scholarly journals Very Elevated IgE, Atopy, and Severe Infection: A Genomics-Based Diagnostic Approach to a Spectrum of Diseases

2021 ◽  
Vol 2021 ◽  
pp. 1-5
Author(s):  
A. Chin ◽  
S. Balasubramanyam ◽  
C. M. Davis
Keyword(s):  
Autosomal Dominant ◽  
Severe Infection ◽  
Severe Atopic Dermatitis ◽  
Genomic Testing ◽  
Atopic Diseases ◽  
Variants Of Unknown Significance ◽  
Hyper Ige Syndrome ◽  
Heterozygous Variant ◽  
Unknown Significance ◽  
Multiple Variants

Elevated IgE has been long recognized as an important clinical marker of atopy but can be seen in a myriad of conditions. The discovery of autosomal dominant STAT3 deficiency marked the first recognition of hyper-IgE syndrome (HIES) and the first primary immunodeficiency linked to elevated IgE. Since then, genomic testing has increased the number of defects with associated mutations causing hyper-IgE syndrome and atopic diseases with FLG, DOCK8, SPINK5, and CARD11, among others. A spectrum of recurrent infections and atopy are hallmarks of elevated IgE with significant phenotypic overlap between each underlying condition. As treatment is predicated on early diagnosis, genomic testing is becoming a more commonly used diagnostic tool. We present a 6-year-old male patient with markedly elevated IgE and severe atopic dermatitis presenting with staphylococcal bacteremia found to have a heterozygous variant in FLG (p.S3247X) and multiple variants of unknown significance in BCL11B, ZAP70, LYST, and PTPRC. We review the genetic defects underpinning elevated IgE and highlight the spectrum of atopy and immunodeficiency seen in patients with underlying mutations. Although no one mutation is completely causative of the constellation of symptoms in this patient, we suggest the synergism of these variants is an impetus of disease.

Dupilumab to treat severe atopic dermatitis in autosomal dominant hyper-IgE syndrome

2020 ◽  
Vol 215 ◽  
pp. 108452 ◽  
Author(s):  
Georgios Sogkas ◽  
Stefanie Hirsch ◽  
Alexandra Jablonka ◽  
Torsten Witte ◽  
Reinhold E. Schmidt ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Autosomal Dominant ◽  
Severe Atopic Dermatitis ◽  
Hyper Ige Syndrome

scholarly journals NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Yacen Hu ◽  
Qiying Sun ◽  
Yafang Zhou ◽  
Fang Yi ◽  
Haiyun Tang ◽  
...  
Keyword(s):  
Clinical Data ◽  
Retrospective Studies ◽  
Autosomal Dominant ◽  
Small Vessel Disease ◽  
Coding Region ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Unknown Significance ◽  
Epidermal Growth ◽  
Distinctive Phenotype

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene. Archetypal disease-causing mutations are cysteine-affecting variants within the 34 epidermal growth factor-like repeat (EGFr) region of the Notch3 extracellular subunit. Cysteine-sparing variants and variants outside the EGFr coding region associated with CADASIL phenotype have been reported. However, the linkage between untypical variants and CADASIL is unclear. In this study, we investigated the spectrum of NOTCH3 variants in a cohort of 38 probands from unrelated families diagnosed as CADASIL. All coding exons of the NOTCH3 gene were analyzed, and clinical data were retrospectively studied. We identified 23 different NOTCH3 variants including 14 cysteine-affecting pathogenic variants, five cysteine-sparing pathogenic variants, two reported cysteine-sparing variants of unknown significance (VUS), and two novel VUS outside EGFr region. In retrospective studies of clinical data, we found that patients carrying cysteine-sparing pathogenic variants showed later symptom onset (51.36 ± 7.06 vs. 44.96 ± 8.82, p = 0.023) and milder temporal lobe involvement (1.50 ± 1.74 vs. 3.11 ± 2.32, p = 0.027) than patients carrying cysteine-affecting pathogenic variants. Our findings suggested that untypical variants comprise a significant part of NOTCH3 variants and may be associated with a distinctive phenotype.

scholarly journals “The molecule’s the thing:” the promise of molecular modeling and dynamic simulations in aiding the prioritization and interpretation of genomic testing results

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 766
Author(s):  
Gavin R. Oliver ◽  
Michael T. Zimmermann ◽  
Eric W. Klee ◽  
Raul A. Urrutia
Keyword(s):  
Molecular Modeling ◽  
Individualized Medicine ◽  
Genomic Testing ◽  
Dynamic Simulations ◽  
Clinical Genomics ◽  
Genomic Variants ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
Current Scenario ◽  
Generation Sequencing

Clinical genomics is now a reality and lies at the heart of individualized medicine efforts. The success of these approaches is evidenced by the increasing volume of publications that report causal links between genomic variants and disease. In spite of early success, clinical genomics currently faces significant challenges in establishing the relevance of the majority of variants identified by next generation sequencing tests. Indeed, the majority of mutations identified are harbored by proteins whose functions remain elusive. Herein we describe the current scenario in genomic testing and in particular the burden of variants of unknown significance (VUSs). We highlight a role for molecular modeling and molecular dynamic simulations as tools that can significantly increase the yield of information to aid in the evaluation of pathogenicity. Though the application of these methodologies to the interpretation of variants identified by genomic testing is not yet widespread, we predict that an increase in their use will significantly benefit the mission of clinical genomics for individualized medicine.

scholarly journals ExACtly zero or once

2017 ◽  
Vol 3 (4) ◽  
pp. e163 ◽  
Author(s):  
Caitlin A. Bennett ◽  
Slavé Petrovski ◽  
Karen L. Oliver ◽  
Samuel F. Berkovic
Keyword(s):  
General Population ◽  
Autosomal Dominant ◽  
De Novo ◽  
Clinical Role ◽  
Variants Of Unknown Significance ◽  
Neurologic Disorders ◽  
Exome Aggregation Consortium ◽  
Unknown Significance ◽  
Strong Segregation

Objective:To assist the interpretation of genomic data for common epilepsies, we asked whether variants implicated in mild epilepsies in autosomal dominant families are present in the general population.Methods:We studied 12 genes for the milder epilepsies and identified published variants with strong segregation support (de novo germline mutation or ≥4 affected family members). These variants were checked in the Exome Aggregation Consortium (ExAC), a database of genetic variation in over 60,000 individuals. We subsequently evaluated variants in these epilepsy genes that lacked strong segregation support. To determine whether the findings in epilepsies were representative of other diseases, we also assessed the presence of variants in other dominant neurologic disorders (e.g., CADASIL).Results:Published epilepsy variants with strong segregation support (n = 65) were absent (n = 61) or present once (n = 4) in ExAC. By contrast, of 46 published epilepsy variants without strong segregation support, 8 occurred recurrently (2–186 times). Similarly, none of the 45 disease-associated variants from other neurologic disorders with strong segregation support occurred more than once in ExAC. Reanalysis using the larger ExAC V2 plus gnomAD reference cohort showed consistent results.Conclusions:Variants causing autosomal dominant epilepsies are ultra-rare in the general population. Variants observed more than once in ExAC were only found among reports without strong segregation support, suggesting that they may be benign. Clinicians are increasingly faced with the interpretation of genetic variants of unknown significance. These data illustrate that variants present more than once in ExAC are less likely to be pathogenic, reinforcing the valuable clinical role of ExAC.

scholarly journals Imbalanced expression for predicted high-impact, autosomal-dominant variants in a cohort of 3,818 healthy samples

2020 ◽  
Author(s):  
Niek de Klein ◽  
Freerk van Dijk ◽  
Patrick Deelen ◽  
Carlos G. Urzua ◽  
Annique Claringbould ◽  
...  
Keyword(s):  
Gene Expression ◽  
Autosomal Dominant ◽  
Rare Variants ◽  
Large Population ◽  
Population Based ◽  
High Impact ◽  
Specific Expression ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Unknown Significance

AbstractBackgroundOne of the growing problems in genome diagnostics is the increasing number of variants that get identified through genetic testing but for which it is unknown what the significance for the disease is (Variants of Unknown Significance - VUS)1,2. When these variants are observed in patients, clinicians need to be able to determine their relevance for causing the patient’s disease. Here we investigated whether allele-specific expression (ASE) can be used to prioritize disease-relevant VUS and therefore assist diagnostics. In order to do so, we conducted ASE analysis in RNA-seq data from 3,818 blood samples (part of the the Dutch BIOS biobank consortium), to ascertain how VUS affect gene expression. We compared the effect of VUS variants to variants that are predicted to have a high impact, and variants that are predicted to be pathogenic but are either recessive or autosomal-dominant with low penetrance.ResultsFor immune and haematological disorders, we observed that 24.7% of known pathogenic variants from ClinVar show allelic imbalance in blood, as compared to 6.6% of known benign variants with matching allele frequencies. However, for other types of disorders, ASE information from blood did not distinguish (likely) pathogenic variants from benign variants. Unexpectedly, we identified 5 genes (ALOX5, COMT, PRPF8, PSTPIP1 and SH3BP2) in which seven population-based samples had a predicted high impact, autosomal-dominant variant. For these genes the imbalanced expression of the major allele compensates for the lower expression of the minor allele.ConclusionsOur analysis in a large population-based gene expression cohort reveals examples of high impact, autosomal-dominant variants that are compensated for by imbalanced expression. Additionally, we observed that ASE analyses in blood are informative for predicting pathogenic variants that are associated with immune and haematological conditions. We have made all our ASE results, including many ASE calls for rare variants (MAF < 1%), available at https://molgenis15.gcc.rug.nl/.

scholarly journals Novel Characteristics of Race-Specific Genetic Functions in Korean CADASIL

Medicina ◽  
2019 ◽  
Vol 55 (9) ◽  
pp. 521 ◽  
Author(s):  
Kim ◽  
Lee
Keyword(s):  
Intracerebral Hemorrhage ◽  
Sanger Sequencing ◽  
Hemorrhagic Stroke ◽  
Autosomal Dominant ◽  
Asian Population ◽  
Radiological Findings ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
Exon 9 ◽  
Exon 11

Background and Objectives: Previous studies found differences in the characteristics of NOTCH3 mutations in Caucasians and Asians with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Therefore, we sought to investigate the correlations between genetic and clinical/radiological findings in Korean CADASIL patients including some variants of unknown significance (VUS). Materials and Methods: We screened 198 patients with a suspected diagnosis of CADASIL between 2005 and 2015 via Sanger sequencing. Results: A total of 34 subjects (52.5 ± 9.5 years) were included. The majority of the mutations were in exon 3 and exon 11. R75P mutations (n = 5), followed by Y465C and R544C mutations (n = 4) were the most prevalent. Patients with those mutations exhibited less frequent anterior temporal (AT) or external capsular (EC) hyperintensities compared to patients with other locus mutations. Hemorrhagic stroke (HS) was found to be associated with mutations in exon 3 (R75P), exon 9 (Y465C), exon 11 (R587C), and exon 22 (R1175W variants), which were common locations in our study. Although it is unclear that genetic differences might affect the phenotypes in ethnicities, Asian population shows less migraine or seizure, but more intracerebral hemorrhage. Unlike in westernized countries, typical AT or EC hyperintensities may not be significant MRI markers, at least in Korean CADASIL patients. Furthermore, similar to R75P phenotypes, it is a novel finding that patients with Y465C and R1175W VUS have less frequent AT involvement than Caucasians. Conclusion: The associations between HS and common genetic locations account for the increased development of intracerebral hemorrhage in Koreans rather than Caucasians. We suggest that some CADASIL mutations appear to impart novel region-specific characteristics.

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