In order to assist the clinical diagnosis and adapt it to the paradigm of precision medicine and next-generation sequencing (NGS)-based genetic tests, we have developed the Hereditary Angioedema Database Annotation (HADA) tool (hyperlink to the tool) built on top of a database of hundreds of known variants affecting function, including a precomputed pathogenic assessment of each variant and a ranked classification according to the current guidelines from the American College of Medical Genetics and Genomics. The curated database of variants affecting function in HAE can be accessed from this repository and is ready to be incorporated into ANNOVAR annotation routines.
At the moment, the database is supplied in GRCh37/hg19 coordinates and integrates information from 492 single nucleotide variants and small insertion/deletions from seven genes (SERPING1, F12, PLG, ANGPT1, KNG1, MYOF, and HS3ST6) that we classified as variants likely affecting function.
HADA can be used as online service at http://hada.hpc.iter.es
Hereditary angioedema (HAE) is a rare genetic disease caused by a dysfunction of the C1 inhibitor or dysregulation of the kinin cascade leading to an increase of vascular permeability, generating recurrent acute swelling episodes commonly localized on the face, trunk, and the extremities. It can also threaten the life of patients when the upper airways or the tissues from the oral cavity are affected. HAE is poorly recognized by physicians. Therefore, ambiguous or delayed diagnoses are common, increasing the risk of patient morbidity and mortality. Genetic testing in HAE has become an important step to reduce the diagnostic odyssey, to increase the diagnostic yield and to tailor treatments. We aimed to provide a resource to assist in the diagnosis of HAE that is adapted to NGS technologies and to the evolving knowledge of the causes of HAE that has the potential to reduce the time to interpret the detected variants in the NGS era by aggregating data from multiple sources.
Linux or macOS.
Download and install ANNOVAR according to the instructions.
Once downloaded, unpack the package by using this command:
tar -zxvf annovar.latest.tar.gz
In ANNOVAR folder, download HADA databases from this repository:
cd annovar/humandb
wget https://github.com/genomicsITER/HADA/blob/master/databases/latest/hg19_hada_20220920.txt
wget https://github.com/genomicsITER/HADA/blob/master/databases/latest/hg19_hada_related_20220920.txt
A toy VCF can be downloaded from this repository. Annotate a VCF file using HADA database and variants in HAE related genes:
perl <path-to-annovar-dir>/table_annovar.pl <path-to-vcf-infile/toy_HADA.vcf> <path-to-annovar-dir>/humandb \
-buildver hg19 \
-out <path-to-vcf-outfile> \
-remove \
-protocol hg19_hada_20220920, hg19_hada_related_genes_20220920 \
-operation f,f \
-nastring . \
-vcfinput
The resulting annotated VCF will be in <path-to-vcf-outfile>.hg19_multianno.vcf
Note: remember to replace the toy_HADA.vcf with your VCF name and the items in <> with your local paths in your computer.
Mendoza-Alvarez A, Muñoz-Barrera A, Rubio-Rodríguez LA, Marcelino-Rodríguez I, Corrales A, Iñigo-Campos A, Callero A, Perez-Rodriguez E, García-Robaina JC, González-Montelongo R, Lorenzo-Salazar JM, Flores C. Interactive web-based resource for annotation of genetic variants causing hereditary angioedema (HADA): Database, development, implementation, and validation. Journal of Medical Internet Research 2020, 22: e19040.
This work was supported by the Ministerio de Ciencia e Innovación (RTC-2017-6471-1; AEI/FEDER, UE) and the Instituto de Salud Carlos III (CD19/00231), which were co-financed by the European Regional Development Funds ‘A way of making Europe’ from the European Union; Cabildo Insular de Tenerife (CGIEU0000219140); and by agreement OA17/008 with the Instituto Tecnológico y de Energías Renovables (ITER) to strengthen scientific and technological education, training, research, development, and innovation in genomics, personalized medicine, and biotechnology. AMA was supported by a fellowship from ULL-Cajasiete. The content of this publication is solely the responsibility of the authors and does not necessarily reflect the views or policies of the funding agencies.
