https://orcid.org/0000-0003-2681-4355
It is now customary to report genetic variants in genome-wide and locus/disease-specific databases. Different databases have different features, which are quite useful to the scientific community. At present, HbVar (http://globin.bx.psu.edu/hbvar [Citation1]; established in 2000, as a continuation of Titus Huisman’s Syllabi for Hemoglobin Variants and Thalassemia mutations and IthaGenes (https://www.ithanet.eu/db/ithagenes [Citation2] established in 2007, along with the recently released IthaPhen (https://www.ithanet.eu/db/ithaphen [Citation3], are disease-specific databases for the documentation and annotation of variants in the globin gene clusters and their associated phenotype.
HbVar encourages variants to be submitted to the database after being published in the literature [Citation4]. The advantage is that diagnostic support for a certain variant’s pathogenicity is peer-reviewed and hematological data are available for consultation. This is to prevent some variants from ending up as personal communications without any supportive evidence. Nevertheless, after the publication of the micro-attribution approach in 2011, HbVar also welcomes submissions of novel variants even before they are published in the literature. In this case, the review of the supporting evidence is more stringent. The IthaGenes and ClinVar [Citation5] policy is to encourage early submission of novel variants to enable early access to such knowledge, even if unpublished, as this may sometimes take years to be published or never happen. A working group of experts, recruited from HEMOGLOBIN’s editorial board, has discussed this issue, and proposed the following structured way to present novel variants to the journal:
All variants, novel and known, should be described in the papers using HGVS nomenclature (http://varnomen.hgvs.org) [Citation6], as well as the traditional name when relevant. Associate Editors handling articles that fail to do this will return them to the authors for correction before selecting reviewers.
All novel variants should be evaluated for potential pathogenicity using the adapted ACMG/AMP variant classification recommendations as described in the recently published article by Kountouris P et al [Citation7]. The variant category and the evidence should be included in the manuscript.
All authors should submit novel variants to at least one of the public gene variant databases, preferably to HbVar and/or IthaGenes, as these are mutually referable, to support the dissemination of phenotype/genotype correlations, which are so important when interpreting the clinical relevance (or lack of clinical relevance) of new variants. The variant submission is required before accepting the article for publication in HEMOGLOBIN.
Obviously, the new way of presenting novel variants to the journal has implications for authors. Ideally, all variants should be accompanied by sufficient diagnostic evidence, according to a fixed strategy [Citation7]. In principle, it is essential that variants delivered to the database, or mentioned in manuscripts submitted to HEMOGLOBIN, should be correctly annotated using bio-informatic tools (which are easy to access) and the class (benign/likely benign, uncertain, likely pathogenic/pathogenic) correctly defined by applying the curation rules as published. As bio-curators are scarce, a minimal requirement has been defined to publish variants in HEMOGLOBIN, in which the variant ID (obtained by IthaGenes or HbVar) is mandatory and additional information is requested from the authors. A template is provided for authors to report novel variants, containing the name, phenotype, hematology, electrophoresis pattern, family studies and Sanger sequencing result and figure, to obtain a variant ID, which can be referred to throughout the manuscript.
A simplified form to collect relevant information on the novel globin gene variant, leading to thalassemia or a structural hemoglobin variant, is added to the Submission Guidelines for Authors. The sub-headings are Title of the article, Abstract (which is equivalent to the submitted paper), Variant (HGVS annotation for protein and coding DNA, name and accession numbers for both HbVar and IthaGenes), Index case (containing phenotype, alpha and beta-genotype, age at clinical and hematological evaluation, age at diagnosis, gender, origin, family- and clinical history and details about treatment, such as transfusion frequency, red cell hematology, iron, erythromorphology and other tests), if other family members are known (pedigree if available), biochemical studies (such as CE/HPLC/enzyme quantification) and molecular studies (specify which technique has been used and figure of results).
The benefit of this additional requirement is a more structured collection of novel hemoglobin and thalassemia variants to support the dissemination of phenotype/genotype correlations, essential to interpret the clinical relevance (or not) of novel variants.
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References
- Giardine B, Borg J, Higgs DR, et al. Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach. Nat Genet. 2011;43(4):295–301. doi:10.1038/ng.785.
- Kountouris P, Lederer CW, Fanis P, et al. IthaGenes: an interactive database for haemoglobin variations and epidemiology. PLOS One. 2014;9(7):e103020. doi:10.1371/journal.pone.0103020.
- Xenophontos M, Minaidou A, Stephanou C, et al. IthaPhen: an interactive database of genotype-phenotype data for hemoglobinopathies. Hemasphere. 2023;7(7):e922. doi:10.1097/HS9.0000000000000922.
- Giardine BM, Joly P, Pissard S, et al. Clinically relevant updates of the HbVar database of human hemoglobin variants and thalassemia mutations. Nucleic Acids Res. 2021;49(D1):D1192–D1196. doi:10.1093/nar/gkaa959.
- Landrum MJ, Chitipiralla S, Brown GR, et al. ClinVar: improvements to accessing data. Nucleic Acids Res. 2020;48(D1):D835–D844. doi:10.1093/nar/gkz972.
- den Dunnen JT, Dalgleish R, Maglott DR, et al. HGVS Recommendations for the Description of Sequence Variants: 2016 Update. Hum Mutat. 2016;37(6):564–569. doi:10.1002/humu.22981.
- Kountouris P, Stephanou C, Lederer CW, ClinGen Hemoglobinopathy Variant Curation Expert Panel, et al. Adapting the ACMG/AMP variant classification framework: a perspective from the ClinGen Hemoglobinopathy Variant Curation Expert Panel. Hum Mutat. 2022;43(8):1089–1096. doi:10.1002/humu.24280.