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Husnain, Muhammad, Trent Wang, Maikel Valdes, James Hoffman, and Lazaros Lekakis. "Multiple Myeloma in a Patient with ANKRD26-Related Thrombocytopenia Successfully Treated with Combination Therapy and Autologous Stem Cell Transplant." Case Reports in Hematology 2019 (June 2, 2019): 1–3. http://dx.doi.org/10.1155/2019/9357572.
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Ankyrin repeat domain-containing protein 26- (ANKRD26-) related thrombocytopenia is a rare, autosomal dominant condition caused by ANKRD26 gene mutation. ANKRD26-related thrombocytopenia is characterized by moderate thrombocytopenia with minimal bleeding, normal platelet size, and dysmegakaryopoiesis on bone marrow evaluation. ANKRD26 mutation has been previously associated with myeloid malignancies, including acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia. We report the first case of multiple myeloma in a patient with ANKRD26 related thrombocytopenia. The patient was successfully treated with contemporary combination therapy followed by melphalan-conditioned autologous stem cell transplant for his multiple myeloma despite preexisting thrombocytopenia.
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Necchi, Vittorio, Alessandra Balduini, Patrizia Noris, Serena Barozzi, Patrizia Sommi, Christian di Buduo, Carlo Balduini, Enrico Solcia, and Alessandro Pecci. "Ubiquitin/proteasome-rich particulate cytoplasmic structures (PaCSs) in the platelets and megakaryocytes of ANKRD26-related thrombocytopenia." Thrombosis and Haemostasis 109, no. 02 (2013): 263–71. http://dx.doi.org/10.1160/th12-07-0497.
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SummaryANKRD26-related thrombocytopenia (ANKRD26-RT) is an autosomaldominant thrombocytopenia caused by mutations in the 5’UTR of the ANKRD26 gene. ANKRD26-RT is characterised by dysmegakaryopoiesis and an increased risk of leukaemia. PaCSs are novel particulate cytoplasmic structures with selective immunoreactivity for polyubiquitinated proteins and proteasome that have been detected in a number of solid cancers, in the epithelia of Helicobacter pylori gastritis and related preneoplastic lesions, and in the neutrophils of Schwachman- Diamond syndrome, a genetic disease with neutropenia and increased leukaemia risk. We searched for PaCSs in blood cells from 14 consecutive patients with ANKRD26-RT. Electron microscopy combined with immunogold staining for polyubiquitinated proteins, 20S and 19S proteasome showed PaCSs in most ANKRD26-RT platelets, as in a restricted minority of platelets from healthy controls and from subjects with other inherited or immune thrombocytopenias. In ANKRD26-RT platelets, the PaCS amount exceeded that of control platelets by a factor of 5 (p<0.0001). Immunoblotting showed that the higher PaCS number was associated with increased amounts of polyubiquitinated proteins and proteasome in ANKRD26-RT platelets. PaCSs were also extensively represented in ANKRD26-RT megakaryocytes, but not in healthy control megakaryocytes, and were absent in other ANKRD26-RT and control blood cells. Therefore, large amounts of PaCSs are a characteristic feature of ANKRD26-RT platelets and megakaryocytes, although these novel cell components are also present in a small subpopulation of normal platelets. The widespread presence of PaCSs in inherited diseases with increased leukaemia risk, as well as in solid neoplasms and their preneoplastic lesions, suggests a link of these structures with oncogenesis.
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Erdomaeva, Ya A., D. V. Fedorova, P. A. Zharkov, M. A. Kurnikova, S. G. Mann, and E. V. Raykina. "ANKRD26-related thrombocytopenia: case report and literature review of inherited thrombocytopenias with predisposition to malignancies." Pediatric Hematology/Oncology and Immunopathology 18, no. 3 (September 13, 2019): 54–61. http://dx.doi.org/10.24287/1726-1708-2019-18-3-54-61.
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ANKRD26-related thrombocytopenia (previously known as thrombocytopenia-2) is a rare form of inherited platelet disorders. Patients with ANKRD26-related thrombocytopenia usually do not suffer from severe bleeding but have predisposition to acute myeloid leukemia and other malignancies. Patients with ANKRD26-related thrombocytopenia and their relatives need genetic consultation and long term follow-up in view of risk of malignant blood disorders. The clinical case of ANKRD26-related thrombocytopenia in two siblings is presented in this paper. Review of literary data on pathogenesis, treatment and follow-up of patients with ANKRD26-related thrombocytopenia is performed. Common questions of diagnosis and management in patients with congenital thrombocytopenias with predisposition to malignant blood disorders are also reviewed. Parents gave their permission for using personal data for clinical research and publications.
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Noris, Patrizia, Silverio Perrotta, Marco Seri, Alessandro Pecci, Chiara Gnan, Giuseppe Loffredo, Nuria Pujol-Moix, et al. "Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families." Blood 117, no. 24 (June 16, 2011): 6673–80. http://dx.doi.org/10.1182/blood-2011-02-336537.
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Abstract Until recently, thrombocytopenia 2 (THC2) was considered an exceedingly rare form of autosomal dominant thrombocytopenia and only 2 families were known. However, we recently identified mutations in the 5′-untranslated region of the ANKRD26 gene in 9 THC2 families. Here we report on 12 additional pedigrees with ANKRD26 mutations, 6 of which are new. Because THC2 affected 21 of the 210 families in our database, it has to be considered one of the less rare forms of inherited thrombocytopenia. Analysis of all 21 families with ANKRD26 mutations identified to date revealed that thrombocytopenia and bleeding tendency were usually mild. Nearly all patients had no platelet macrocytosis, and this characteristic distinguishes THC2 from most other forms of inherited thrombocytopenia. In the majority of cases, platelets were deficient in glycoprotein Ia and α-granules, whereas in vitro platelet aggregation was normal. Bone marrow examination and serum thrombopoietin levels suggested that thrombocytopenia was derived from dysmegakaryopoiesis. Unexplained high values of hemoglobin and leukocytes were observed in a few cases. An unexpected finding that warrants further investigation was a high incidence of acute leukemia. Given the scarcity of distinctive characteristics, the ANKRD26-related thrombocytopenia has to be taken into consideration in the differential diagnosis of isolated thrombocytopenias.
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Guison, Jérôme, Gilles Blaison, Oana Stoica, Remy Hurstel, Marie Favier, and Remi Favier. "Idiopathic pulmonary embolism in a case of severe family ANKRD26 thrombocytopenia." Mediterranean Journal of Hematology and Infectious Diseases 9, no. 1 (June 16, 2017): e2017038. http://dx.doi.org/10.4084/mjhid.2017.038.
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Venous thrombosis affecting thrombocytopenic patients is challenging. We report the case of a thrombocytopenic woman affected by deep vein thrombosis and pulmonary embolism leading to the discovery of a heterozygous mutation in the gene encoding ankyrin repeat domain 26 (ANKRD26) associated with a heterozygous factor V (FV) Leiden mutation. This woman was diagnosed with left lower-limb deep vein thrombosis complicated by pulmonary embolism. Severe thrombocytopenia was observed. The genetic study evidenced a heterozygous FV Leiden mutation. Molecular study sequencing was performed after learning that her family had a history of thrombocytopenia. Previously described heterozygous mutation c-127C>A in the 5′ untranslated region (5′UTR) of the ANKRD26 gene was detected in the patient, her aunt, and her grandmother. ANKRD26-related thrombocytopenia and thrombosis are rare. This is, to our knowledge, the first case reported in the medical literature. This mutation should be screened in patients with a family history of thrombocytopenia.
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Kojić, Snežana. "MARP Protein Family: A Possible Role in Molecular Mechanisms of Tumorigenesis." Journal of Medical Biochemistry 29, no. 3 (July 1, 2010): 157–64. http://dx.doi.org/10.2478/v10011-010-0024-9.
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MARP Protein Family: A Possible Role in Molecular Mechanisms of TumorigenesisThe MARP (muscle ankyrin repeat protein) family comprises three structurally similar proteins: CARP/Ankrd1, Ankrd2/Arpp and DARP/Ankrd23. They share four conserved copies of 33-residue ankyrin repeats and contain a nuclear localization signal, allowing the sorting of MARPs to the nucleus. They are found both in the nucleus and in the cytoplasm of skeletal and cardiac muscle cells, suggesting that MARPs shuttle within the cell enabling them to play a role in signal transduction in striated muscle. Expression of MARPs is altered under different pathological conditions. In skeletal muscle, CARP/Ankrd1 and Ankrd2/Arpp are up-regulated in muscle in patients suffering from Duchene muscular dystrophy, congenital myopathy and spinal muscular atrophy. Mutations inAnkrd1gene (coding CARP/Ankrd1) were identified in dilated and hypertrophic cardiomyopathies. Altered expression of MARPs is also observed in rhabdomyosarcoma, renal oncocytoma and ovarian cancer. In order to functionally characterize MARP family members CARP/Ankrd1 and Ankrd2/Arpp, we have found that both proteins interact with the tumor suppressor p53 bothin vivoandin vitroand that p53 up-regulates their expression. Our results implicate the potential role of MARPs in molecular mechanisms relevant to tumor response and progression.
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Vincenot, Anne, Marie-Françoise Hurtaud-Roux, Olivier René, Sylvie Binard, Odile Fenneteau, and Nicole Schlegel. "ANKRD26 normocytic thrombocytopenia: a family report." Annales de biologie clinique 74, no. 3 (May 2016): 317–22. http://dx.doi.org/10.1684/abc.2016.1142.
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Noris, Patrizia, Remi Favier, Marie-Christine Alessi, Amy E. Geddis, Shinji Kunishima, Paula G. Heller, Paola Giordano, et al. "ANKRD26-related thrombocytopenia and myeloid malignancies." Blood 122, no. 11 (September 12, 2013): 1987–89. http://dx.doi.org/10.1182/blood-2013-04-499319.
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Morozova, D. S., A. A. Martyanov, M. A. Panteleev, P. A. Zharkov, D. V. Fedorova, and A. N. Sveshnikova. "Observation of granulocyte function during ex vivo thrombus formation for patients with ANKRD26-associated thrombocytopenia." Pediatric Hematology/Oncology and Immunopathology 19, no. 1 (March 28, 2020): 27–34. http://dx.doi.org/10.24287/1726-1708-2020-19-1-27-34.
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ANKRD26-associated thrombocytopenia is a non-syndromic hereditary thrombocytopenia for which there are currently no formal diagnostic criteria. It is known that the probability of myeloid leukemia in patients with pathogenetic variants in the ANKRD26 gene significantly increases, however, studies of the functioning of granulocytes in this pathology have not been conducted. Aims: Analysis of the functioning of granulocytes and platelets during ex vivo thrombosis in patients with ANKRD26-associated thrombocytopenia. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. Two patients and 10 healthy volunteers were included in the study. Intracellular signaling and platelet functional responses were observed by continuous flow cytometry. Ex vivo thrombus formation and granulocyte functioning were observed on a fluorescence microscope in parallel-plane flow chambers containing fibrillar collagen. Upon physiological activation (ADP, collagen) of patients’ platelets in vitro, there were no significant differences between the platelets of patients and healthy donors. However, the observed ex vivo size of platelet aggregates was significantly reduced in comparison with healthy donors and published data on patients with other thrombocytopenias. The observed number and activity (movement velocity) of granulocytes of patients was within normal values. However, significant morphological differences were observed for granulocytes of patients compared with granulocytes of healthy donors: there was an increased spreading of granulocytes, in particular, expressed in a large number of thin pseudopodia, as well as an increased curvature of the motion trajectories of granulocytes. Ex vivo observation of thrombus formation in patients with ANKRD26- associated thrombocytopenia, a significantly reduced thrombus size is observed with normal platelet activity and increased variability in the shape of granulocytes.
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Gnan, Chiara, Patrizia Noris, Felisa C. Molinas, Shinji Kunishima, Paula Graciela Heller, Akihiro Iguchi, Alessandro Pecci, et al. "Mutations Identified in Thrombocytopenia THC2 Are Likely to Dysregulate ANKRD26 Expression." Blood 118, no. 21 (November 18, 2011): 708. http://dx.doi.org/10.1182/blood.v118.21.708.708.
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Abstract Abstract 708 Thrombocytopenia 2 (THC2, MIM 188000) is an autosomal dominant form of thrombocytopenia described for the first time in a large Italian family, which allowed us to map a locus on 10p11.1-p12. Since the recent identification of ANKRD26 (Pippucci et al, Am J Hum Genet 88:115, 2011), as the gene responsible for the disease, the screening led to recognition of 25 families (91 patients). Although most families were of Italian origin, patients were also from North America, Argentina, Senegal, Japan and Spain, indicating that the disease is distributed worldwide. Confirming recently published data (Noris et al, Blood 117:6673, 2011), this cohort showed that thrombocytopenia was moderate and bleeding tendency was usually mild. Most patients were characterized by deficiency of both glycoprotein Ia and a-granules but normal platelet aggregation in vitro. Bone marrow examination and serum thrombopoietin levels were indicative of dysmegakaryopoiesis. Moreover, there was evidence of leukemia risk in patients with ANKRD26 mutations. The 12 mutations identified so far are all localized in a short stretch of 22 nucleotides of the 5' untranslated region (5'UTR). The effect of three mutations was evaluated in a reporter gene assay with the luciferase gene under the control of the wild type and mutated 5'UTR. When constructs were transfected in K562 and undifferentiated DAMI cell lines, no significant difference in luciferase activity was observed. However, when the constructs were transfected in megakaryocytes obtained from differentiation of the DAMI cells, a significant increase in activity was reported, suggesting that the 5'UTR plays a regulatory role of the ANKRD26 expression during megakaryopoiesis (Pippucci et al, Am J Hum Genet 88:115, 2011). To further investigate the mechanisms responsible for the ANKRD26 expression, we tested the activity of a putative regulatory region (730 bp), containing 574 bp upstream of the transcription initiation site and the 5'UTR. The effect of two mutations (c.-128G>A and c.-116C>T) was evaluated in both orientations using a luciferase assay in HeLa cells. There was no significant difference between wild type and mutated inserts cloned in either sense or antisense orientation, though there was a slight transcriptional increase of the sense mutated constructs and a reduction of the antisense mutated sequences in comparison with the wild type inserts. In order to test the promoter region in a more suitable model, the same constructs were transfected in DAMI differentiated megakaryocytes. Whereas the antisense wild type and mutated constructs did not show any transcriptional activity, the sense mutated constructs generated a statistically significant increase of activity, suggesting that the mechanisms controlling the expression of ANKRD26 are different in the two cell lines. The role of 5'UTR was further investigated by testing a fragment (574 bp) in which 5'UTR was deleted. In megakaryocytes, this sequence generated a statistically significant increase of the luciferase activity compared to the 730 bp insert. On the contrary, the same constructs transfected in Hela cells resulted in a reduction of the luciferase activity. From these preliminary data we hypothesize that the 5'UTR region plays an important role inhibiting the ANKRD26 expression during megakaryopoiesis through the binding of factors, whose recognition sites are destroyed by mutations identified in patients. Consistent with this hypothesis, ANKRD26 is expressed in human CD34+ and BFU-E but hardly detectable in CD41+ cells. Disclosures: No relevant conflicts of interest to declare.
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Eisfeld, Ann-Kathrin, Jessica Kohlschmidt, Krzysztof Mrózek, Alice S. Mims, Christopher J. Walker, Deedra Nicolet, James S. Blachly, et al. "Mutations in Genes Associated with Familial Predisposition to Myeloid Neoplasms: Their Frequency and Associations with Pretreatment Characteristics in Adult Patients (Pts) with Presumably Sporadic De Novo Acute Myeloid Leukemia (AML)." Blood 132, Supplement 1 (November 29, 2018): 1478. http://dx.doi.org/10.1182/blood-2018-99-120085.
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Abstract The effects of germline variants in the development of myeloid neoplasms, including AML, were largely neglected for decades. However, several myeloid neoplasms with germline predisposition have been recently recognized as separate entities in the 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia. In addition to genes whose mutations are associated with bone marrow failure syndromes, and are long-known contributors to Mendelian disorders that have myelodysplastic syndromes/AML as the main clinical feature (e.g., germline CEBPA, GATA2 and RUNX1 mutations), 3 more genes were included: ANKRD26, DDX41 and SRP72. Mutations in these genes were described in few families, and are thus considered to be very rare. However, it is possible that their frequency might be underestimated, because the associated phenotypes are often vague and family history not routinely considered. To establish the frequency of ANKRD26, DDX41 and SRP72 mutations, and to characterize molecular and clinical features associated with these mutations, we determined mutational status of 83 cancer- and leukemia-associated genes using 2 targeted sequencing panels in diagnostic samples of 1,021 clinically well-characterized adult pts with de novo AML AML treated on trials conducted by the Alliance for Clinical Trials in Oncology. Mutations in the 3 familial genes were found in 46 pts (4.5%), specifically, mutations in ANKRD26 in 15, DDX41 in 17 and SRP72 in 19 pts. Three pts had mutations in either 2 or all 3 genes. Mutations occurred at varying variant allele fractions (VAFs, median: 0.47; range: 0.10-0.98), with 76% of mutations observed with VAFs >35%. Mutations were found throughout the genes. Pts harboring mutations in any of the 3 genes were predominantly younger (median age, 54 years; range, 19-77), 65% of them were male, and 48% belonged to the 2017 European LeukemiaNet (ELN) favorable genetic risk group. The co-mutation profiles partially differed among the genes. NPM1 mutations were the most frequent co-mutations, occurring in 47%, 41%, and 42% of pts with mutations in ANKRD26, DDX41, and SRP72, respectively. However, ANKRD26-mutated pts frequently harbored FLT3-ITD and mutations in DNMT3A, IDH2 and SRSF2 genes (each detected in 20% of pts). DDX41-mutated pts commonly had mutations in NRAS (18%), SMARCA2 (12%) and TP53 (12%). SRP72-mutated pts often had mutations in TET2 (26%), CEBPA (23%) and IDH1 (21%). With the exception of a higher complete remission rate in ANKRD26-mutated pts (93% compared with 73% for DDX41- and 81% for SRP72-mutated pts), the clinical outcomes were very similar. Considering all 3 genes combined, the median 3-year disease-free survival rate of 25% and median 3-year overall survival rate of 44% resembled those of pts belonging to the ELN intermediate risk group. We next tested whether the variants detected in our cohort of pts with presumably sporadic AML were of germline or somatic origin. We performed Sanger sequencing on germline material (buccal swab or remission samples) of 28 pts who had mutations detected at VAF>35% and material available. Germline origin was determined for the mutations detected in 24 of 28 pts tested (86%; ANKRD26, 9/10 tested pts; SRP72, 9/11 pts; DDX41, 8/10 pts). Of the detected germline changes, 7/9 ANKRD26 mutations, 6/10 DDX41 mutations and 5/9 SRP72 mutations were predicted to have deleterious effects on the respective proteins via Polyphen. The 1 pt with mutations in all 3 genes were found to be somatic mutations. Additional genes whose germline mutations are known to occur in families, such as GATA2, CEBPA and RUNX1, were sequenced for somatic mutations in our pt cohort, but not yet tested for potential germline origin in our analysis. Thus, it is likely that the frequency of familial AML mutations is even higher in our cohort. To our knowledge, this is the first study that tested the frequency of 3 leukemia-predisposing gene mutations in a large cohort of adults with presumably sporadic AML. The relatively high number of germline mutations in these 3 genes highlights the importance of testing for germline mutations. Thus, inclusion of those genes in diagnostic sequencing panels should be considered, and critical consideration of obtained family history should be strongly encouraged for providers taking care of pts with myeloid malignancies. Support: U10CA180821, U10CA180882, U10CA180861, U24CA196171 Disclosures Mims: Novartis: Consultancy; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Kolitz:Magellan Health: Consultancy, Honoraria.
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Polokhov, D. M., D. V. Fedorova, A. V. Pshonkin, A. A. Ignatova, E. A. Ponomarenko, M. Yu Aleksenko, I. V. Mersiyanova, et al. "Platelet phenotype in children with ANKRD26-related thrombocytopenia." Pediatric Hematology/Oncology and Immunopathology 20, no. 2 (May 22, 2021): 65–73. http://dx.doi.org/10.24287/1726-1708-2021-20-2-65-73.
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The mechanisms of hemorrhagic manifestations in patients with ANKRD26associated thrombocytopenia (ANKRD26-AT) are poorly understood. The aim of this work is to detect possible morpho-functional disorders of platelets in patients with mutations in the ANKRD26gene by flow cytometry with activation. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. 8 children aged from 1.5 to 15 years were examined. The platelet count ranged from 29 to 172 thousand/μl, with a median of 60 thousand/μl. The severity of hemorrhagic manifestations was assessed on a standardized scale (Pediatric Bleeding Questionnaire, PBQ) and it ranged from 0 to 5 points, with a median of 3.5 points. Platelet activation was performed with a CRP + TRAP mixture. Comparison was carried out with the results of examination of 26 apparently healthy children (control group, CG) aged 2 to 15 years. When compared with CG, patients showed an increase in platelet size (FSC; p= 0.018) and granularity (SSC; p< 0.001) after activation. In contrast to the CG, the correlation between FSC and SSC of platelets in patients was not significant (cor. = 0.55; p= 0.15). Patients showed a high, significant relationship between the number and FSC of platelets (cor. = –0.93; p< 0.001), as well as an increased density of CD42b (p < 0.001) and a decrease in the proportion of procoagulant platelets (p= 0.01) after activation. The revealed changes indicate violations of the mechanisms of activation and shape changes of platelets in patients with ANKRD26-AT.
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Coelho, D. Pereira, J. Azevedo, P. Martinho, T. Nascimento, S. Marini, A. Barbosa Ribeiro, E. Cortesão, et al. "PS1496 ANKRD26-RELATED THROMBOCYTOPENIA: STUDY OF 3 FAMILIES." HemaSphere 3, S1 (June 2019): 689. http://dx.doi.org/10.1097/01.hs9.0000564244.71382.2b.
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Al Daama, Saad A., Yousef H. Housawi, Walid Dridi, Mohammed Sager, F. George Otieno, Cuiping Hou, Lyam Vasquez, et al. "A missense mutation in ANKRD26 segregates with thrombocytopenia." Blood 122, no. 3 (July 18, 2013): 461–62. http://dx.doi.org/10.1182/blood-2013-03-489344.
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Kuzmanovic, Teodora, Metis Hasipek, Samuel Li, Thomas Laframboise, Valeria Visconte, Sunisa Kongkiatkamon, Seth J. Corey, et al. "ANKRD26 Coding Variants in Myeloid Neoplasia." Blood 140, Supplement 1 (November 15, 2022): 4013–15. http://dx.doi.org/10.1182/blood-2022-170645.
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Ho, Thanh, Juliana Perez Botero, William J. Hogan, Saad S. Kenderian, Naseema Gangat, Ayalew Tefferi, Roshini S. Abraham, et al. "Clinical Spectrum of Germline Mutations with Predisposition to Myeloid Neoplasms- 2016 World Health Organization Classification Update." Blood 128, no. 22 (December 2, 2016): 300. http://dx.doi.org/10.1182/blood.v128.22.300.300.
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Abstract Background: The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms has specifically categorized germline mutations that are associated with myeloid clonal evolution (Arber et al. Blood 2016). This group consists of myeloid neoplasms with an isolated germline predisposition (CEBPA, DDX41), myeloid neoplasms associated with congenital thrombocytopenia (ETV6, RUNX1, ANKRD26) and germline myeloid neoplasms with multi-organ dysfunction (GATA2, chromosomal breakage disorders, telomere biology disorders etc). We carried out this study to describe the clinical spectrum of germline disorders with predisposition to myeloid neoplasms as categorized by the 2016 WHO classification revision. Methods: After Institutional Review Board (IRB) approval, the adult and pediatric bone marrow failure syndrome database (1990-2016) and the electronic medical record were queried for germline disorders involving GATA2, CEBPA, DDX41, ETV6, RUNX1, ANKRD26, Down syndrome and Noonan syndrome. Chromosomal breakage assays (Diepoxybutane/Mitomycin-C), flow-fluorescent in-situ hybridization (FISH) for telomere length assessment, Fanconi anemia complementation assays and Sanger/Next Generation sequencing (NGS) for the aforementioned germline disorders with myeloid predisposition were carried out in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories. These disorders were then classified based on the 2016 WHO classification revision. Results : 54 individuals (37 families) were included in the study. Eleven (20%) patients belonging to 5 families were identified as having germline mutations with a preexisting platelet disorder: ETV6 (n=1), ANKRD26 (n=5), RUNX1 (n=5). Forty-three (79%) patients (32 families) had inherited syndromes with multi-organ dysfunction: GATA2 (n=11, 26%), bone marrow failure syndromes (n=14, 33%) and telomere biology disorder (n=14, 33%). There was one patient with neurofibromatosis with a germline PTPN11 mutation who developed juvenile myelomonocytic leukemia, while there were three patients with Down syndrome; 2 with transient abnormal myelopoiesis and one who developed acute megakaryocytic leukemia. The clinical phenotype, prevalence and characteristics of myeloid clonal evolution and outcomes are presented in Table 1. No patients with germline CEBPA or DDX41 mutations were identified. Patients with germline platelet disorders did not have any prominent non-hematological manifestations. Erythrocytosis (20%) with long-standing thrombocytopenia (100%) was a unique feature associated with ANKRD26 mutations. Non-hematologic clues such as human papillomavirus (HPV)-driven warts, primary lymphedema (Emberger syndrome) and frequent atypical infections with monocytopenia were seen in patients with germline GATA2 mutations, and preceded myeloid clonal evolution (morphologic, cytogenetic and molecular). Notably, the age at presentation and penetrance of myeloid transformation was variable, with individuals from the same family developing symptoms during the first decade of life and others remaining asymptomatic to date (fifth decade). Somatic ASXL1 mutations were detected in all 3 (100%) patients with GATA2 mutations and in one patient with ANKRD26 mutation that developed myeloid clonal evolution. In our study myeloid clonal evolution was seen in 40% with RUNX1 mutations, 27% with GATA2 mutations, and 20% with ANKRD26 mutations. We could not calculate the same for bone marrow failure syndromes as the total number of cases seen are still being assessed. Outcomes with allogeneic stem cell transplantation were favorable in appropriately selected patients (Table 1). Conclusion : The 2016 WHO revision to the classification of myeloid neoplasms highlights the importance of recognition and molecular characterization of germline mutations (syndromic and non-syndromic) with risk for myeloid clonal evolution. While some of these disorders (GATA2, Fanconi anemia, telomere biology disorders) may have important non-hematological clues, many present with isolated thrombocytopenia (RUNX1, ETV6). The age and frequency of myeloid evolution is highly variable. Acquisition of somatic ASXL1 mutations at the time of clonal myeloid transformation highlights the role of epigenetic dysregulation in disease evolution. Disclosures Kenderian: Novartis: Patents & Royalties, Research Funding.
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Cantor, Alan, Md Almamun, Nah-Young Shin, and Daniel Yuan. "2004 – GERMLINE ANKRD26 MUTATIONS IN FAMILIAL THROMBOCYTOPENIA AND LEUKEMIA PREDISPOSITION." Experimental Hematology 111 (2022): S33. http://dx.doi.org/10.1016/j.exphem.2022.07.036.
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Bluteau, Dominique, Alessandra Balduini, Nathalie Balayn, Manuela Currao, Paquita Nurden, Caroline Deswarte, Guy Leverger, et al. "Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation." Journal of Clinical Investigation 124, no. 2 (January 16, 2014): 580–91. http://dx.doi.org/10.1172/jci71861.
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Dong, X. J., H. P. Guan, Q. D. Zhang, M. Yerle, and B. Liu. "Mapping of porcine ANKRD1, ANKRD2, ANKRD23, VGLL2 and VGLL4 using somatic cell and radiation hybrid panels." Animal Genetics 38, no. 4 (August 2007): 424–25. http://dx.doi.org/10.1111/j.1365-2052.2007.01613.x.
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Kraemer, Bjoern, and Andrew Weyrich. "Polyubiquinated protein depots in platelets and megakaryocytes from patients with ANKRD26-RT." Thrombosis and Haemostasis 109, no. 02 (2013): 180. http://dx.doi.org/10.1160/th13-01-0025.
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Staubitz, Julia Isabelle, Thomas Johannes Musholt, Arno Schad, Erik Springer, Hauke Lang, Krishnaraj Rajalingam, Wilfried Roth, and Nils Hartmann. "ANKRD26-RET - A novel gene fusion involving RET in papillary thyroid carcinoma." Cancer Genetics 238 (October 2019): 10–17. http://dx.doi.org/10.1016/j.cancergen.2019.07.002.
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Chen, Ming-Huei, Lisa R. Yanek, Joshua D. Backman, John D. Eicher, Jennifer E. Huffman, Yoav Ben-Shlomo, Andrew D. Beswick, et al. "Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation." Platelets 30, no. 2 (November 29, 2017): 164–73. http://dx.doi.org/10.1080/09537104.2017.1384538.
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Acs, Peter, Peter O. Bauer, Balazs Mayer, Tapan Bera, Rhonda Macallister, Eva Mezey, and Ira Pastan. "A novel form of ciliopathy underlies hyperphagia and obesity in Ankrd26 knockout mice." Brain Structure and Function 220, no. 3 (March 16, 2014): 1511–28. http://dx.doi.org/10.1007/s00429-014-0741-9.
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Bera, T. K., X. F. Liu, M. Yamada, O. Gavrilova, E. Mezey, L. Tessarollo, M. Anver, Y. Hahn, B. Lee, and I. Pastan. "A model for obesity and gigantism due to disruption of the Ankrd26 gene." Proceedings of the National Academy of Sciences 105, no. 1 (December 27, 2007): 270–75. http://dx.doi.org/10.1073/pnas.0710978105.
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Kuzmanovic, Teodora, Bhumika J. Patel, Jibran Durrani, Hassan Awada, Cassandra M. Kerr, Bartlomiej P. Przychodzen, Samuel Li, et al. "ANKRD26 Coding Variants Presenting with Giant Platelets and a Predisposition to Myeloid Neoplasia." Blood 134, Supplement_1 (November 13, 2019): 4233. http://dx.doi.org/10.1182/blood-2019-130520.
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Mutations (MT) in the 5' untranslated region (UTR) of ANKRD26 (A26) are implicated in ANKRD26- related thrombocytopenia (A26-RT), an autosomal dominant disorder of mild to moderate thrombocytopenia (TP) often presenting in adulthood, although severe and pediatric cases are reported. Erythrocyte and leukocyte counts are normal to increased, with unremarkable morphology. Platelet (plt) size is usually normal, as with ETV6- and RUNX1-mutated TP. Together, A26, ETV6, and RUNX1 germline (GL) MT comprise a separate 2016 WHO category of myeloid neoplasms (MN) with GL predisposition and preexisting platelet disorders. Normal plt size separates A26-RT from other familial TPs with giant plts. No consistent morphological plt aberrations have been reported. Bleeding history is absent or mild, and while TP is not life threating, 8-10% of patients (pts) develop a MN, including a 30-fold increased risk for AML relative to the general population. A26 is an inner membrane adaptor protein with 2 major domains: ankyrin repeats (ANKR) and coil-coil (C-C), both of which interact with signaling and cytoskeletal proteins. A26-RT MT are almost exclusively in the 5'UTR, however, rare A26 coding variants (A26-CV) are reported to segregate with familial TP. Still, some studies on A26-RT limit sequencing to the 5'UTR. As such, A26-CV are not well represented or described. We performed whole-exome sequencing (WES) on 195 pts with MN seen at Cleveland Clinic between 2004 and 2012, and downloaded WES .bam files from online sources, totaling 653 MN cases. Using a standard pipeline for discovery of rare GL variants (<1% population frequency), we identified 22 pts with A26-CV (6 MDS, 3 MDS/MPN, 13 AML) with 13 unique variants (2 benign/likely benign, 1 variant of unknown significance, 10 not found) and a median (med) VAF of 47%. Half of the variants were within either ANKR or C-C domains. The occurrence of these variants in our cohort was 3% vs.1% of the healthy population (p=0.0001). Complete clinical description was available for 8 A26-CV pts, all diagnosed with MDS or MDS/MPN at med age of 64. Two pts had antecedent bruising 1 year prior to diagnosis (dx). No prior bleeding was noted. Three pts had prior TP, two of whom had bicytopenia and pancytopenia. First degree family history (FH) was positive for cancer in 6 pts (75%), including 2 pts with FH of hematologic neoplasms. One pt had a 2nd-degree relative with a non-malignant hematologic condition requiring transfusions. At dx, cytogenetics were normal and complex in 2 pts each (25%). Deletions in chromosomes 5, 17, 20, and Y were observed in 1 pt each, and monosomy 7 in 2 pts. On bone marrow aspirate, 6 pts (75%) had dysmegakaryopoiesis, found in interstitial patterns and clusters. Mild to moderate dyserythropoiesis was observed in 5 pts (63%), and 5 pts had dysgranulopoiesis. The med blast percentage was 1.5% (range 0-8%), with 5 pts having hypercellular marrow, med 65% (range 40-95%). On corresponding CBC, pts were anemic (med hemoglobin of 9.5 g/dL), with the majority (n=5) showing signs of erythroid dysplasia, and also thrombocytopenic (med plt of 99 k/μL), with giant plts observed in 3 pts. Two pts had both giant plts and abnormal erythroid morphology. Hypo and monolobate, hyposegmented, and hypogranular forms were observed in the 3 lineages, as well as detached nuclear lobes, budding, segmentation, and nuclear-cytoplasmic dyssynchrony. On next generation sequencing, co-occurring SRSF2 and ASXL1 MT were observed in 3 and 2 pts, respectively. In sum, we have identified 22 A26-CV in MN, suggesting a role in predisposition as with A26-RT. We have seen in our cohort that A26-CV pts present differently from those with A26-RT. They have a variable past medical history and limited FH of TP, are anemic, with multilineage dysplasia observed not just in bone marrow, but also on peripheral blood smear, especially in megakaryocytes and erythrocytes. This is not surprising, as A26 is expressed in both lineages. The presence of giant plts is noteworthy. The mechanism for hypomorphic A26-CV may differ from that of the A26 5' UTR, which increase A26 levels in late-stage megakaryopoiesis by abrogating RUNX1/FLI1 binding, leading to aberrant proplatelet formation. Given the plt size and presence of nuclear phenotypes, altered interactions with signaling and cytoskeletal proteins could be involved, and may represent a novel A26 phenotype. Further investigation and association of A26-CV with MN ontogeny is under way. Disclosures Mukherjee: Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor; Bristol-Myers Squibb: Speakers Bureau. Advani:Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Macrogenics: Research Funding; Glycomimetics: Consultancy, Research Funding; Pfizer: Honoraria, Research Funding; Abbvie: Research Funding. Nazha:Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; Abbvie: Consultancy. Gerds:Imago Biosciences: Research Funding; Sierra Oncology: Research Funding; Roche: Research Funding; Incyte: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy; CTI Biopharma: Consultancy, Research Funding. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion: Consultancy; Novartis: Consultancy.
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Nestorovic, Aleksandra, Jovana Jasnic-Savovic, Georgine Faulkner, Dragica Radojkovic, and Snezana Kojic. "Ankrd1-mediated signaling is supported by its interaction with zonula occludens-1." Archives of Biological Sciences 66, no. 3 (2014): 1233–42. http://dx.doi.org/10.2298/abs1403233n.
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The muscle ankyrin repeat protein Ankrd1 is localized in a mechanosensory complex of the sarcomeric I-band. It is involved in signaling pathways activated in response to mechanical stretch. It also acts as a transcriptional cofactor in the nucleus, playing an important role in cardiogenesis and skeletal muscle differentiation. To investigate its regulatory function in signaling we employed protein array methodology and identified 10 novel Ankrd1 binding partners among PDZ domain proteins known to act as platforms for multiprotein complex assembly. The zonula occludens protein-1 (ZO-1) was chosen for further analysis since its interaction with Ankrd2 had already been demonstrated. Both Ankrd2 and Ankrd1 have similar functions and localize in the same regions. We confirmed the interaction of Ankrd1 with ZO-1 protein and determined their subcellular distribution in HeLa cells, showing their colocalization in the cytoplasm. Our findings corroborate the role of Ankrd1 in intracellular signaling.
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Glembotsky, Ana C., Rosana F. Marta, Yesica R. Espasandin, Nora P. Goette, Fernando Negro, Noris Patrizia, Anna Savoia, et al. "Application of a Diagnostic Algorithm for Inherited Thrombocytopenia Patients in the Setting of a Developing Country." Blood 118, no. 21 (November 18, 2011): 1163. http://dx.doi.org/10.1182/blood.v118.21.1163.1163.
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Abstract Abstract 1163 Inherited thrombocytopenias are rare genetic disorders which frequently represent a diagnostic challenge, even after extensive diagnostic work-up. This is due to the requirement of specialized laboratory tests and to the fact that the underlying disease-causing mutation remains in many cases still unknown. Increasing knowledge regarding the molecular etiology of inherited thrombocytopenias contributes both to patient diagnosis, prognosis and genetic counseling and may lead to the identification of novel regulators of platelet production. Recently, mutations in the ANKRD26 gene have been described, which underlie inherited thrombocytopenias with normal platelet size. We applied a previously proposed algorithm (Haematologica 2003; 88: 582–592) and developed a twining program in collaboration with a specialized center to improve the diagnostic yield in a cohort of patients in Argentina. Based on this algorithm, patients were classified according both to the presence or absence of clinical or laboratory features other than thrombocytopenia and to platelet size. Simple laboratory tests, such as platelet function studies, peripheral blood smear and flow cytometry were performed in all cases, while confirmatory tests were performed according to initial diagnostic suspicion, and included analysis of non-muscle myosin heavy chain IIA distribution in neutrophils by immunofluorescence and mutational screening of candidate genes, such as MYH9, RUNX1, MPL, WASP, GPIBA and ANKRD26. Studies unavailable at the local institution were performed in a specialized center in the setting of the twining program. Thirty-five patients, belonging to 14 pedigrees, were included, age 32 (4–72) years old, 20 were female. Platelet count was 83 (5–170)×109/L, 49% were classified as macrothrombocytopenia, 46% had normal platelet size while 6% harboured small platelets. In the latter, a diagnosis of X-linked thrombocytopenia secondary to WASP mutation was made. Four pedigrees with macrothrombocytopenia had MYH9-related disease, one had Bernard-Soulier syndrome, while in four other, no molecular diagnosis was reached. Among pedigrees with normal platelet size, one had FPD/LMA due to RUNX1 mutation, whereas the c.-127A>G mutation in 5'UTR region of the ANKRD26 gene was detected in another family. In addition, a working diagnosis of familial ITP was made in a three-generation pedigree who had autosomal dominant thrombocytopenia and normal platelet size, based on the finding of shortened platelet life-span and complete response to splenectomy. Overall, a molecular diagnosis was established in 9 of 14 (64%) pedigrees, and MYH9-RD comprised the most frequent single disorder. Application of this diagnostic algorithm proved feasible in a resource-limited setting, as data provided by careful medical history and simple laboratory tests allowed to identify patients in whom further, specialized studies were justified. Collaboration of a specialized center was essential for molecular diagnosis and proved invaluable to build local capacities. Disclosures: No relevant conflicts of interest to declare.
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М.Ю., Донников,, Илларионов, Р.А., Изотова, Т.А., Колбасин, Л.Н., and Коваленко, Л.В. "Evaluation of the effectiveness of next generation sequencing in the clinical practice of the medical genetic consultation in Khanty-Mansi region." Nauchno-prakticheskii zhurnal «Medicinskaia genetika, no. 9 (September 30, 2022): 38–40. http://dx.doi.org/10.25557/2073-7998.2022.09.38-40.
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Актуальность. Полноэкзомное секвенирование на основе NGS, принятое с 2016 г. в качестве аутсорсинговой услуги, все чаще используется в рутинной клинической практике окружной медико-генетической консультации (МГК). Оценка диагностических возможностей полноэкзомного секвенирования необходима для обоснования проведения NGS непосредственно в региональных клинических условиях. Цель: оценить эффективность диагностики генетических заболеваний у детей в ХМАО-Югра методом полноэкзомного секвенирования. Методы. Полноэкзомное секвенирование методом NGS, валидация данных NGS и анализ сегрегации в семье методом секвенирования по Сэнгеру. Результаты. Молекулярные диагнозы были установлены у 27% (27/100) детей, что соответствует данным, опубликованным в других источниках. Наследственные заболевания чаще диагностировались у лиц с аномалиями нервной, костной и дыхательной систем. Были выявлены преимущественно аутосомно-доминантные заболевания, среди которых наиболее частыми были нейрофиброматоз, несовершенный остеогенез, ахондроплазия. Анализ семейной сегрегации патологических вариантов выявил 5 новых вариантов в генах TSC1, KAT6A, ANKRD26, ARID1B, RPGRIP1. Background. NGS-based exome sequencing, accepted as an outsourced service since 2016, is increasingly being used in the routine clinical practice of our medical genetic counseling centre. Evaluation of the diagnostic capabilities of exome sequencing is necessary to substantiate the effectiveness of NGS in situ in regional clinical settings. Aim: to evaluate the effectiveness of diagnosing genetic diseases in children in Khanty-Mansi region using exome sequencing. Methods. Exome sequencing by NGS, validation of NGS data by Sanger sequencing, family segregation analysis by Sanger sequencing. Results. Molecular diagnoses were reported in 27% (27/100) of children, in line with data published elsewhere. The diagnoses were more often diagnosed in persons with anomalies of the nervous, skeletal and respiratory systems. Predominantly autosomal dominant diseases were identified, among which the most common were neurofibromatosis, osteogenesis imperfecta, achondroplasia. Family segregation revealed 5 new variants in the TSC1, KAT6A, ANKRD26, ARID1B, RPGRIP1 genes.
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Tsumura, Aaron M., Brian J. Druker, Diana Brewer, Richard Press, and Theodore P. Braun. "BCR-ABL+ Chronic Myeloid Leukemia Arising in a Family With Inherited ANKRD26-Related Thrombocytopenia." JCO Precision Oncology, no. 5 (February 2021): 415–17. http://dx.doi.org/10.1200/po.20.00318.
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Fiore, Mathieu, Noémie Saut, Marie-Christine Alessi, and Jean-François Viallard. "Successful use of eltrombopag for surgical preparation in a patient with ANKRD26-related thrombocytopenia." Platelets 27, no. 8 (June 8, 2016): 828–29. http://dx.doi.org/10.1080/09537104.2016.1190446.
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Raciti, G. A., T. K. Bera, O. Gavrilova, and I. Pastan. "Partial inactivation of Ankrd26 causes diabetes with enhanced insulin responsiveness of adipose tissue in mice." Diabetologia 54, no. 11 (August 13, 2011): 2911–22. http://dx.doi.org/10.1007/s00125-011-2263-9.
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Vrzalova, Zuzana, Katerina Stano Kozubik, Lenka Radova, Jakub Trizuljak, Sarka Pospisilova, and Michael Doubek. "Characterization of Pathogenic Variants Associated with Hereditary Thrombocytopenias in Families from the Czech Republic." Blood 134, Supplement_1 (November 13, 2019): 2343. http://dx.doi.org/10.1182/blood-2019-122696.
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Introduction Inherited thrombocytopenias (IT) are a heterogeneous group of 33 different forms of monogenic disorders caused by molecular defects affecting 40 genes at least. The pathogenic germline variants play an important role in the development and maintenance of hematopoietic system (megakaryopoesis and thrombopoesis). These changes lead to disruption of these processes and are presented as the thrombocytopenia phenotype (low platelet count, blood-examination). However, patients are occasionally misdiagnosed with the immune thrombocytopenia and unsuccessfully treated with steroid therapy and splenectomy. In some patients, accurate diagnosis of IT can only be established based on the results of molecular genetic testing. Furthermore, it has also been shown that some hematological conditions with Mendelian type of hereditability precede the development of hematooncological disease. Patients and Methods DNA samples from peripheral blood or buccal swabs of four unrelated families were isolated. The whole exome sequencing (WES) was performed using the NextSeq 500 Illumina instrument with adequate chemistry and sequencing libraries were prepared according to the SeqCap EZ Human Exome Probes v3 protocol. The generated data were processed using in-house bioinformatics pipelines. The detected pathogenic variants were confirmed by Sanger sequencing. Moreover, the novel variant was analyzed in silico using analytical procedures including protein modelling, too. Germline DNA analysis was performed on all available samples and somatic DNA analysis was done for the oncological patient. Within each family, the obtained pathogenic variants were compared between the individuals with IT phenotype and their disease-free relatives. Results The pathogenic variants were characterized in four families with different forms of IT. Moreover, the additional genetic variants were detected in three of them which predispose to the development of hematological malignancies. In the first family, a novel heterozygous variant c.320C>T; p.(Thr107Met) in TUBB1 gene is probably responsible for essential thrombocytopenia disease because all rare TUBB1 variants until now have been detected in patients with macrothrombocytopenia. The known pathogenic variant c.1402G>T; p.(Val468Phe) in JAK2 gene (10.9% frequency) was identified in a family member suffering from the myeloproliferative disease. In the second family, heterozygous pathogenic variants c.3076C>T; p.(Arg1026Trp) in ITGA2B gene and c.3188G>A; p.(Arg1063His) in JAK2 gene were detected, associated with platelet-type bleeding disorders and hereditary erythrocytosis with megakaryocytic atypia and predisposition for hematological malignancy, respectively. It is known that stomach tumor occurred in patient´s family before. In the third family, heterozygous pathogenic variant c.3493C>T; p.(Arg1165Cys) in MYH9 gene was identified in a patient with macrothrombocytopenia. This variant was associated with Sebastian syndrome, macrothrombocytopenia and granulocyte inclusions and predisposition to kidney failure, hearing loss, and cataracts. In the fourth family, ANKRD26-related thrombocytopenia with predisposition to myeloid malignancy was probably identified in a patient with detected heterogeneous known variant c.-140C>G in 5´ UTR of ANKRD26 gene. Moreover, the novel c.682C>T; p.(Arg228Trp) variant in SYTL3 gene with uncertain significance was detected in this patient. Conclusions The pathogenic variants were detected in unrelated affected families with macrothrombocytopenia, platelet-type bleeding disorders and hereditary erythrocytosis with megakaryocytic atypia, Sebastian syndrome, and ANKRD26-related thrombocytopenia. Moreover, the genetic variants predispose to myeloid malignancy were identified. Molecular genetic testing helped the clinicians to determine the correct diagnosis in these patients. This study was supported by Ministry of Health of the Czech Republic (grant No 16-29447A), and TA CR (TE02000058). Disclosures No relevant conflicts of interest to declare.
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Zhang, Bing, Yoonha Choi, Dana Ng, Ziming Weng, Clara Lo, Yohannes Ghebremariam, Engin Özkan, et al. "Identification Of The Disease-Causing Mutation In Autosomal Dominant Familial Immune Thrombocytopenia By Genome-Wide Linkage Analysis and Whole Genome Sequencing." Blood 122, no. 21 (November 15, 2013): 565. http://dx.doi.org/10.1182/blood.v122.21.565.565.
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Abstract Background Immune thrombocytopenia (ITP) is an autoimmune-mediated bleeding disorder characterized by low blood platelet count. The etiology of ITP remains an area of active research, and the predisposing risk factors are unclear. Genetic studies on the hereditary form of ITP, which is very rare, may help to decipher the underlying cause of disease predisposition. Herein we report a four-generation family from Michigan with multiple members affected with ITP during childhood (Figure 1). The pedigree is consistent with an autosomal dominant inheritance pattern. We performed the first family-based genetic study of ITP using genome-wide linkage analysis in combination with whole genome sequencing (WGS) in order to identify the disease-causing mutation. Methods Peripheral blood specimens were collected from eight family members for DNA extraction and clinical information of the four affected individuals was obtained. Genome-wide genotyping was performed with high density Illumina HumanOmni1-Quad BeadChips, followed by linkage analysis with MERLIN. Two affected family members (II2 and IV1) were chosen for WGS on Illumina HiSeq with 30X coverage. Sequence alignment and variant calling were done with DNAnexus. The variants, which are common (minor allele frequency >=1%), outside of the linkage region, not shared by the two members, or silent mutations, were removed. Copy number variation (CNV) data obtained from the arrays were analyzed to identify co-segregation with the phenotype. Conservation of sequence, predicted impact on protein function and biological plausibility were considered to further filter the variants. The final disease-causing candidate variant NOS3 (nitric oxide synthase 3) c.1267G>A was validated by Sanger sequencing. The potential impact of this variant on the NOS3 protein function was evaluated by protein structure modeling. Furthermore, the wild-type and mutant NOS3 expression constructs were generated and transfected into COS-7 cells for transient protein expression. The total NOx production (nitrite and nitrate), measured with a HPLC assay, was normalized to expressed NOS3 and phospho-NOS3 protein, quantitated with western blot. Results Mutations within the 5'UTR of ANKRD26 gene were reported to account for the autosomal dominant thrombocytopenia in some cases; however, no mutation was detected within the 5'UTR of ANKRD26 in this family and the linkage analysis also confirmed ANKRD26 gene being outside of the linkage region. The disease locus is mapped to a total of 215MB chromosomal region (6.92% of genome) by parametric linkage analysis with a LOD score of 1.1953. Within the linkage region, no CNV co-segregates with the phenotype. After removing common variants from those shared by II2 and IV1, no indel variants and 12 non-synonymous SNP variants were identified within the coding sequence. Following further removal of the SNP variants with low conservation scores or predicted by Polyphen to be a benign change on protein function, 5 variants from 5 genes remained, of which NOS3 is most biologically plausible based on the well-known role of NO in autoimmunity and oxidative stress. The co-segregation of the NOS3 variant with the phenotype of ITP in this family was validated via Sanger sequencing. Finally, an in vitro study demonstrated reduced NO production by mutant NOS3 protein compared to wild type NOS3 protein. Conclusion In this first genetic study of familial ITP, we identified the disease-causing mutation by using family-based linkage analysis and WGS. This finding will not only uncover the underlying genetic cause for the predisposition to childhood ITP in this Michigan kindred, but may also provide useful insights on the understanding of the pathogenesis of ITP in general. Disclosures: No relevant conflicts of interest to declare.
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Lazaro, Estibaliz, Clémence Houssin, Loic Sentilhes, Laura Blouin, and Mathieu Fiore. "Successful management of a pregnant woman with severe ANKRD26-related thrombocytopenia and anti-HPA-5b alloimmunization." Platelets 31, no. 6 (October 12, 2019): 827–29. http://dx.doi.org/10.1080/09537104.2019.1678116.
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Liu, Xiu-Fen, Tapan K. Bera, Charissa Kahue, Thelma Escobar, Zhaoliang Fei, Gregory A. Raciti, and Ira Pastan. "ANKRD26 and Its Interacting Partners TRIO, GPS2, HMMR and DIPA Regulate Adipogenesis in 3T3-L1 Cells." PLoS ONE 7, no. 5 (May 30, 2012): e38130. http://dx.doi.org/10.1371/journal.pone.0038130.
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Király, Péter Attila, Krisztián Kállay, Dóra Marosvári, Gábor Benyó, Anita Szőke, Judit Csomor, and Csaba Bödör. "Familiáris myelodysplasiás szindróma és akut myeloid leukaemia klinikai és genetikai háttere." Orvosi Hetilap 157, no. 8 (February 2016): 283–89. http://dx.doi.org/10.1556/650.2016.30375.
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Myelodysplastic syndrome and acute myeloid leukaemia are mainly sporadic diseases, however, rare familial cases exist. These disorders are considered rare, but are likely to be more common than currently appreciated, and are characterized by the autosomal dominant mutations of hematopoietic transcription factors. These syndromes have typical phenotypic features and are associated with an increased risk for developing overt malignancy. Currently, four recognized syndromes could be separated: familial acute myeloid leukemia with mutated CEBPA, familial myelodysplastic syndrome/acute myeloid leukemia with mutated GATA2, familial platelet disorder with propensity to myeloid malignancy with RUNX1 mutations, and telomere biology disorders due to mutations of TERC or TERT. Furthermore, there are new, emerging syndromes associated with germline mutations in novel genes including ANKRD26, ETV6, SRP72 or DDX41. This review will discuss the current understanding of the genetic basis and clinical presentation of familial leukemia and myelodysplasia. Orv. Hetil., 2016, 157(8), 283–289.
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Kewan, Tariq, Ryan Noss, Lucy A. Godley, Heesun J. Rogers, and Hetty E. Carraway. "Inherited Thrombocytopenia Caused by Germline ANKRD26 Mutation Should Be Considered in Young Patients With Suspected Myelodysplastic Syndrome." Journal of Investigative Medicine High Impact Case Reports 8 (January 2020): 232470962093894. http://dx.doi.org/10.1177/2324709620938941.
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Thrombocytopenia 2 (THC2) is an autosomal dominant disorder characterized by ankyrin repeat domain 26 mutation and moderate thrombocytopenia. THC2 exposes patients to a low risk of bleeding and an increased likelihood of myelodysplastic syndrome/acute myeloid leukemia. Germline evaluation for a genetic disorder should be considered when a patient presents with isolated thrombocytopenia and associated dysmegakaryopoiesis. In this case report, we present a male patient who presented with isolated thrombocytopenia but was ultimately confirmed to have an inherited THC2 thrombocytopenia/myelodysplastic syndrome. Given the rarity of the disease, no clear guidelines on how to follow THC2 patients over the long term have been established. We recommend a monthly complete blood count and clinical visits every 3 months at a minimum.
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Balduini, Alessandra, Hana Raslova, Christian A. Di Buduo, Alessandro Donada, Matthias Ballmaier, Manuela Germeshausen, and Carlo L. Balduini. "Clinic, pathogenic mechanisms and drug testing of two inherited thrombocytopenias, ANKRD26-related Thrombocytopenia and MYH9-related diseases." European Journal of Medical Genetics 61, no. 11 (November 2018): 715–22. http://dx.doi.org/10.1016/j.ejmg.2018.01.014.
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Perez Botero, J., J. L. Oliveira, D. Chen, K. K. Reichard, D. S. Viswanatha, P. L. Nguyen, R. K. Pruthi, et al. "ASXL1 mutated chronic myelomonocytic leukemia in a patient with familial thrombocytopenia secondary to germline mutation in ANKRD26." Blood Cancer Journal 5, no. 5 (May 2015): e315-e315. http://dx.doi.org/10.1038/bcj.2015.41.
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Porter, Christopher C. "Germ line mutations associated with leukemias." Hematology 2016, no. 1 (December 2, 2016): 302–8. http://dx.doi.org/10.1182/asheducation-2016.1.302.
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Abstract Several genetic syndromes have long been associated with a predisposition to the development of leukemia, including bone marrow failure syndromes, Down syndrome, and Li Fraumeni syndrome. Recent work has better defined the leukemia risk and outcomes in these syndromes. Also, in the last several years, a number of other germ line mutations have been discovered to define new leukemia predisposition syndromes, including ANKRD26, GATA2, PAX5, ETV6, and DDX41. In addition, data suggest that a substantial proportion of patients with therapy related leukemias harbor germ line mutations in DNA damage response genes such as BRCA1/2 and TP53. Recognition of clinical associations, acquisition of a thorough family history, and high index-of-suspicion are critical in the diagnosis of these leukemia predisposition syndromes. Accurate identification of patients with germ line mutations associated with leukemia can have important clinical implications as it relates to management of the leukemia, as well as genetic counseling of family members.
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Difilippo, Emma Catherine, Alejandro Ferrer, Laura Schultz-Rogers, Naseema Gangat, Shakila P. Khan, Aref Al-Kali, Abhishek A. Mangaonkar, et al. "Spectrum of Hematological Malignancies in 130 Patients with Germline Predisposition Syndromes - Mayo Clinic Germline Predisposition Study." Blood 136, Supplement 1 (November 5, 2020): 34–35. http://dx.doi.org/10.1182/blood-2020-139050.
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Introduction Germline predisposition syndromes (GPS) are inherited disorders associated with germinal aberrations that increase the risk of malignancies. While aberrations in certain genes increase the risk for all types of malignancies (Tp53, ATM, CDKN2A, CHEK2), there is a growing list of genes associated specifically with hematological malignancies (GATA2, RUNX1, DDX41, ETV6, ANKRD26). At our institution, we have established a hematology GPS clinic to diagnose and manage GPS and with this report, detail our experience with 130 patients. Methods GPS were investigated in pediatric and adult patients with one or more first degree relatives with hematological/visceral malignancies or in those with antecedent thrombocytopenia (ANKRD26, RUNX1, ETV6), or with specific syndromic features (short telomere syndromes/STS, GATA2 haploinsufficiency, Fanconi anemia/FA, Shwachman-Diamond syndrome/SDS). Depending on the phenotype, specific functional assays such as flow-FISH for telomere length assessment and chromosomal breakage assays were ordered. After informed consent and genetic counselling, germline testing was carried out on peripheral blood mononuclear cell, skin fibroblast, or hair follicle-derived DNA. A custom-designed marrow failure NGS panel (200 genes) was used in most cases and interrogation of variants, in silico studies, and functional assays were carried out as previously described (Mangaonkar et al MC Proc 2019). Copy number variations were identified by aCGH. At the time of progression/worsening cytopenias, bone marrow/lymph node biopsies and NGS (next generation sequencing) were carried out where indicated. Results 130 patients with germline predisposition have been identified to date. The spectrum of disorders seen include STS 29 (22%), FA 17 (13%), GATA2 16 (12%), Diamond Blackfan anemia/DBA 13 (10%), RUNX1-FPD 12 (9%), ATM deletions/mutations 11 (8%), ANKRD26 6 (5%), SDS 5 (4%), DDX41 4 (3%), MPL 3 (2%), CHEK2, MECOM, Tp53 mutations 2 (2%) each, and CBL, CEPBA, ELANE, NF1, CDKN2A, CSF3R, ETV6, and GATA1 mutations, 1 (1%) each. Evidence for clonal evolution (CCUS) and hematological malignancies were seen in 51 (39%) patients, involving all the aforementioned genes/syndromes with the exception of DBA, CBL, ETV6, MPL, CSF3R, and GATA1. Seven (64%) of 11 patients with germline ATM deletions/mutations developed lymphoid malignancies; homozygous ATM (Follicular NHL-1, Burkitt lymphoma-1, T-ALL-1, T-LPD-1) and heterozygous ATM (T-PLL-1, DLBCL-1, CLL-1). Clonal evolution occurred in 11 (69%) of 16 GATA2 haploinsufficient patients (CCUS-2, MDS-3, CMML-1, AML-5) and in 7 (58%) of 12 RUNX1-FPD patients (CCUS-1, MDS-1, MDS/MPN-3, AML-2). Five of 29 (17%) STS patients had clonal progression (CCUS-2, MDS-2, AML-1), and 5 (29%) of 17 FA patients progressed to MDS-2 or AML-3. JMML was seen in one patient with a germline NF1 mutation, while 1 (20%) of 5 SDS patients progressed to AML. NGS data at progression was available in 24 (55%) of 44 myeloid/CCUS progressions, with somatic truncating ASXL1 mutations being most frequent (29%), followed by RAS pathway mutations (15%). AML/MDS progressions in STS, FA, and SDS were universally associated with complex/monosomal karyotypes, translating to refractory disease. Seventeen (39%) of 44 patients with myeloid predisposition underwent allogenic HCT (GATA2-7, FA-3, RUNX1-FPD-3, STS-2, NF1-1, Tp53-1), with 10 (59%) being alive at last follow up (Table 1). Conclusion We demonstrate the spectrum of germline aberrations associated with predisposition to hematological malignancies and outline the phenotypic heterogeneity of clonal transformation. The advent of NGS allows identification of clonal progression earlier than morphological changes, with mutations in ASXL1 and RAS pathway genes being commonly implicated. This study supports the universal development of dedicated germline predisposition clinics. Disclosures Pruthi: CSL Behring: Honoraria; Genentech Inc.: Honoraria; Bayer Healthcare: Honoraria; HEMA Biologics: Honoraria; Instrumentation Laboratory: Honoraria; Merck: Honoraria.
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Iqbal, Zafar, Muhammad Absar, Tanveer Akhtar, Aamer Aleem, Abid Jameel, Sulman Basit, Anhar Ullah, et al. "Integrated Genomic Analysis Identifies ANKRD36 Gene as a Novel and Common Biomarker of Disease Progression in Chronic Myeloid Leukemia." Biology 10, no. 11 (November 15, 2021): 1182. http://dx.doi.org/10.3390/biology10111182.
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Background: Chronic myeloid leukemia (CML) is initiated in bone marrow due to chromosomal translocation t(9;22) leading to fusion oncogene BCR-ABL. Targeting BCR-ABL by tyrosine kinase inhibitors (TKIs) has changed fatal CML into an almost curable disease. Despite that, TKIs lose their effectiveness due to disease progression. Unfortunately, the mechanism of CML progression is poorly understood and common biomarkers for CML progression are unavailable. This study was conducted to find novel biomarkers of CML progression by employing whole-exome sequencing (WES). Materials and Methods: WES of accelerated phase (AP) and blast crisis (BC) CML patients was carried out, with chronic-phase CML (CP-CML) patients as control. After DNA library preparation and exome enrichment, clustering and sequencing were carried out using Illumina platforms. Statistical analysis was carried out using SAS/STAT software version 9.4, and R package was employed to find mutations shared exclusively by all AP-/BC-CML patients. Confirmation of mutations was carried out using Sanger sequencing and protein structure modeling using I-TASSER followed by mutant generation and visualization using PyMOL. Results: Three novel genes (ANKRD36, ANKRD36B and PRSS3) were mutated exclusively in all AP-/BC-CML patients. Only ANKRD36 gene mutations (c.1183_1184 delGC and c.1187_1185 dupTT) were confirmed by Sanger sequencing. Protein modeling studies showed that mutations induce structural changes in ANKRD36 protein. Conclusions: Our studies show that ANKRD36 is a potential common biomarker and drug target of early CML progression. ANKRD36 is yet uncharacterized in humans. It has the highest expression in bone marrow, specifically myeloid cells. We recommend carrying out further studies to explore the role of ANKRD36 in the biology and progression of CML.
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Pecci, A., P. Noris, and C. L. Balduini. "Inherited thrombocytopenias." Hämostaseologie 32, no. 04 (2012): 259–70. http://dx.doi.org/10.5482/ha12050001.
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SummaryThe chapter of inherited thrombocytopenias has expanded greatly over the last decade and many “new” forms deriving from mutations in “new” genes have been identified. Nevertheless, nearly half of patients remain without a definite diagnosis because their illnesses have not yet been described. The diagnostic approach to these diseases can still take advantage of the algorithm proposed by the Italian Platelet Study Group in 2003, although an update is required to include the recently described disorders. So far, transfusions of platelet concentrates have represented the main tool for preventing or treating bleedings, while haematopoietic stem cell transplantation has been reserved for patients with very severe forms. However, recent disclosure that an oral thrombopoietin mimetic is effective in increasing platelet count in patients with MYH9-related thrombocytopenia opened new therapeutic perspectives.This review summarizes the general aspects of inherited thrombocytopenias and describes in more detail MYH9-related diseases (encompassing four thrombocytopenias previously recognized as separate diseases) and the recently described ANKRD26-related thrombocytopenia, which are among the most frequent forms of inherited thrombocytopenia.
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Churpek, Jane E. "Inherited Predisposition to Myelodysplastic Syndrome and Acute Leukemia." Blood 124, no. 21 (December 6, 2014): SCI—31—SCI—31. http://dx.doi.org/10.1182/blood.v124.21.sci-31.sci-31.
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Although generally thought of as pediatric conditions, inherited forms of myelodysplastic syndrome (MDS) and acute leukemia (AL) are increasingly recognized among adult patients. At present, at least nine genes, including ANKRD26, CEBPA, GATA2, PAX5, RUNX1, SRP72, TERC, TERT, and TP53, are known to cause familial MDS and/or AL syndromes. Several other promising candidate genes are emerging from ongoing research on the many pedigrees identified without a mutation in one of these already recognized genes. Clinical recognition of individuals with these syndromes is essential for optimal care of the patient and his/her at-risk family members and requires familiarity with the subtle clinical features of each syndrome and a high index of suspicion by the treating physician. Once recognized, genetic testing should be performed to identify the specific syndrome present as each can have unique aspects to their clinical care. For example, individuals with familial MDS/AL due to TERT or TERC abnormalities require monitoring of lung function and screening for head and neck and anogenital cancers, whereas individuals with platelet dysfunction due to familial platelet disorder/RUNX1 or ANKRD26 mutations require careful planning prior to surgical procedures to prevent bleeding complications. Due to significant overlap in the clinical presentation, often a multigene-based approach to genetic testing is necessary. Unique aspects of genetic testing in this population include: 1) tissue type selection as many of the genes that cause the familial MDS/AL syndromes are also somatically mutated in hematologic malignancies so results from DNA derived from peripheral blood or bone marrow in an individual with MDS or AL are difficult to interpret; and 2) urgency as allogeneic hematopoietic stem cell transplantation may be pursued quickly and requires knowledge of the specific mutation in the family to identify the optimal stem cell donor. The management of affected individuals who have not yet developed hematologic malignancies can be challenging as many may show morphologic signs of dysplasia in the bone marrow that may not truly represent overt malignancy. The decision of when to pursue allogeneic hematopoietic stem cell transplantation with curative intent is especially difficult. Ongoing research to define the specific events that trigger malignant transformation and how to optimally detect these events is underway. Practical algorithms for the clinical recognition, genetic testing, and management of individuals with these syndromes based on currently available knowledge as well as research seeking to improve the clinical care of these patients will be explored. A summary of the yield of next generation sequencing-based genetic testing strategies for familial presentations of MDS/AL will also be provided. Disclosures No relevant conflicts of interest to declare.
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Stano Kozubik, K., J. Trizuljak, Z. Vrzalova, L. Radova, I. Blahakova, J. Stika, P. Smejkal, et al. "P1648: ANALYSIS OF ANKRD26 GENE 5’UTR VARIANTS IN A COHORT OF CZECH PATIENTS WITH SUSPECTED HEREDITARY HEMATOLOGICAL DISORDER." HemaSphere 6 (June 2022): 1529–30. http://dx.doi.org/10.1097/01.hs9.0000849448.51581.9a.
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Averina, M., H. Jensvoll, H. Strand, and M. Sovershaev. "A novel ANKRD26 gene variant causing inherited thrombocytopenia in a family of Finnish origin: Another brick in the wall?" Thrombosis Research 151 (March 2017): 41–43. http://dx.doi.org/10.1016/j.thromres.2017.01.001.
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Xu, Xiaofei, Lan Zhang, Shengjie Wang, Keyi Jin, Chen DAN, and Jian Huang. "Relapse with BCR-ABL1 Elevation in Chronic Myeloid Leukemia after Progression to Multiple Myeloma from Monoclonal Gammopathy of Undetermined Significance with a Persistent KMT2D Mutation." Blood 138, Supplement 1 (November 5, 2021): 4608. http://dx.doi.org/10.1182/blood-2021-145904.
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Abstract Chronic myeloid leukemia (CML) and monoclonal gammopathy of undetermined significance (MGUS) are two different hematologic malignancies, the former arising from the myeloid cell lineage, and the latter arising from plasma cells. The concurrent diagnosis of CML and MGUS progression to multiple myeloma (MM) in one patient is an extremely rare event. A 59-year-old male was diagnosed with CML and MGUS with no discomfort in August 2012. Bone marrow (BM) aspiration suggested chronic myelogenous leukemia in chronic phase and perhaps myeloproliferative with 6.5% mature plasma cells (Figure 1A). FISH analysis detected that the BCR-ABL1 expression was 130%. And Next-generation sequencing (NGS) of BM showed: ASXL1 , KMT2D , SPEN , BRINP3 , ANKRD26 , PLCG1 , CUX1 were mutated (Figure 2I). The patient started oral imatinib 400 mg per day and achieved a complete cytogenetic response at 3 months. In September 2019, his IgG levels were 2,790 mg/dl (Figure 2J and serum immunofixation electrophoresis revealed monoclonal (M) protein of IgG-Lambda type (Figure 1E). BM aspiration revealed 9.5% plasma cell infiltration, including 6% mature plasma cells and 3.5% proplasmacyte (Figure 1C and 2H). Flow cytometry in BM showed 6.3% plasmacytoma and abnormal cell expressing CD38+CD138+CD56+CD117+clambda+ (Figure 1F). BM biopsy showed hematopoietic hyperplasia with abnormal growth of immature cells (Figure 1B). Fluorescent in situ hybridization (FISH) was negative. Mutations of KMT2D, SPEN, BRINP3, ANKRD26, PLCG1, CUX1, and ZMYM3 still existed(Figure 2I). In January 2020, examination of a new BM aspiration revealed that mature plasma cells were 3% and plasmablast and proplasmacyte were 4.5% (Figure 2H). In February 2020, he stopped IM therapy with undetectable BCR-ABL1 copies because he met the requirement of stopping TKI therapy . In March 2020, IgG levels were 3520 mg/dl and serum immunofixation electrophoresis still revealed monoclonal (M) protein of IgG-Lambda type. His BM aspiration demonstrated 13.5% plasma cells in April 2020 (Figure 2B and 2H). Flow cytometry in BM showed 6.44% (Figure 2F). BM biopsy showed extremely increased proliferation with abnormal growth of abnormal cells (Figure 2A). FISH demonstrated the presence of t(4;14)(p16;q32)(IGH/FGFR3) , 13q14 deletion（RB-1） and 13q14.3 （D13S319） (Figure 2C, 2D and 2E). The patient was diagnosed as MM (IgGλ type, D-S stage IA; ISS stage II) . BCR-ABL1 copies were still not detected at this point (Figure 2G). The patient continued his follow-up treatment of MM without chemotherapy.However, in June 2020, he was considered to have a molecular relapse with 0.2013% BCR-ABL1 copies in the peripheral blood (Figure 2G). NGS showed that the variant allele fractions of KMT2D, SPEN, BRINP3, ANKRD26, PLCG1, CUX1, and ZMYM3 mutations were similar to former . He restarted 400 mg daily IM therapy and BCR-ABL1 copies were undetectable againafter one month therapy (Figure 2G). BM aspiration revealed that the percentage of plasma cells increased to 25.5% in August 2020 (Figure 2H). Then the patient was started on treatment for ISS stage II standard risk myeloma with ID regimen: ixazomib 4 mg on days 1, 8 , 15 and dexamethasone 20 mg on days 1, 8, 15 , 22 in 28-day cycles. After 6 cycles , the patient got VGPR. BM aspiration demonstrated 13% plasma cells (Figure 2H). And he continued to receive myeloma treatment and imatinib . BCR-ABL1 were <MR4.5 (Figure 2G). Our research indicated that KMT2D mutation may make MGUS progress to MM with NK cells functional defects and then promote the recurrence of BCR-ABL1. Co-existence of these two diseases is rare, therefore, additional investigations are warranted. Acknowledgment:The research was supported by the Public Technology Application Research Program of Zhejiang, China (LGF21H080003), the Key Project of Jinhua Science and Technology Plan, China (2020XG-29 and 2020-3-011), the Academician Workstation of the Fourth Affiliated Hospital of the Zhejiang University School of Medicine (2019-2024), the Key Medical Discipline of Yiwu, China (Hematology, 2018-2020) and the Key Medical Discipline of Jinhua, China (Hematology, 2019-2021). Correspondence to: Dr Jian Huang, Department of Hematology, The Fourth Affiliated Hospital of Zhejiang University School of Medicine. N1 Shangcheng Road. Yiwu, Zhejiang, Peoples R China. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Louzil, Jan, Jana Stikarova, Dana Provaznikova, Ingrid Hrachovinova, Tereza Fenclova, Jan Musil, Martin Radek, et al. "Diagnosing Czech Patients with Inherited Platelet Disorders." International Journal of Molecular Sciences 23, no. 22 (November 19, 2022): 14386. http://dx.doi.org/10.3390/ijms232214386.
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A single-center study was conducted on 120 patients with inherited disorders of primary hemostasis followed at our hematological center. These patients presented a variety of bleeding symptoms; however, they had no definitive diagnosis. Establishing a diagnosis has consequences for the investigation of probands in families and for treatment management; therefore, we aimed to improve the diagnosis rate in these patients by implementing advanced diagnostic methods. According to the accepted international guidelines at the time of study, we investigated platelet morphology, platelet function assay, light-transmission aggregometry, and flow cytometry. Using only these methods, we were unable to make a definitive diagnosis for most of our patients. However, next-generation sequencing (NGS), which was applied in 31 patients, allowed us to establish definitive diagnoses in six cases (variants in ANKRD26, ITGA2B, and F8) and helped us to identify suspected variants (NBEAL2, F2, BLOC1S6, AP3D1, GP1BB, ANO6, CD36, and ITGB3) and new suspected variants (GFI1B, FGA, GP1BA, and ITGA2B) in 11 patients. The role of NGS in patients with suspicious bleeding symptoms is growing and it changes the diagnostic algorithm. The greatest disadvantage of NGS, aside from the cost, is the occurrence of gene variants of uncertain significance.
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Bogomolovas, Julius, Kathrin Brohm, Jelena Čelutkienė, Giedrė Balčiūnaitė, Daiva Bironaitė, Virginija Bukelskienė, Dainius Daunoravičus, et al. "Induction of Ankrd1 in Dilated Cardiomyopathy Correlates with the Heart Failure Progression." BioMed Research International 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/273936.
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Progression of idiopathic dilated cardiomyopathy (IDCM) is marked with extensive left ventricular remodeling whose clinical manifestations and molecular basis are poorly understood. We aimed to evaluate the clinical potential of titin ligands in monitoring progression of cardiac remodeling associated with end-stage IDCM. Expression patterns of 8 mechanoptotic machinery-associated titin ligands (ANKRD1,ANKRD2,TRIM63,TRIM55,NBR1,MLP,FHL2, andTCAP) were quantitated in endomyocardial biopsies from 25 patients with advanced IDCM. When comparing NYHA disease stages, elevatedANKRD1expression levels marked transition from NYHA < IV to NYHA IV.ANKRD1expression levels closely correlated with systolic strain depression and short E wave deceleration time, as determined by echocardiography. On molecular level, myocardialANKRD1and serum adiponectin correlated with lowBAX/BCL-2ratios, indicative of antiapoptotic tissue propensity observed during the worsening of heart failure. ANKRD1 is a potential marker for cardiac remodeling and disease progression in IDCM.ANKRD1expression correlated with reduced cardiac contractility and compliance. The association ofANKRD1with antiapoptotic response suggests its role as myocyte survival factor during late stage heart disease, warranting further studies on ANKRD1 during end-stage heart failure.
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Bastida, José María, José Ramón Gonzalez-Porras, José Rivera, and María Luisa Lozano. "Role of Thrombopoietin Receptor Agonists in Inherited Thrombocytopenia." International Journal of Molecular Sciences 22, no. 9 (April 21, 2021): 4330. http://dx.doi.org/10.3390/ijms22094330.
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In the last decade, improvements in genetic testing have revolutionized the molecular diagnosis of inherited thrombocytopenias (ITs), increasing the spectrum of knowledge of these rare, complex and heterogeneous disorders. In contrast, the therapeutic management of ITs has not evolved in the same way. Platelet transfusions have been the gold standard treatment for a long time. Thrombopoietin receptor agonists (TPO-RA) were approved for immune thrombocytopenia (ITP) ten years ago and there is evidence for the use of TPO-RA not only in other forms of ITP, but also in ITs. We have reviewed in the literature the existing evidence on the role of TPO-RAs in ITs from 2010 to February 2021. A total of 24 articles have been included, 4 clinical trials, 3 case series and 17 case reports. A total of 126 patients with ITs have received TPO-RA. The main diagnoses were Wiskott–Aldrich syndrome, MYH9-related disorder and ANKRD26-related thrombocytopenia. Most patients were enrolled in clinical trials and were treated for short periods of time with TPO-RA as bridging therapies towards surgical interventions, or other specific approaches, such as hematopoietic stem cell transplantation. Here, we have carried out an updated and comprehensive review about the efficacy and safety of TPO-RA in ITs.