scholarly journals Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples

2016 ◽  
Author(s):  
Roddy Walsh ◽  
Kate Thomson ◽  
James S Ware ◽  
Birgit H Funke ◽  
Jessica Woodley ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Sequence Data ◽  
Disease Genes ◽  
Mendelian Disease ◽  
Data Generation ◽  
Autosomal Dominant Disorder ◽  
Rare Variation ◽  
Mendelian Diseases ◽  
Mendelian Gene ◽  
Reference Samples

The accurate interpretation of variation in Mendelian disease genes has lagged behind data generation as sequencing has become increasingly accessible. Ongoing large sequencing efforts present huge interpretive challenges, but also provide an invaluable opportunity to characterize the spectrum and importance of rare variation. Here we analyze sequence data from 7,855 clinical cardiomyopathy cases and 60,706 ExAC reference samples to better understand genetic variation in a representative autosomal dominant disorder. We show that in some genes previously reported as important causes of a given cardiomyopathy, rare variation is not clinically informative and there is a high likelihood of false positive interpretation. By contrast, in other genes, we find that diagnostic laboratories may be overly conservative when assessing variant pathogenicity. We outline improved interpretation approaches for specific genes and variant classes and propose that these will increase the clinical utility of testing across a range of Mendelian diseases.

scholarly journals Estimating the Selective Effect of Heterozygous Protein Truncating Variants from Human Exome Data

2016 ◽  
Author(s):  
Christopher A. Cassa ◽  
Donate Weghorn ◽  
Daniel J. Balick ◽  
Daniel M. Jordan ◽  
David Nusinow ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Sequence Data ◽  
Human Tumor ◽  
Purifying Selection ◽  
Wide Distribution ◽  
Disease Genes ◽  
Mendelian Disease ◽  
Large Set ◽  
Critical Function ◽  
Genome Wide

The dispensability of individual genes for viability has interested generations of geneticists. For some genes it is essential to maintain two functional chromosomal copies, while other genes may tolerate the loss of one or both copies. Exome sequence data from 60,706 individuals provide sufficient observations of rare protein truncating variants (PTVs) to make genome-wide estimates of selection against heterozygous loss of gene function. The cumulative frequency of rare deleterious PTVs is primarily determined by the balance between incoming mutations and purifying selection rather than genetic drift. This enables the estimation of the genome-wide distribution of selection coefficients for heterozygous PTVs and corresponding Bayesian estimates for individual genes. The strength of selection can help discriminate the severity, age of onset, and mode of inheritance in Mendelian exome sequencing cases. We find that genes under the strongest selection are enriched in embryonic lethal mouse knockouts, putatively cell-essential genes inferred from human tumor cells, Mendelian disease genes, and regulators of transcription. Using an essentiality screen, we find a large set of genes under strong selection that are likely to have critical function but that have not yet been studied extensively.

scholarly journals Gene pathogenicity prediction of Mendelian diseases via the Random Forest algorithm

2019 ◽  
Author(s):  
Sijie He ◽  
Weiwei Chen ◽  
Hankui Liu ◽  
Shengting Li ◽  
Dongzhu Lei ◽  
...  
Keyword(s):  
Random Forest ◽  
Area Under The Curve ◽  
Disease Genes ◽  
Mendelian Disease ◽  
Random Forest Algorithm ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
Mendelian Diseases ◽  
Pathogenicity Prediction ◽  
Machine Learning Approach

AbstractThe study of Mendelian diseases and the identification of their causative genes are of great significance in the field of genetics. The evaluation of the pathogenicity of genes and the total number of Mendelian disease genes are both important questions worth studying. However, very few studies have addressed these issues to date, so we attempt to answer them in this study.We calculated gene pathogenicity prediction (GPP) score by a machine learning approach (random forest algorithm) to evaluate the pathogenicity of genes. When we applied the GPP score to the testing gene set, we obtained accuracy of 80%, recall of 93% and area under the curve (AUC) of 0.87. Our results estimated that a total of 10,399 protein-coding genes were Mendelian disease genes. Furthermore, we found the GPP score was positively correlated with the severity of disease.Our results indicate that GPP score may provide a robust and reliable guideline to predict the pathogenicity of protein-coding genes. To our knowledge, this is the first trial to estimate the total number of Mendelian disease genes.

Efficacy and safety of denosumab treatment in a prepubertal patient with cherubism

2020 ◽  
Vol 33 (7) ◽  
pp. 963-966
Author(s):  
Haruka Kawamura ◽  
Satoshi Watanabe ◽  
Takashi I ◽  
Izumi Asahina ◽  
Hiroyuki Moriuchi ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Therapeutic Potential ◽  
Giant Cells ◽  
Efficacy And Safety ◽  
Autosomal Dominant Disorder ◽  
Osteolytic Lesions ◽  
Case Presentation ◽  
Childhood Growth ◽  
Receptor Activator ◽  
Denosumab Treatment

AbstractBackgroundDenosumab is an inhibitor of receptor activator of nuclear factor kappa-B ligand, which strongly suppresses osteoclasts. Cherubism is a rare autosomal dominant disorder characterized by symmetrical swelling of the jaws, in which the bone is replaced by a fibrous granuloma containing osteoclast-like giant cells.Case presentationWe report the efficacy and safety of denosumab treatment in a prepubertal boy with progressive cherubism. The treatment consisting of eight subcutaneous denosumab injections (120 mg/dose) in 6 months not only suppressed the expansion of the osteolytic lesions but also dramatically ossified them. However, a transiently decreased growth rate and rebounded asymptomatic hypercalcemia were associated with the treatment.ConclusionsThe present case demonstrated the therapeutic potential of denosumab for treatment of cherubism, although adverse effects, especially those on childhood growth, remain obscure. Further studies are needed to establish a safe and effective protocol for denosumab treatment of children.

PLEXIFORM NEUROFIBROMA OF THE BRACHIAL PLEXUS – A RARE CASE REPORT

2021 ◽  
pp. 13-15
Author(s):  
Surya Rao Rao Venkata Mahipathy ◽  
Alagar Raja Durairaj ◽  
Narayanamurthy Sundaramurthy ◽  
Anand Prasath Jayachandiran ◽  
Suresh Rajendran
Keyword(s):  
Brachial Plexus ◽  
Rare Case ◽  
Autosomal Dominant ◽  
Plexiform Neurofibroma ◽  
Autosomal Dominant Disorder ◽  
Surgical Debulking ◽  
Rare Case Report ◽  
Benign Tumours ◽  
Common Benign Tumour

Neurobroma is a common benign tumour occurring as part of an autosomal dominant disorder, neurobromatosis type 1, leading to the formation of benign tumours or neurobromas of the peripheral nervous system. Large neurobromas of the brachial plexus are rare and present a difcult challenge for surgeon due to the anatomical complexity of the brachial plexus. Dermal neurobromas usually present with swelling and occasional pain, but neurobromas associated with the brachial plexus present with pain and neurological symptoms. These plexiform neurobromas of the brachial plexus are known to undergo malignant transformation. Here, we present a case of a large plexiform neurobroma affecting the left brachial plexus and extending till the elbow, conrmed with MRI and surgical debulking was done.

Progressive Diaphyseal Dysplasia: Genetics and Clinical and Radiologic Manifestations

PEDIATRICS ◽  
1984 ◽  
Vol 74 (3) ◽  
pp. 399-405
Author(s):  
Yehezkel Naveh ◽  
Joseph K. Kaftori ◽  
Uri Alon ◽  
Jacob Ben-David ◽  
Moshe Berant
Keyword(s):  
Autosomal Dominant ◽  
Autosomal Dominant Disorder ◽  
Generation Family ◽  
Progressive Diaphyseal Dysplasia ◽  
Radiographic Screening ◽  
Osteosclerotic Dysplasia ◽  
Structural Deformity ◽  
Diaphyseal Dysplasia ◽  
Engelmann Disease

Progressive diaphyseal dysplasia was found in a three-generation family including 13 affected individuals, the largest family reported to date. Our study confirms that progressive diaphyseal dysplasia, also known as Engelmann's or Camurati-Engelmann disease, is an autosomal dominant disorder with variable osseous and muscular manifestations. Disease distribution among patients, within a given patient, or even in individual bones is unpredictable. The femur is the most commonly and severely affected bone and hence most useful for radiographic screening of possible patients. Radiographs provide a meaningful assessment of disease activity and extent. The severity of symptoms is generally proportionate to severity of involvement shown by roentgenography. Exophthalmos due to osteosclerotic dysplasia of the skull occurred in more than half of the patients with progressive diaphyseal dysplasia. Twelve-year follow-up of this family, with affected individuals ranging in age from 6 months to 12 years, indicates that progressive diaphyseal dysplasia may progress or become quiescent and be remarkably inactive despite advanced osteosclerosis and structural deformity.

scholarly journals Neurofibromatosis

2014 ◽  
Vol 34 (1) ◽  
pp. 81-82
Author(s):  
D Sharma ◽  
S Murki ◽  
V Madhavi
Keyword(s):  
Birth Weight ◽  
Low Birth Weight ◽  
Autosomal Dominant ◽  
Nerve Tissue ◽  
Autosomal Dominant Disorder ◽  
Café Au Lait Spots

Neurofibromatosis is a genetically-inherited disorder in which the nerve tissue grows tumors (neurofibromas) that may be benign and may cause serious damage by compressing nerves and other tissues. Neurofibromatosis is an autosomal dominant disorder, which means only one copy of the affected gene is needed for the disorder to develop(1). We report a baby who was admitted with us in view of prematurity (34 weeks gestation ) and low birth weight (1.32 Kg). Baby’s  mother was antenatally diagnosed with NF 1(figure no 1,2). Baby had multiple café au lait spots all over the bodies (figure no 3,4). Baby was discharged from nursery in well condition.DOI: http://dx.doi.org/10.3126/jnps.v34i1.8535 J Nepal Paediatr Soc 2014;34(1):81-82 

scholarly journals Familial Hypocalciuric Hypercalcaemia (FHH): A Case Report

2018 ◽  
Vol 3 (09) ◽  
Author(s):  
Tivya Kulasegaran ◽  
Pranav Kumar
Keyword(s):  
Differential Diagnosis ◽  
Case Report ◽  
Parathyroid Hormone ◽  
Autosomal Dominant ◽  
Genetic Test ◽  
Calcium Sensor ◽  
Clearance Ratio ◽  
Autosomal Dominant Disorder ◽  
Casr Gene ◽  
Inactivating Mutation

Familial hypocalciuric hypercalcaemia (FHH) is a rare genetic autosomal dominant disorder, with 3 variants described. An inactivating mutation in the calcium sensor receptor (CASR) gene causes the subtype 1, which represents 65% of the cases. Inactivation of Ca-sensing receptors (CaSR) can also lead to hypercalcemia associated with increased parathyroid hormone (PTH) secretion.[1] It is characterised by causes mild asymptomatic hypercalcemia[2] and hypocalciuria with normal or elevated PTH. FHH is generally asymptomatic and treatment is not needed. Differential diagnosis with primary hyperparathyroidism (PHPT) is crucial and based on calcium-creatinine clearance ratio (CCCR), which, when under 0.02 points to the diagnosis of FHH.[3] Genetic test is necessary for confirmation.[4]

scholarly journals Bridging the TB data gap: in silico extraction of rifampicin-resistant tuberculosis diagnostic test results from whole genome sequence data

2019 ◽  
Author(s):  
Kamela Charmaine S. Ng ◽  
Jean Claude S. Ngabonziza ◽  
Pauline Lempens ◽  
Bouke Catherine de Jong ◽  
Frank van Leth ◽  
...  
Keyword(s):  
Sequence Data ◽  
Whole Genome Sequence ◽  
Whole Genome ◽  
Data Generation ◽  
Continuous Analysis ◽  
Middle Income ◽  
Tb Control ◽  
Sequencing Technologies ◽  
Surveillance Programs ◽  
Low And Middle Income

AbstractBackgroundMycobacterium tuberculosis rapid diagnostic tests (RDTs) are widely employed in routine laboratories and national surveys for detection of rifampicin-resistant (RR)-TB. However, as next generation sequencing technologies have become more commonplace in research and surveillance programs, RDTs are being increasingly complemented by whole genome sequencing (WGS). While comparison between RDTs is difficult, all RDT results can be derived from WGS data. This can facilitate continuous analysis of RR-TB burden regardless of the data generation technology employed. By converting WGS to RDT results, we enable comparison of data with different formats and sources particularly for low and middle income high TB burden countries that employ different diagnostic algorithms for drug resistance surveys. This allows national TB control programs (NTPs) and epidemiologists to utilize all available data in the setting for improved RR-TB surveillance.MethodsWe developed the Python-based MTB Genome to Test (MTBGT) tool that transforms WGS-derived data into laboratory-validated results of the primary RDTs – Xpert MTB/RIF, XpertMTB/RIF Ultra, GenoType MDRTBplus v2.0, and GenoscholarNTM+MDRTB II. The tool was validated through RDT results of RR-TB strains with diverse resistance patterns and geographic origins and applied on routine-derived WGS data.ResultsThe MTBGT tool correctly transformed the SNP data into the RDT results and generated tabulated frequencies of the RDT probes as well as rifampicin susceptible cases. The tool supplemented the RDT probe reactions output with the RR-conferring mutation based on identified SNPs. The MTBGT tool facilitated continuous analysis of RR-TB and Xpert probe reactions from different platforms and collection periods in Rwanda.ConclusionOverall, the MTBGT tool allows low and middle income countries to make sense of the increasingly generated WGS in light of the readily available RDT results, and assess whether currently implemented RDTs adequately detect RR-TB in their setting. With its feature to transform WGS to RDT results and facilitate continuous RR-TB data analysis, the MTBGT tool may bridge the gap between and among data from periodic surveys, continuous surveillance, research, and routine tests, and may be integrated within the existing national connectivity platform for use by the NTP and epidemiologists to improve setting-specific RR-TB control. The MTBGT source code and accompanying documentation is available at https://github.com/KamelaNg/MTBGT.

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