagnosis ◽  
Mitochondrial Diseases ◽  
Genomic Testing ◽  
Existential Crisis ◽  
Specific Description ◽  
Genetic Abnormalities ◽  
Biochemical Abnormalities

Primary genetic mitochondrial diseases are often difficult to diagnose, and the term ‘possible’ mitochondrial disease is used frequently by clinicians when such a diagnosis is suspected. There are now many known phenocopies of mitochondrial disease. Advances in genomic testing have shown that some patients with a clinical phenotype and biochemical abnormalities suggesting mitochondrial disease may have other genetic disorders. In instances when a genetic diagnosis cannot be confirmed, a diagnosis of ‘possible’ mitochondrial disease may result in harm to patients and their families, creating anxiety, delaying appropriate diagnosis and leading to inappropriate management or care. A categorisation of ‘diagnosis uncertain’, together with a specific description of the metabolic or genetic abnormalities identified, is preferred when a mitochondrial disease cannot be genetically confirmed.

Attitudes Toward Pre-implantation Genetic Diagnosis (PGD) for Genetic Disorders Among Potential Users in Malaysia

2015 ◽  
Vol 22 (1) ◽  
pp. 133-146 ◽  
Author(s):  
Angelina Patrick Olesen ◽  
Siti Nurani Mohd Nor ◽  
Latifah Amin
Keyword(s):  
Genetic Disorders ◽  
Genetic Diagnosis

scholarly journals Comprehensive Analysis of Tissue-wide Gene Expression and Phenotype Data Reveals Tissues Affected in Rare Genetic Disorders

Cell Systems ◽  
2017 ◽  
Vol 5 (2) ◽  
pp. 140-148.e2 ◽  
Author(s):  
Ariel Feiglin ◽  
Bryce K. Allen ◽  
Isaac S. Kohane ◽  
Sek Won Kong
Keyword(s):  
Gene Expression ◽  
Genetic Disorders ◽  
Comprehensive Analysis ◽  
Phenotype Data

scholarly journals Case Report: A de novo CTNNB1 Nonsense Mutation Associated With Neurodevelopmental Disorder, Retinal Detachment, Polydactyly

2020 ◽  
Vol 8 ◽  
Author(s):  
Zhongling KE ◽  
Yanhui CHEN
Keyword(s):  
Retinal Detachment ◽  
Gene Mutation ◽  
De Novo ◽  
Clinical Phenotype ◽  
Neurodevelopmental Disorder ◽  
Genetic Diagnosis ◽  
Spastic Diplegia ◽  
Rehabilitation Training ◽  
Asian Patients ◽  
Insight Into

CTNNB1 gene mutation was firstly reported related to intellectual disability in 2012, to explore the clinical phenotype and genotype characteristics of CTNNB1 mutation, we collected and analyzed the clinical data of a child with a neurodevelopmental disorder caused by a mutation of CTNNB1. The child had dysmorphic features, microcephaly, hypotonia, polydactyly, retinal detachment, and neurodevelopmental disorder, with a de novo mutation of CTNNB1 c.1603C &gt; T, p.R535X. The patient was diagnosed as Neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV) and was given rehabilitation training. After 4 months of rehabilitation training, she improved in gross motor function. We found that CTNNB1 mutation can cause neurodevelopmental disorder, which could be accompanied by retinal detachment and polydactyly. The retinal detachment had only been reported in two Asian patients, and we firstly reported the phenotype of polydactyly in the CTNNB1 mutation. This report not only helps to expand the clinical phenotype spectrum of the CTNNB1 gene mutation but also prompts a new insight into genetic diagnosis in patients with a neurodevelopmental disorder, retinal detachment, and polydactyly.

The current state and legal framework of preimplantation genetic diagnosis (PGD) in Japan

2004 ◽  
Vol 1 (3) ◽  
Author(s):  
Mariko Nishizawa
Keyword(s):  
High Risk ◽  
Preimplantation Genetic Diagnosis ◽  
Reproductive Medicine ◽  
Genetic Disorders ◽  
Genetic Diagnosis ◽  
Legal Framework ◽  
Reproductive Technology ◽  
Current State ◽  
Reproductive Technique ◽  
Policy Discussion

AbstractBecause of the rapid advances currently taking place in reproductive technology, Japan is being pressed to adjust its conventional approach to reproductive medicine. One example of the innovations in the technology is the reproductive technique known as preimplantation genetic diagnosis, or PGD (PGD is seen by some as a reproductive technique that can help couples who are at high risk of passing on serious genetic disorders to their offspring. However, it is a contested technology. Concerns are increasingly being raised about the lack of sufficient public debate and policy discussion concerning the test's ethical and social implications. The need for policy discussions and a comprehensive legal system to control all areas of reproductive medicine, including PGD, should be more widely addressed.

scholarly journals Whole exome analysis of primary immunodeficiency

2018 ◽  
Vol 22 (5) ◽  
pp. 620-626
Author(s):  
E. S. Rahmani ◽  
Н. Azarpara ◽  
M. Karimipoor ◽  
Н. Rahimi
Keyword(s):  
Primary Immunodeficiency ◽  
Genetic Disorders ◽  
Single Gene ◽  
Correct Diagnosis ◽  
Severe Combined Immunodeficiency ◽  
Genetic Diagnosis ◽  
Cost Effective ◽  
Mendelian Disease ◽  
Inherited Disorders ◽  
Whole Exome

The human primary immunodeficiency diseases (PIDs) refer to a rare heterogeneous group of single-gene inherited disorders causing malfunctions in the immune system, and thus the affected patients have a predisposition to severe life-threatening infections. The heterogeneous nature of PIDs, which involves at list 300 different genes, makes diagnosis of the disease a complex issue. Although studies revealed that six million people have a kind of PID, but due to a complex diagnosis procedure many affected individuals have not gotten a correct diagnosis. However, thanks to advancing in the DNA sequencing method and availability of sophisticated sequencers molecular characterization of genetic disorders have been revolutionized. The whole exome sequencing (WES) method can help clinicians detect Mendelian disease and other complex genetic disorders. The presented study used WES to investigate two infants with symptoms of primary immunodeficiency including hemophagocytic lymphohistio­cytosis (HLH) and severe combined immunodeficiency (SCID). It has been shown that the HLH patient had a mutation in the UNC13D gene (NM_199242.2:c.627delT), and the SCID patient had a mutation in the RAG1 gene (NM_000448.2:c.322C>G). It has been demonstrated that WES is a fast and cost-effective method facilitating genetic diagnosis in PID sufferers.

scholarly journals MITF p.Arg217Thr Variant Identified in a Han Chinese Family with Tietz/Waardenburg Syndrome

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Rong Yu ◽  
Lv Liu ◽  
Ya-Li Li ◽  
Liang-Liang Fan
Keyword(s):  
Hearing Loss ◽  
Genetic Disorders ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Han Chinese ◽  
White Hair ◽  
Chinese Family ◽  
Waardenburg Syndrome ◽  
Genetic Lesion

Waardenburg syndrome (WS) is a group of rare genetic disorders characterized by hearing loss, changes in coloring of hair, skin, and eyes, and alterations in the shape of the face. Tietz syndrome is another rare disorder which presented similar phenotypes to WS. Patients with Tietz/Waardenburg syndrome often present with pale blue eyes, albino skin, and distinctive hair coloring, such as a patch of white hair or hair that prematurely turns gray. At present, more than six candidate genes are responsible for four types of Waardenburg syndrome and Tietz syndrome. This study is aimed at identifying the pathogenic gene variants in a three-generation Han Chinese family with hearing loss, blue-gray iris, albino skin, and white hair. In order to discover the molecular genetic lesion underlying the disease phenotype, whole exome sequencing in the proband, with Tietz/Waardenburg syndrome phenotypes, of a Han Chinese family from HeBei, China, was conducted. A novel heterozygous c.650G>C/p.Arg217Thr variant in melanocyte inducing transcription factor (MITF) was identified. Sanger sequencing further validated that this mutation existed in three affected individuals and absent in healthy family members. Bioinformatics analysis predicted that this mutation was deleterious. Our study further identified the genetic lesion of the family. Simultaneously, our study may also contribute to genetic counseling, embryonic screening of in vitro fertilized embryos, and prenatal genetic diagnosis of patients with Tietz/Waardenburg syndrome, especially for the proband, unmarried and unpregnant women, to reduce familial transmission in this Han Chinese family.

scholarly journals Matching whole genomes to rare genetic disorders: Identification of potential causative variants using phenotype-weighted knowledge in the CAGI SickKids5 clinical genomes challenge

2019 ◽  
Author(s):  
Lipika R. Pal ◽  
Kunal Kundu ◽  
Yizhou Yin ◽  
John Moult
Keyword(s):  
Genetic Disorders ◽  
Genetic Diagnosis ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Sequencing Data ◽  
Disease Class ◽  
Phenotypic Profile ◽  
Whole Genomes ◽  
Matching Score ◽  
Coding Variants

ABSTRACTPrecise identification of causative variants from whole-genome sequencing data, including both coding and non-coding variants, is challenging. The CAGI5 SickKids clinical genome challenge provided an opportunity to assess our ability to extract such information. Participants in the challenge were required to match each of 24 whole-genome sequences to the correct phenotypic profile and to identify the disease class of each genome. These are all rare disease cases that have resisted genetic diagnosis in a state-of-the-art pipeline. The patients have a range of eye, neurological, and connective-tissue disorders. We used a gene-centric approach to address this problem, assigning each gene a multi-phenotype-matching score. Mutations in the top scoring genes for each phenotype profile were ranked on a six-point scale of pathogenicity probability, resulting in an approximately equal number of top ranked coding and non-coding candidate variants overall. We were able to assign the correct disease class for 12 cases and the correct genome to a clinical profile for five cases. The challenge assessor found genes in three of these five cases as likely appropriate. In the post-submission phase, after careful screening of the genes in the correct genome we identified additional potential diagnostic variants, a high proportion of which are non-coding.

scholarly journals Rare Tauopathies

2019 ◽  
Vol 39 (02) ◽  
pp. 264-273 ◽  
Author(s):  
Farwa Ali ◽  
Keith Josephs
Keyword(s):  
Clinical Phenotype ◽  
Genetic Disorders ◽  
Underlying Mechanism ◽  
Emission Tomography ◽  
Disease Modification ◽  
Tau Pathology ◽  
Protein Tau ◽  
Positron Emission ◽  
Cellular Inclusions ◽  
The Brain

Tauopathies are rare neurodegenerative disorders related to microtubule-associated protein tau, which functions to stabilize microtubules. Pathological changes caused by overexpression or hyperphosphorylation of tau lead to the disengagement of tau from microtubules and accumulation of toxic intracellular inclusions. Tau pathology is the underlying mechanism for several sporadic and genetic disorders. These are collectively known as tauopathies. Each tauopathy is differentiated from others by its neuropathological features such as the presence of specific isoforms of tau, type of cellular inclusions, and the regions of the brain affected. Neuropathological features, with a few exceptions however, do not correspond to distinct clinical phenotypes. There is considerable phenotypic overlap between the different tauopathies. Interaction between tau and other protein inclusions further alters the clinical phenotype.Recent advances in the development of tau biomarkers, especially the development of tau radioligands used in positron emission tomography neuroimaging, and a better understanding of biology and pathology of tau are important first steps toward the ultimate goal of accurate diagnosis and disease modification in tauopathies.

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