{'fraction_non_alphanumeric': 0.02666666666666667, 'fraction_numerical': 0.008055555555555555, 'mean_word_length': 5.187285223367698, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
The implication of ‘unknown significance’ variants in next‐generation sequencing in diagnosis and donor selection for allogenic haematopoietic stem cell transplantation. Report of a case of myelodysplastic syndrome with a polymorphism in the tyrosine kinase 2 (TYK2) gene

In recent years, the increasing availability and implementation by clinical centres of next-generation sequencing (NGS) technology in the field of haematological neoplasia have led to advances in the diagnostic and prognostic stratification of patients. The jump from investigational NGS to the clinical field in myelodysplastic syndromes (MDS) and other neoplasia is helping us to better understand and stratify patient risk, potentially enabling the use of targeted therapies in clinical trials, when available. The current and potential use of NGS in the field of MDS was recently reviewed by Spaulding et al. and will be further expanded in the next few years with new applications. By way of example, today it is being used as a complementary test for minimal residual disease (MRD) before allogenic haematopoietic cell transplantation (HSCT) in acute myeloid leukaemia (AML). As more centres use NGS in their clinical practice, we will find more situations where NGS can be useful. It is also true that the information we acquire from NGS can confound us when we find the implication of unknown significance genes in our patient’s tests, which is why it is important to follow clinical guidelines and use different databases when variants of unknown significance or implication are found. We report our experience with one such case in which NGS played a role in donor selection for HSCT. A 40-year-old male with a previous history of lymphoblastic T-cell lymphoma, 30 years previously in his childhood, was referred to our centre for persistent symptomatic anaemia. After excluding other causes of anaemia, a bone marrow (BM) aspirate and BM biopsy were taken with the provisional diagnosis of idiopathic cytopenia of undetermined significance (ICUS) due to only mild dysplasia not meeting the World Health Organization (WHO) criteria for MDS. The karyotype was normal. The patient started support treatment, with increasing blood transfusion needs that justified chelation therapy. As a complementary diagnostic test, a myeloid NGS panel (Fig 1) was performed, finding the NM_003331 variant: c.G1325A: p.R442Q detected in the tyrosine kinase 2 gene (TYK2) (frequency 49 5%). This variant is catalogued as an ‘uncertain significance’ gene; nevertheless, it encodes the Janus kinase (JAKs) protein family of tyrosine kinases. Not knowing the real significance of this variant, a database and bibliography research was performed, finding that other variants in this gene have been described to be associated with primary immunodeficiency with T-cell lymphopenia with some reported cases in the same family, and a case of Epstein–Barr virus (EBV)-associated B-cell lymphoma. As this variant had not been reported in MDS, we continued the follow-up and support treatment. After 5 months, the patient became refractory to support treatment with severe anaemia. A new BM aspirate confirmed progression to MDS with multilineage dysplasia, and a low-risk Revised International Prognostic Scoring System (IPSS-R) score. Considering the past childhood lymphoblastic T-cell lymphoma in our patient, the progression from ICUS to MDS, and the indication for HSCT due to the high blood transfusion needs of 1 or 2 units weekly, we repeated a new NGS confirming once more the TYK2 gene polymorphism with no other new relevant findings.