LOVD-DASH:A Comprehensive LOVD Database Coupled With Diagnosis And At-risk Assessment System For Hemoglobinopathies

Background and PurposeHemoglobinopathies are the most common monogenic disorders worldwide.The major(3-hemoglobinopathies,especially sickle cell disease and β-thalassemia,are lethal hemoglobinopathies that have caused global health burdens due to their serious pathogenicity and high prevalence.Previous efforts and programs for preventing hemoglobinopathies have proved to be effective in the Mediterranean populations,especially for β-thalassemia,showing a reduction from 1:250 live births to 1:1660 in 2009.The birth rates of hemoglobinopathies,however,remain high.In China,approximately 36,000 newborns are estimated with hemoglobin disorders of various types each year,which in turn may cause a serious social burden.Previous observations involving hemoglobin switching have shown that elevated fetal hemoglobin expression ameliorates the severity of β-hemoglobinopathies.Thus,an accurate diagnosis of hemoglobinopathies calls for not only the proper genotyping of the disease-causing mutations in globin gene clusters,but also newly identified variants in modifier genes,such as KLF1,BCL11A,and GATA1,which are responsible for altered expression of γ-globin and also influence β-thalassemia severity.Substantial effort has been made to establish the databases to record global mutation spectra causing and modifying hemoglobinopathies.HbVar,built by Giardine et al.has thus far been an authoritative hemoglobinopathy database for both researchers and clinicians.The number of fetuses with hemoglobinopathies can be largely reduced if a robust system for clinicians is developed to master standard guidelines and to rapidly make correct clinical management choices for hemoglobinopathy patients or at-risk couples.Methods and ResultsWe present herein a comprehensive variant database of hemoglobinopathies focusing on a Chinese population,recording the details of all reported variants through literature peer review-curation and existing databases.Moreover,unpublished data from our laboratory,including all the phenotype-genotype datasets derived from high-throughput sequencing data of 2,087 hemoglobinopathy patients and 20,222 general southern Chinese individuals,were also merged into the database.The addition of 18 novel functional variants from these genes has been detected using this high-throughput approach.All the variants are classified according to ACMG recommendations.Details of all the variants are integrated into the Leiden Open Variation Database,which is available at http://www.genomed.org/LOVD/index.php.An online diagnosis and at-risk assessment system for inherited hemoglobinopathy(DASH)has also been established based on the following:(ⅰ)the integrity of the hemoglobinopathy mutation spectrum of a Chinese population;(ⅱ)the availability of a comprehensive phenotype-genotype dataset corresponding to the 22,309 samples;and(ⅲ)the detailed information of variants according to the latest version of HbVar.Aiming to accomplish the molecular screening and clinical genotyping of hemoglobinopathies in a Chinese population,DASH consists of three main workflows.DASH not only infers the thalassemia trait based on the input of the hematologic phenotype,but also recognizes the uploaded copy number variants(CNVs)and single nucleotide variants(SNVs)data then interprets the data with a specific hemoglobinopathy annotation library.Both disease-causing and modifier variants will be evaluated for a combined analysis,which will ultimately lead to an overall hemoglobinopathy diagnosis.Furthermore,the system will conduct at-risk assessment of known disease-causing mutations and reveal critical clinical information for potential offspring.A diagnostic and assessment report will be automatically presented which could provide accurate suggestions on diagnosis and genetic counseling of hemoglobinopathies.DASH is available at www.smuhemoglobinopathy.com.(http://39.107.56.29)ConclusionsHere,we used hemoglobinopathies as a model to establish the LOVD-China variant database and DASH system because hemoglobinopathies are the most common monogenic diseases worldwide,and are associated with multiple mutations in disease-causing genes,as well as modifier genes.The LOVD-China with DASH system is the first automatic auxiliary diagnosis platform for hemoglobinopathies,and thus provides a standard platform for screening,diagnosis,and prevention of hemoglobinopathies.Both these websites will be updated and curated with the increasing production in data by molecular screening,traditional diagnostic approaches and by the submission of clinicians.We hope that LOVD-DASH will be a paradigm in online diagnosis of genetic disorders and may be an inspiration for other genetic disorders.In this study we portrayed the most comprehensive mutation spectrum of hemoglobinopathies in a Chinese population.In addition,LOVD-DASH will make a contribution in research and clinical application and provide a new method for treatment and precaution of hemoglobinopathies in Chinese patients.With the LOVD database and DASH system,we are one step closer to complete molecular screening and accurate clinical genotyping of hemoglobinopathies.