scholarly journals Oligogenic combinations of rare variants influence specific phenotypes in complex disorders

2021 ◽  
Author(s):  
Vijay Kumar Pounraja ◽  
Santhosh Girirajan
Keyword(s):  
Rare Variants ◽  
Clinical Feature ◽  
New Paradigm ◽  
Combinatorial Explosion ◽  
Complex Disorders ◽  
Rare Mutations ◽  
Data Mining Approach ◽  
Specific Clinical Feature ◽  
Complex Inheritance ◽  
Aggregate Burden

ABSTRACTGenetic studies of complex disorders such as autism and intellectual disability (ID) are often based on enrichment of individual rare variants or their aggregate burden in affected individuals compared to controls. However, these studies overlook the influence of combinations of rare variants that may not be deleterious on their own due to statistical challenges resulting from rarity and combinatorial explosion when enumerating variant combinations, limiting our ability to study oligogenic basis for these disorders. We present a framework that combines the apriori algorithm and statistical inference to identify specific combinations of mutated genes associated with complex phenotypes. Our approach overcomes computational barriers and exhaustively evaluates variant combinations to identify non-additive relationships between simultaneously mutated genes. Using this approach, we analyzed 6,189 individuals with autism and identified 718 combinations significantly associated with ID, and carriers of these combinations showed lower IQ than expected in an independent cohort of 1,878 individuals. These combinations were enriched for nervous system genes such as NIN and NGF, showed complex inheritance patterns, and were depleted in unaffected siblings. We found that an affected individual can carry many oligogenic combinations, each contributing to the same phenotype or distinct phenotypes at varying effect sizes. We also used this framework to identify combinations associated with multiple comorbid phenotypes, including mutations of COL28A1 and MFSD2B for ID and schizophrenia and ABCA4, DNAH10 and MC1R for ID and anxiety/depression. Our framework identifies a key component of missing heritability and provides a novel paradigm to untangle the genetic architecture of complex disorders.SIGNIFICANCEWhile rare mutations in single genes or their collective burden partially explain the genetic basis for complex disorders, the role of specific combinations of rare variants is not completely understood. This is because combinations of rare variants are rarer and evaluating all possible combinations would result in a combinatorial explosion, creating difficulties for statistical and computational analysis. We developed a data mining approach that overcomes these limitations to precisely quantify the influence of combinations of two or more mutated genes on a specific clinical feature or multiple co-occurring features. Our framework provides a new paradigm for dissecting the genetic causes of complex disorders and provides an impetus for its utility in clinical diagnosis.

scholarly journals A Systematic Review on Extreme Phenotype Strategies to Search for Rare Variants in Genetic Studies of Complex Disorders

2020 ◽  
Author(s):  
Sana Amanat ◽  
Teresa Requena ◽  
Jose Antonio Lopez-Escamez
Keyword(s):  
Systematic Review ◽  
Candidate Genes ◽  
Rare Variants ◽  
De Novo ◽  
Complex Diseases ◽  
De Novo Mutations ◽  
Genetic Studies ◽  
Complex Disorders ◽  
Extreme Phenotype ◽  
Age Related

Exome sequencing has been commonly used in rare diseases by selecting multiplex families or singletons with an extreme phenotype (EP) to search for rare variants in coding regions. The EP strategy covers both extreme ends of a disease spectrum and it has been also used to investigate the contribution of rare variants to heritability in complex clinical traits. We have conducted a systematic review to find evidence supporting the use of EP strategies to search for rare variants in genetic studies of complex diseases, to highlight the contribution of rare variation to the genetic structure of multiallelic conditions. After performing the quality assessment of the retrieved records, we selected 19 genetic studies considering EP to demonstrate genetic association. All the studies successfully identified several rare variants, de novo mutations and many novel candidate genes were also identified by selecting an EP. There is enough evidence to support that the EP approach in patients with an early onset of the disease can contribute to the identification of rare variants in candidate genes or pathways involved in complex diseases. EP patients may contribute to a better understanding of the underlying genetic architecture of common heterogeneous disorders such as tinnitus or age-related hearing loss.

scholarly journals Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

2018 ◽  
Author(s):  
Lucilla Pizzo ◽  
Matthew Jensen ◽  
Andrew Polyak ◽  
Jill A. Rosenfeld ◽  
Katrin Mannik ◽  
...  
Keyword(s):  
Family History ◽  
Genetic Background ◽  
Rare Variants ◽  
De Novo ◽  
Genetic Diagnosis ◽  
Clinical Information ◽  
Disease Genes ◽  
Complete Evaluation ◽  
Rare Cnvs ◽  
Complex Disorders

AbstractPurposeTo assess the contribution of rare variants in the genetic background towards variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive mutations.MethodsWe analyzed quantitative clinical information, exome-sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated mutations.ResultsThe number of rare secondary mutations in functionally intolerant genes (second-hits) correlated with the expressivity of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in probands with autism carrying gene-disruptive mutations (n=184, p=0.03) compared to their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of second-hits compared to those with mild/no family history (p=0.001). The number of secondary variants also correlated with the severity of cognitive impairment in probands carrying pathogenic rare CNVs (n=53) or de novo mutations in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These second-hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for genes affecting cellular and developmental processes.ConclusionAccurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate gene mutation is identified.

scholarly journals A Systematic Review of Extreme Phenotype Strategies to Search for Rare Variants in Genetic Studies of Complex Disorders

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 987
Author(s):  
Sana Amanat ◽  
Teresa Requena ◽  
Jose Antonio Lopez-Escamez
Keyword(s):  
Systematic Review ◽  
Candidate Genes ◽  
Rare Variants ◽  
De Novo ◽  
Complex Diseases ◽  
Genetic Studies ◽  
Complex Disorders ◽  
Extreme Phenotype ◽  
Disease Spectrum ◽  
Age Related

Exome sequencing has been commonly used to characterize rare diseases by selecting multiplex families or singletons with an extreme phenotype (EP) and searching for rare variants in coding regions. The EP strategy covers both extreme ends of a disease spectrum and it has been also used to investigate the contribution of rare variants to the heritability of complex clinical traits. We conducted a systematic review to find evidence supporting the use of EP strategies in the search for rare variants in genetic studies of complex diseases and highlight the contribution of rare variations to the genetic structure of polygenic conditions. After assessing the quality of the retrieved records, we selected 19 genetic studies considering EPs to demonstrate genetic association. All studies successfully identified several rare or de novo variants, and many novel candidate genes were also identified by selecting an EP. There is enough evidence to support that the EP approach for patients with an early onset of a disease can contribute to the identification of rare variants in candidate genes or pathways involved in complex diseases. EP patients may contribute to a better understanding of the underlying genetic architecture of common heterogeneous disorders such as tinnitus or age-related hearing loss.

scholarly journals Clinical diagnosis of rigid forms of flatfeet in children

2016 ◽  
Vol 4 (3) ◽  
pp. 59-62
Author(s):  
Andrei V Sapogovskiy
Keyword(s):  
Clinical Diagnosis ◽  
Clinical Feature ◽  
Clinical Test ◽  
Test Evaluation ◽  
Clinical Tests ◽  
Tarsal Coalition ◽  
Tarsal Bones ◽  
Different Types ◽  
Specific Clinical Feature ◽  
Foot Mobility

Introduction. Tarsal coalition is congenital bony, cartilaginous, or fibrous fusion between tarsal bones. The most specific clinical feature of these patients is limitation of tarsal joints mobility. Foot mobility is evaluated using a few clinical tests-tip-toe test, Jack test, and manual evaluation of passive foot inversion/eversion. However, these tests do not have high rates of sensitivity and specificity, and cannot be used to make differential diagnosis among the different types of coalitions.Aims. To improve the clinical diagnosis of calcaneonavicular coalitions.Materials and methods. We present a new clinical test-evaluation of calcaneonavicular segment mobility. To evaluate this test, we studied a group of 100 children (155 feet), which included those with talocalcaneal coalitions (22 patients/30 feet), calcaneonavicular coalitions (28 patients/45 feet), and those without tarsal coalitions (50 patients/80 feet).Results. The sensitivity of the test was 95.6%, and specificity was 93.3%. This test had good reproducibility, as evidenced by the inter-rater reliability coefficient of 0.818.Conclusions. The clinical test presented here can be used to identify patients with calcaneonavicular coalitions, which could not be identified using other clinical tests of foot mobility

scholarly journals Exome sequencing identifies novel AD-associated genes.

2020 ◽  
Author(s):  
Henne Holstege ◽  
Marc Hulsman ◽  
Camille Charbonnier ◽  
Benjamin Grenier-Boley ◽  
Olivier Quenez ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Genetic Variants ◽  
Rare Variants ◽  
Mendelian Inheritance ◽  
Loss Of Function ◽  
App Processing ◽  
Complex Disorders ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
The Impact

Background: With the development of next-generation sequencing technologies, it is possible to identify rare genetic variants that influence the risk of complex disorders. To date, whole exome sequencing (WES) strategies have shown that specific clusters of damaging rare variants in the TREM2, SORL1 and ABCA7 genes are associated with an increased risk of developing Alzheimers Disease (AD), reaching odds ratios comparable with the APOE-ε4 allele, the main common AD genetic risk factor. Here, we set out to identify additional AD-associated genes by an exome-wide investigation of the burden of rare damaging variants in the genomes of AD cases and cognitively healthy controls. Method: We integrated the data from 25,982 samples from the European ADES consortium and the American ADSP consortium. We developed new techniques to homogenise and analyse these data. Carriers of pathogenic variants in genes associated with Mendelian inheritance of dementia were excluded. After quality control, we used 12,652 AD cases and 8,693 controls for analysis. Genes were analysed using a burden analysis, including both non-synonymous and loss-of-function rare variants, the impact of which was prioritised using REVEL. Result: We confirmed that carrying rare protein-damaging genetic variants in TREM2, SORL1 or ABCA7 is associated with increased AD-risk. Moreover, we found that carrying rare damaging variants in the microglial ATP8B4 gene was significantly associated with AD, and we found suggestive evidence that rare variants in ADAM10, ABCA1, ORC6, B3GNT4 and SRC genes associated with increased AD risk. High-impact variants in these genes were mostly extremely rare and enriched in AD patients with earlier ages at onset. Additionally, we identified two suggestive protective associations in CBX3 and PRSS3. We are currently replicating these associations in independent datasets. Conclusion: With our newly developed homogenisation methods, we identified novel genetic determinants of AD which provide further evidence for a pivotal role of APP processing, lipid metabolism, and microglia and neuro-inflammatory processes in AD pathophysiology.

scholarly journals Novel Ultra-Rare Exonic Variants Identified in a Founder Population Implicate Cadherins in Schizophrenia

2020 ◽  
Author(s):  
Todd Lencz ◽  
Jin Yu ◽  
Raiyan Rashid Khan ◽  
Shai Carmi ◽  
Max Lam ◽  
...  
Keyword(s):  
Rare Variant ◽  
Rare Variants ◽  
Gene List ◽  
Ashkenazi Jewish ◽  
Founder Population ◽  
Total N ◽  
Gene Set ◽  
Complex Disorders ◽  
Gene Sets ◽  
Common Genetic Variants

AbstractIMPORTANCESchizophrenia is a serious mental illness with high heritability. While common genetic variants account for a portion of the heritability, identification of rare variants associated with the disorder has proven challenging.OBJECTIVETo identify genes and gene sets associated with schizophrenia in a founder population (Ashkenazi Jewish), and to determine the relative power of this population for rare variant discovery.DESIGN, SETTING, AND PARTICIPANTSData on exonic variants were extracted from whole genome sequences drawn from 786 patients with schizophrenia and 463 healthy control subjects, all drawn from the Ashkenazi Jewish population. Variants observed in two large publicly available datasets (total n≈153,000, excluding neuropsychiatric patients) were filtered out, and novel ultra-rare variants (URVs) were compared in cases and controls.MAIN OUTCOMES AND MEASURESThe number of novel URVs and genes carrying them were compared across cases and controls. Genes in which only cases or only controls carried novel, functional URVs were examined using gene set analyses.RESULTSCases had a higher frequency of novel missense or loss of function (MisLoF) variants compared to controls, as well as a greater number of genes impacted by MisLoF variants. Characterizing 141 “case-only” genes (in which ≥ 3 AJ cases in our dataset had MisLoF URVs with none found in our AJ controls), we replicated prior findings of both enrichment for synaptic gene sets, as well as specific genes such as SETD1A and TRIO. Additionally, we identified cadherins as a novel gene set associated with schizophrenia including a recurrent mutation in PCDHA3. Several genes associated with autism and other neurodevelopmental disorders including CACNA1E, ASXL3, SETBP1, and WDFY3, were also identified in our case-only gene list, as was TSC2, which is linked to tuberous sclerosis. Modeling the effects of purifying selection demonstrated that deleterious rare variants are greatly over-represented in a founder population with a tight bottleneck and rapidly expanding census, resulting in enhanced power for rare variant association studies.CONCLUSIONS AND RELEVANCEIdentification of cell adhesion genes in the cadherin/protocadherin family is consistent with evidence from large-scale GWAS in schizophrenia, helps specify the synaptic abnormalities that may be central to the disorder, and suggests novel potential treatment strategies (e.g., inhibition of protein kinase C). Study of founder populations may serve as a cost-effective way to rapidly increase gene discovery in schizophrenia and other complex disorders.

scholarly journals A Data Mining Approach Identified Salivary Biomarkers That Discriminate between Two Obesity Measures

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Ping Shi ◽  
J. Max Goodson
Keyword(s):  
Data Mining ◽  
Waist Circumference ◽  
Classification Performance ◽  
The Body ◽  
Clinical Feature ◽  
Fitness Level ◽  
Factors Associated ◽  
Salivary Biomarkers ◽  
Data Mining Approach ◽  
Bootstrap Percentile

Background. A key mechanism of obesity involves dysregulation of metabolic and inflammatory markers. This study aimed to identify salivary biomarkers and other factors associated with obesity using an ensemble data mining approach. Methods. For a random cohort of over 700 subjects from 8137 Kuwait children (10.00 ± 0.67 years), four data mining methods were applied to identify important variables associated with obesity, including logistic regression by lasso regularization (Lasso), multivariate adaptive regression spline (MARS), random forests (RF), and boosting classification trees (BT). Each algorithm generated a variable importance rank list, based on an internal cross-validation procedure. An aggregated importance ranking was constructed by averaging the rank ordering of variables from individual list, weighted by the classification performance of respective models. Subsequently, the subset of top-ranking variables that were identified with at least three algorithms was evaluated by classification performance using receiver operating characteristic (ROC) analysis with bootstrap percentile resampling. Results. Obesity was defined either by the waist circumference (OBW) or by the body mass index (BMI) (OBWHO). We identified C-reactive protein (CRP), insulin, leptin, adiponectin, as salivary biomarkers associated with OBW, plus a clinical feature fitness level. A similar set of biomarkers was identified for OBWHO, but not including leptin. Tree-based clustering analysis revealed patterns that were significantly different between the OBW and OBWHO subjects. Conclusion. A data mining approach based on multiple algorithms is useful for identifying factors associated with phenotypes, especially in cases where relationships are not salient, and a consensus from multiple methods can help produce a more generalizable subset of features. In this case, we have demonstrated that evaluation using the waist circumference includes association with high levels of salivary leptin, which is not seen with evaluation by BMI.

scholarly journals Primary Fallopian Tube Carcinoma Discovered as an Incidental Finding - A Case Report

2018 ◽  
Vol 17 (2) ◽  
pp. 64-67
Author(s):  
Mrinalini Singh ◽  
Sanjay Das ◽  
Shilpi Shaukin
Keyword(s):  
Fallopian Tube ◽  
Incidental Finding ◽  
Malignant Tumour ◽  
Ovarian Neoplasm ◽  
Clinical Feature ◽  
Fallopian Tube Carcinoma ◽  
Primary Fallopian Tube Carcinoma ◽  
Specific Clinical Feature ◽  
One Year ◽  
Gynaecological Tumours

Introduction: Primary malignant tumour of fallopian tube is very rare. The reported incidence of tumour varies from 0.1 to 1.8% of all gynaecological cancers. There is no specific clinical feature and therefore the disease is often misdiagnosed as ovarian neoplasm or other gynaecological tumours. A preoperative diagnosis even by radiological assay is many times difficult because the features are similar to ovarian neoplasm, tubo-ovarian abscess or hydrosalpinx. We report a case of 45 years old female who presented with multiple episodes of pervaginum bleeding since past one year and was diagnosed as primary fallopian tube carcinoma on histopathology examination.

scholarly journals The Role of Seizure-RelatedSEZ6as a Susceptibility Gene in Febrile Seizures

2011 ◽  
Vol 2011 ◽  
pp. 1-4 ◽  
Author(s):  
John C. Mulley ◽  
Xenia Iona ◽  
Bree Hodgson ◽  
Sarah E. Heron ◽  
Samuel F. Berkovic ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Dna Sequence ◽  
Febrile Seizure ◽  
Rare Variants ◽  
Strong Association ◽  
Susceptibility Gene ◽  
Febrile Seizures ◽  
Chinese Cohort ◽  
Complex Inheritance

Sixty cases of febrile seizures from a Chinese cohort had previously been reported with a strong association between variants in the seizure-related (SEZ) 6 gene and febrile seizures. They found a striking lack of genetic variation in their controls. We found genetic variation inSEZ6at similar levels at the same DNA sequence positions in our 94 febrile seizure cases as in our 96 unaffected controls. Two of our febrile seizure cases carried rare variants predicted to have damaging consequences. Combined with some of the variants from the Chinese cohort, these data are compatible with a role forSEZ6as a susceptibility gene for febrile seizures. However, the polygenic determinants underlying most cases of febrile seizures with complex inheritance remain to be determined.

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