Oligogenic combinations of rare variants influence specific phenotypes in complex disorders

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.

The Successful Treatment of High Lethal Dose ‎Paraquat Poisoning With Hemoperfusion

Paraquat (PQ), as an herbicide, is mostly used by farmers, especially in the north-west of Iran. Easy access to PQ is the reason for PQ intoxication in farm­ers. However, poisoning with PQ is rare. Most of the PQ-poisoned patients ingest it deliberately and following a suicidal attempt. PQ poisoning treatment has a poor outcome; only a small dose of slightly more than 10 mL PQ could be harmful and damage lungs forever. Under the conditions of no specific clinical feature, proper history, and diagnostic test, diagnosis is usually difficult. The ingestion of PQ in toxic doses could be fatal, destroying the lungs, kidney, heart, gastrointestinal tract, liver, and other organs. To remove PQ from the blood and intoxicants, one of the best recommendations is Hemo­perfusion (HP), as an extracorporeal method. In this case report, according to our treatments, early management of high lethal dose PQ poisoning, especially with HP could reduce the morbidity and mortality rates.

A case of iliopsoas hematoma as a complication of tetanus in a patient who did not receive anticoagulant therapy

Background The specific clinical feature of tetanus is whole body muscle spasms. These spasms are intensely painful and sometime lead to some injuries. Vertebral fractures have been reported as a common complication of tetanus, however iliopsoas hematoma is a rare complication. We describe a case of iliopsoas hematoma in a tetanus patient who had not been treated with any anticoagulant or antiplatelet agents. Case presentation A 72-year-old female patient was transferred to our hospital 7 days after the onset of tetanus. An iliopsoas hematoma was identified in her right iliopsoas muscle on computed tomography. There was no extravasation; thus, the hematoma improved with conservative therapy. There were no episodes that suggested a bleeding tendency, or no factors associated with hemorrhagic conditions. Conclusion This is the first report of iliopsoas hematoma as a complication in a tetanus patient who did not received anticoagulation therapy. The possibility of IPH as a complication of tetanus should be considered before and during the administration of anticoagulation therapy.

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

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.

Clinical profile, degree of severity and underlying factors of acute pancreatitis among a group of Bangladeshi patients

Background and objectives: Acute pancreatitis is a common condition for hospital admission. In Bangladesh, no study has yet investigated the clinical profile, degree of severity and underlying factors of acute pancreatitis. The aim of the present study was to determine the clinical profile, degree of severity and underlying factors of acute pancreatitis in a cohort of Bangladeshi patients.Methods: This prospective study was conducted from April 2016 to March 2017 on patients admitted with acute pancreatitis at Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM) General Hospital, Dhaka, Bangladesh. History and clinical features of each patient was systematically recorded. Diagnosis of acute pancreatitis was made by clinical findings, serum amylase and lipase levels (> 3 times the upper limit of normal values), evidences of acute pancreatitis by ultrasonography and computed tomography (CT). Severity of acute pancreatitis was classified according to the revised version of Atlanta classification.Results: A total of 40 patients with acute pancreatitis were enrolled in the study. Male and female were equally distributed. The mean age was 44.3±2.7 years. Among 40 cases, 26 (65.0%) and 14 (35%) had moderate and severe acute pancreatitis respectively. No specific clinical feature including ascites or pleural effusion was found significantly related to severity of the disease. Gall stone and metabolic (hypertriglyceridaemia/hypercalcemia) causes were present in 62.5% cases, but none had significant association with the severity of the disease.Conclusion: The present study has demonstrated that no specific observed clinical feature or underlying factor was related to the degree of severity of acute pancreatitis in a cohort of Bangladeshi patients.IMC J Med Sci 2018; 12(1): 6-10

Clinical diagnosis of rigid forms of flatfeet in children

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

Cognitive dysfunction in spinocerebellar ataxias

Spinocerebellar ataxias (SCAs) comprise a heterogeneous group of complex neurodegenerative diseases, characterized by the presence of progressive cerebellar ataxia, associated or otherwise with ophthalmoplegia, pyramidal signs, extrapyramidal features, pigmentary retinopathy, peripheral neuropathy, cognitive dysfunction and dementia. Objective: To verify the presence of cognitive dysfunction among the main types of SCA described in the literature. Methods: the review was conducted using the search system of the PUBMED and OMIM databases. Results: Cognitive dysfunction occurs in a considerable proportion of SCA, particularly in SCA 3, which is the most frequent form of SCA worldwide. Dementia has been described in several other types of SCA such as SCA 2, SCA 17 and DRPLA. Mental retardation is a specific clinical feature of SCA 13. Conclusions: The role of the cerebellum in cognitive functions has been observed in different types of SCAs which can manifest varying degrees of cognitive dysfunction, dementia and mental retardation.