Bayesian modeling to predict malignant hyperthermia susceptibility and pathogenicity of RYR1, CACNA1S and STAC3 variants

Aim: Identify variants in RYR1, CACNA1S and STAC3, and predict malignant hyperthermia (MH) pathogenicity using Bayesian statistics in individuals clinically treated as MH susceptible (MHS). Materials & methods: Whole exome sequencing including RYR1, CACNA1S and STAC3 performed on 64 subjects with: MHS; suspected MH event or first-degree relative; and MH negative. Variant pathogenicity was estimated using in silico analysis, allele frequency and prior data to calculate Bayesian posterior probabilities. Results: Bayesian statistics predicted CACNA1S variant p.Thr1009Lys and RYR1 variants p.Ser1728Phe and p.Leu4824Pro are likely pathogenic, and novel STAC3 variant p.Met187Thr has uncertain significance. Nearly a third of MHS subjects had only benign variants. Conclusion: Bayesian method provides new approach to predict MH pathogenicity of genetic variants.

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Combining whole exome sequencing with in silico analysis and clinical data to identify candidate variants in pediatric left ventricular noncompaction

International Journal of Cardiology ◽

10.1016/j.ijcard.2021.11.001 ◽

2021 ◽

Author(s):

John Collyer ◽

Fuyi Xu ◽

Undral Munkhsaikhan ◽

Neely F. Alberson ◽

Buyan-Ochir Orgil ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Clinical Data ◽

In Silico ◽

In Silico Analysis ◽

Left Ventricular ◽

Left Ventricular Noncompaction ◽

Ventricular Noncompaction ◽

Whole Exome ◽

Silico Analysis

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A Monoallelic Variant in REST Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family

Genes ◽

10.3390/genes12111765 ◽

2021 ◽

Vol 12 (11) ◽

pp. 1765

Author(s):

Noluthando Manyisa ◽

Isabelle Schrauwen ◽

Leonardo Alves de Souza Rios ◽

Shaheen Mowla ◽

Cedrik Tekendo-Ngongang ◽

...

Keyword(s):

Hearing Impairment ◽

South African ◽

Autosomal Dominant ◽

Tertiary Structure ◽

In Silico Analysis ◽

Hek 293 ◽

Disulphide Bonds ◽

Whole Exome ◽

293 Cells ◽

Silico Analysis

Hearing impairment (HI) is a sensory disorder with a prevalence of 0.0055 live births in South Africa. DNA samples from a South African family presenting with progressive, autosomal dominant non-syndromic HI were subjected to whole-exome sequencing, and a novel monoallelic variant in REST [c.1244GC; p.(C415S)], was identified as the putative causative variant. The co-segregation of the variant was confirmed with Sanger Sequencing. The variant is absent from databases, 103 healthy South African controls, and 52 South African probands with isolated HI. In silico analysis indicates that the p.C415S variant in REST substitutes a conserved cysteine and results in changes to the surrounding secondary structure and the disulphide bonds, culminating in alteration of the tertiary structure of REST. Localization studies using ectopically expressed GFP-tagged Wild type (WT) and mutant REST in HEK-293 cells show that WT REST localizes exclusively to the nucleus; however, the mutant protein localizes throughout the cell. Additionally, mutant REST has an impaired ability to repress its known target AF1q. The data demonstrates that the identified mutation compromises the function of REST and support its implication in HI. This study is the second report, worldwide, to implicate REST in HI and suggests that it should be included in diagnostic HI panels.

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Variants of Uncertain Significance inBRCA1andBRCA2assessment of in silico analysis and a proposal for communication in genetic counselling

Journal of Medical Genetics ◽

10.1136/jmedgenet-2012-100961 ◽

2012 ◽

Vol 50 (2) ◽

pp. 74-79 ◽

Cited By ~ 17

Author(s):

Setareh Moghadasi ◽

Nandy Hofland ◽

Joyce N Wouts ◽

Frans B L Hogervorst ◽

Juul T Wijnen ◽

...

Keyword(s):

Genetic Counselling ◽

In Silico ◽

In Silico Analysis ◽

Variants Of Uncertain Significance ◽

Uncertain Significance ◽

Silico Analysis

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Identification of two novel COL10A1 heterozygous mutations in two Chinese pedigrees with Schmid-type metaphyseal chondrodysplasia

10.21203/rs.2.11650/v2 ◽

2019 ◽

Author(s):

Lingchi Kong ◽

Li Shi ◽

Wenbo Wang ◽

Rongtai Zuo ◽

Mengwei Wang ◽

...

Keyword(s):

Family Members ◽

In Silico Analysis ◽

Coxa Vara ◽

Missense Mutations ◽

Autosomal Dominant Disorder ◽

Metaphyseal Chondrodysplasia ◽

Whole Exome ◽

Col10a1 Gene ◽

Silico Analysis ◽

Nc1 Domain

Abstract Background: Schmid-type metaphyseal chondrodysplasia (MCDS) is an autosomal dominant disorder caused by COL10A1 mutations, which is characterized by short stature, waddling gait, coxa vara and bowing of the long bones. However, descriptions of the expressivity of MCDS are rare. Methods: Two probands and available family members affected with MCDS were subjected to clinical and radiological examination. Genomic DNA of all affected individuals was subjected to whole-exome sequencing, and candidate mutations were verified by Sanger sequencing in all available family members and in 250 normal control donors. A spatial model of the type X collagen (α1) C-terminal noncollagenous (NC1) domain was further constructed. Results: We found that the phenotype of affected family members exhibited irregular dominance. Mutation analysis indicated that there were two novel heterozygous missense mutations, [c.1765T>A (p.Phe589Ile)] and [c.1846A>G (p.Lys616Glu)] in the COL10A1 gene in family 1 and 2, respectively. The two novel substitution sites were highly conserved and the mutations were predicted to be deleterious by in silico analysis. Furthermore, protein modeling revealed that the two substitutions were located in the NC1 domain of collagen X (α1), which potentially impacted the trimerization of collagen X (α1) and combination with molecules in the pericellular matrix. Conclusion: Two novel mutations were identified in the present study, which will facilitate diagnosis of MCDS and further expand the spectrum of the COL10A1 mutations associated with MCDS patients. In addition, our research revealed the phenomenon of irregular dominance in MCDS.

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Detection and in silico Analysis of rmpA Gene from Soilborne Pathogenic Bacteria

International Journal of Drug Delivery Technology ◽

10.25258/ijddt.v9i3.19 ◽

2019 ◽

Vol 9 (o3) ◽

Author(s):

Laith AbdulHassan Mohamed-Jawad

Keyword(s):

Klebsiella Pneumoniae ◽

Staphylococcus Epidermidis ◽

Pathogenic Bacteria ◽

In Silico Analysis ◽

Multiple Sequence ◽

Bacterial Gene ◽

New Approach ◽

Geological Processes ◽

Bacillus Spp ◽

Silico Analysis

Soil serves as an ecosystem for diverse microbes that perform various roles and that range from useful organisms in biological and geological processes to dangerous transmitters of diseases. Most type of soilborne bacteria are harmful to humans and causing severe problems. Klebsiella pneumoniae consider a serious nosocomial pathogen that cause pneumonia, UTIs, wound and liver abscesses. One hundred fifty (150) soil samples isolated randomly during the period November 2014- February 2015. Bacterium Klebsiella pneumoniae was the commonest pathogen (36.70%) followed by Staphylococcus aureus (22.78%), Staphylococcus epidermidis (12.65%), Bacillus spp. (10.12%), Pseudomonas aeruginosa (5.06%), Enterobacter cloacae (5.06%), Streptococcus spp.(2.53%), Citrobacter spp.(1.26%) and Pantoea spp.(1.26%) respectively. All K. pneumoniae isolates detected and confirmed by conventional PCR using rmpA gene size 530bp. The positive isolates were sequenced and search for homology. The multiple sequence alignment showed that our bacterial gene have differences in NAD-dependent epimerase and NAD (p)- binding domain sequence at different sites. The differences in the nucleotides at gene sequence for the isolated strain which may give new approach for developing higher sensitive K. pneumoniae strains and for better understanding of the rmpA gene structure that should provide new tools for disease management. Keywords:

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Pharmacogenetics and pathophysiology of CACNA1S mutations in malignant hyperthermia

Physiological Genomics ◽

10.1152/physiolgenomics.00126.2016 ◽

2017 ◽

Vol 49 (2) ◽

pp. 81-87 ◽

Cited By ~ 10

Author(s):

Teresa A. Beam ◽

Emily F. Loudermilk ◽

David F. Kisor

Keyword(s):

Malignant Hyperthermia ◽

Malignant Hyperthermia Susceptibility ◽

Incomplete Penetrance ◽

Variable Expression ◽

Pathogenic Variants ◽

Whole Exome ◽

Gated Channel ◽

Life Threatening ◽

Ryanodine Receptor 1 ◽

Significant Linkage

A review of the pharmacogenetics (PGt) and pathophysiology of calcium voltage-gated channel subunit alpha1 S ( CACNA1S) mutations in malignant hyperthermia susceptibility type 5 (MHS5; MIM #60188) is presented. Malignant hyperthermia (MH) is a life-threatening hypermetabolic state of skeletal muscle usually induced by volatile, halogenated anesthetics and/or the depolarizing neuromuscular blocker succinylcholine. In addition to ryanodine receptor 1 (RYR1) mutations, several CACNA1S mutations are known to be risk factors for increased susceptibility to MH (MHS). However, the presence of these pathogenic CACNA1S gene variations cannot be used to positively predict MH since the condition is genetically heterogeneous with variable expression and incomplete penetrance. At present, one or at most six CACNA1S mutations display significant linkage or association either to clinically diagnosed MH or to MHS as determined by contracture testing. Additional pathogenic variants in CACNA1S, either alone or in combination with genes affecting Ca2+ homeostasis, are likely to be discovered in association to MH as whole exome sequencing becomes more commonplace.

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Cushing syndrome in a pediatric patient with a KCNJ5 variant and successful treatment with low dose ketoconazole

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab118 ◽

2021 ◽

Author(s):

Christina Tatsi ◽

Andrea Gutierrez Maria ◽

Cole Malloy ◽

Lin Lin ◽

Edra London ◽

...

Keyword(s):

Pediatric Patient ◽

Low Dose ◽

Cushing Syndrome ◽

In Silico Analysis ◽

Pathogenic Variants ◽

Whole Exome ◽

Gene Defects ◽

Early Human ◽

Silico Analysis

Abstract Context Pathogenic variants in KCNJ5, encoding the GIRK4 (Kir3.4) potassium channel, have been implicated in the pahogenesis of familial hyperaldosteronism (FH) type-III (FH-III) and sporadic primary hyperaldosteronism (PA). In addition to aldosterone, glucocorticoids (GCs) are often found in PA in association with KCNJ5 pathogenic variants, albeit at subclinical levels. However, to date no GIRK4 defects have been linked to Cushing syndrome (CS). Patient We present the case of a 10-year-old child who presented with CS at an early age due to bilateral adrenocortical hyperplasia (BAH). The patient was placed on low-dose ketoconazole (KZL), which controlled hypercortisolemia and CS-related signs. Discontinuation of KZL for even 6 weeks led to recurrent CS. Results Screening for known genes causing cortisol-producing BAHs (PRKAR1A, PRKACA, PRKACB, PDE11A, PDE8B, ARMC5) failed to identify any gene defects. Whole-exome sequencing (WES) showed a novel KCNJ5 pathogenic variant (c.506T>C, p.L169S) inherited from her father. In vitro studies showed that the p.L169S variant affects conductance of the Kir3.4 channel without affecting its expression or membrane localization. Although there were no effects on steroidogenesis in vitro, there were modest changes in protein kinase A activity. In silico analysis of the mutant channel proposed mechanisms for the altered conductance. Conclusions We present a pediatric patient with CS due to BAH and a germline defect in KCNJ5. Molecular investigations of this KCNJ5 variant failed to show a definite cause of her CS. However, this KCNJ5 variant differed in its function from KCNJ5 defects leading to PA. We speculate that GIRK4 (Kir3.4) may play a role in early human adrenocortical development and zonation and participate in the pathogenesis of pediatric BAH.

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Bayesian Modeling of Muscle Biopsy Contracture Testing for Malignant Hyperthermia Susceptibility

Survey of Anesthesiology ◽

10.1097/00132586-199812000-00062 ◽

1998 ◽

Vol 42 (6) ◽

pp. 364???365

Author(s):

JULIAN C.P. LOKE ◽

DAVID H. MACLENNAN

Keyword(s):

Malignant Hyperthermia ◽

Muscle Biopsy ◽

Bayesian Modeling ◽

Malignant Hyperthermia Susceptibility

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A GP1BA Variant in a Czech Family with Monoallelic Bernard-Soulier Syndrome

International Journal of Molecular Sciences ◽

10.3390/ijms23020885 ◽

2022 ◽

Vol 23 (2) ◽

pp. 885

Author(s):

Magdalena Skalníková ◽

Kateřina Staňo Kozubík ◽

Jakub Trizuljak ◽

Zuzana Vrzalová ◽

Lenka Radová ◽

...

Keyword(s):

In Silico Analysis ◽

Bleeding Tendency ◽

The Novel ◽

Prolonged Bleeding Time ◽

Whole Exome ◽

Low Platelet Count ◽

Von Willebrand ◽

Willebrand Factor ◽

Silico Analysis ◽

Bernard Soulier Syndrome

Bernard-Soulier syndrome (BSS) is a rare inherited disorder characterized by unusually large platelets, low platelet count, and prolonged bleeding time. BSS is usually inherited in an autosomal recessive (AR) mode of inheritance due to a deficiency of the GPIb-IX-V complex also known as the von Willebrand factor (VWF) receptor. We investigated a family with macrothrombocytopenia, a mild bleeding tendency, slightly lowered platelet aggregation tests, and suspected autosomal dominant (AD) inheritance. We have detected a heterozygous GP1BA likely pathogenic variant, causing monoallelic BSS. A germline GP1BA gene variant (NM_000173:c.98G > A:p.C33Y), segregating with the macrothrombocytopenia, was detected by whole-exome sequencing. In silico analysis of the protein structure of the novel GPIbα variant revealed a potential structural defect, which could impact proper protein folding and subsequent binding to VWF. Flow cytometry, immunoblot, and electron microscopy demonstrated further differences between p.C33Y GP1BA carriers and healthy controls. Here, we provide a detailed insight into its clinical presentation and phenotype. Moreover, the here described case first presents an mBSS patient with two previous ischemic strokes.

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