Paroxysmal nocturnal hemoglobinuria-related thrombosis in the era of novel therapies: a 2043-patient-year analysis.

ABSTRACT: Thrombophilia is one of the principal features of paroxysmal nocturnal hemoglobinuria (PNH) and constitutes the main cause of disease morbidity/mortality. Anticomplement treatment has revolutionized the natural history of PNH, with control of the hemolytic process and abolition of thrombotic events (TEs). However, no guidelines exist for the management of thromboembolic complications in this setting, with type and duration of anticoagulation depending on individual practices. Besides, a scarcity of data is present on the efficacy of direct oral anticoagulants (DOACs). Herein, we accrued a large real-world cohort of patients with PNH from 4 US centers to explore features, predictors of TE, and anticoagulation strategies. Among 267 patients followed up for a total of 2043 patient-years, 56 (21%) developed TEs. These occurred at disease onset in 43% of cases, involving more frequently the venous system, typically as Budd-Chiari syndrome. Rate of TEs was halved in patients receiving complement inhibitors (21 vs 40 TEs per 1000 patient-years in untreated cases, with a 2-year cumulative incidence of thrombosis of 3.9% vs 18.3%, respectively), and varied according to PNH granulocytes and erythrocytes clone size, type, disease activity parameters, as well as number (≥2 mutations, or less) and variant allelic frequency of PIGA mutations. Anticoagulation with warfarin (39%), DOACs (37%), and low-molecular weight heparin (16%) was administered for a median of 29 months (interquartile range [IQR], 9-61.8). No thrombotic recurrence was observed in 19 patients treated with DOACs at a median observation of 17.1 months (IQR, 8.9-45) whereas 14 cases discontinued anticoagulation without TE recurrence at a median time of 51.4 months (IQR, 29.9-86.8).

Association of aberrant ASNS imprinting with asparaginase sensitivity and chromosomal abnormality in childhood BCP-ALL.

Karyotype is an important prognostic factor in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), but the underlying pharmacogenomics remain unknown. Asparaginase is an integral component in current chemotherapy for childhood BCP-ALL. Asparaginase therapy depletes serum asparagine. Normal hematopoietic cells can produce asparagine by asparagine synthetase (ASNS) activity, but ALL cells are unable to synthesize adequate amounts of asparagine. The ASNS gene has a typical CpG island in its promoter. Thus, methylation of the ASNS CpG island could be one of the epigenetic mechanisms for ASNS gene silencing in BCP-ALL. To gain deep insights into the pharmacogenomics of asparaginase therapy, we investigated the association of ASNS methylation status with asparaginase sensitivity. The ASNS CpG island is largely unmethylated in normal hematopoietic cells, but it is allele-specifically methylated in BCP-ALL cells. The ASNS gene is located at 7q21, an evolutionally conserved imprinted gene cluster. ASNS methylation in childhood BCP-ALL is associated with an aberrant methylation of the imprinted gene cluster at 7q21. Aberrant methylation of mouse Asns and a syntenic imprinted gene cluster is also confirmed in leukemic spleen samples from ETV6-RUNX1 knockin mice. In 3 childhood BCP-ALL cohorts, ASNS is highly methylated in BCP-ALL patients with favorable karyotypes but is mostly unmethylated in BCP-ALL patients with poor prognostic karyotypes. Higher ASNS methylation is associated with higher L-asparaginase sensitivity in BCP-ALL through lower ASNS gene and protein expression levels. These observations demonstrate that silencing of the ASNS gene as a result of aberrant imprinting is a pharmacogenetic mechanism for the leukemia-specific activity of asparaginase therapy in BCP-ALL.

Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases.

Most B cell precursor acute lymphoblastic leukemia (BCP ALL) can be classified into known major genetic subtypes, while a substantial proportion of BCP ALL remains poorly characterized in relation to its underlying genomic abnormalities. We therefore initiated a large-scale international study to reanalyze and delineate the transcriptome landscape of 1,223 BCP ALL cases using RNA sequencing. Fourteen BCP ALL gene expression subgroups (G1 to G14) were identified. Apart from extending eight previously described subgroups (G1 to G8 associated with MEF2D fusions, TCF3-PBX1 fusions, ETV6-RUNX1-positive/ETV6-RUNX1-like, DUX4 fusions, ZNF384 fusions, BCR-ABL1/Ph-like, high hyperdiploidy, and KMT2A fusions), we defined six additional gene expression subgroups: G9 was associated with both PAX5 and CRLF2 fusions; G10 and G11 with mutations in PAX5 (p.P80R) and IKZF1 (p.N159Y), respectively; G12 with IGH-CEBPE fusion and mutations in ZEB2 (p.H1038R); and G13 and G14 with TCF3/4-HLF and NUTM1 fusions, respectively. In pediatric BCP ALL, subgroups G2 to G5 and G7 (51 to 65/67 chromosomes) were associated with low-risk, G7 (with ≤50 chromosomes) and G9 were intermediate-risk, whereas G1, G6, and G8 were defined as high-risk subgroups. In adult BCP ALL, G1, G2, G6, and G8 were associated with high risk, while G4, G5, and G7 had relatively favorable outcomes. This large-scale transcriptome sequence analysis of BCP ALL revealed distinct molecular subgroups that reflect discrete pathways of BCP ALL, informing disease classification and prognostic stratification. The combined results strongly advocate that RNA sequencing be introduced into the clinical diagnostic workup of BCP ALL.

KMT2A-rearranged diffuse large B-cell lymphoma in a child: a case report and molecular characterization.

KMT2A-rearranged diffuse large B-cell lymphoma (DLBCL) is rare in both the adult and pediatric populations, and its biological features are unclear. We here report the case of a 19-month-old female with a right temporal bone tumor that was ultimately diagnosed as DLBCL by tumor biopsy. There was no morphological evidence of bone marrow infiltration at diagnosis. The tumor nearly completely dissolved after scheduled chemotherapy for mature B-cell lymphoma; however, leukemic conversion occurred 2 months after completion of chemotherapy. Additional chemotherapy including hematopoietic cell transplantation in a non-remission state was unsuccessful, and disease progression ultimately resulted in the death of the patient 18 months after the diagnosis. We detected the KMT2A-MLLT3 fused transcript in the bone marrow of the patient with primary and recurrent cancer. RNA-sequencing of the bone marrow with recurrent cancer confirmed the KMT2A-MLLT3 fusion gene, although fusion genes involving BCL6, BCL2, or were not detected. Moreover, RNA-sequencing revealed overexpression of MEIS1 and MEF2C, which are highly expressed in KMT2A-rearranged leukemia, whereas the HOXA gene cluster was not overexpressed. The current case formed part of the KMT2A-rearranged acute lymphoblastic leukemia cluster in a T-distributed stochastic neighbor embedding plot. The aggressive clinical course and RNA-sequencing results of the present case suggest that KMT2A-rearranged DLBCL shares biological features with KMT2A-rearranged leukemia.

[Chronic-phase chronic myeloid leukemia with intracranial hemorrhage complicated with tumor lysis syndrome].

A 14-year-old male with autism was admitted to our hospital owing to altered consciousness and gait disturbance. Blood tests showed a white blood cell (WBC) count of 728,600/µl, and brain computed tomography revealed intracranial hemorrhage and a midline shift of the brain. The chronic phase of chronic myeloid leukemia (CML) was confirmed as per bone marrow aspiration findings. The patient underwent emergency craniotomy for hematoma removal, and he subsequently received hydroxyurea and rasburicase combination therapy. However, he developed tumor lysis syndrome (TLS) and died on the second day of hospitalization. Histopathological examination of autopsy specimens did not reveal any condition that could account for his death other than CML. Several reports have described intracranial hemorrhage during the accelerated phase or blast crisis of CML, but few have described this complication during the chronic phase. TLS concomitant with CML in the chronic phase or following hydroxyurea (an inhibitor of DNA synthesis) administration is rare. It is essential for clinicians to be aware that patients with chronic phase CML and high WBC counts may develop TLS, following the administration of hydroxyurea alone. In addition, extreme caution is warranted in severe cases accompanied by intracranial hemorrhage.

Tandem high-dose chemotherapy with autologous stem cell rescue for stage M high-risk neuroblastoma: Experience using melphalan/etoposide/carboplatin and busulfan/melphalan regimens.

The efficacy of tandem HDCT against high-risk neuroblastoma has been reported; however, an optimal regimen remains to be established. In this paper, we report our experience using tandem HDCT comprising the MEC and BuMel regimens in patients with high-risk neuroblastoma. We retrospectively analyzed four patients with stage M high-risk neuroblastoma who received HDCT with MEC followed by BuMel combined with autologous stem cell rescue. Although none of their metastatic lesions had disappeared after induction chemotherapy, three patients showed a CR after tandem HDCT. Gastrointestinal mucosal injuries and renal dysfunction were observed as non-hematologic adverse events of grade 3 or higher. Gastrointestinal mucosal injuries were observed in all four patients following the first HDCT and in one patient following the second HDCT and were treated with parenteral nutrition and analgesics. One patient experienced renal dysfunction during the first HDCT, which was alleviated by sufficient hydration and diuretics and resulted in the reduction of melphalan dosage for the second HDCT. SOS was not observed in any patient. The HDCT regimens examined in this study were observed to be feasible and did not result in any life-threatening adverse events. Our findings indicate that tandem HDCT comprising MEC and BuMel is a potentially effective regimen for patients with high-risk neuroblastoma, including for those who respond poorly to induction chemotherapy, although additional studies in a larger population should be conducted to verify any long-term outcomes and toxicity.

Familial cases of pseudohypoaldosteronism type II harboring a novel mutation in the Cullin 3 gene.

Pseudohypoaldosteronism type II (PHA II) is inherited in an autosomal dominant manner and is characterized by hypertension, hyperkalemia, and hyperchloremic metabolic acidosis. The enhancement of with-no-lysine kinase (WNK) functions is correlated to the pathogenesis of the condition. Cullin 3 (CUL3) forms an E3 ubiquitin ligase complex, and it can ubiquitinate WNK. Most CUL3 gene mutations are distributed in sites, such as intron 8 splice acceptor, intron 9 splice donor, and putative intron 8 splice branch sites, which are involved in the splicing of exon 9. These mutations result in the deletion of exon 9, which reduces the activity of ubiquitination against WNK and inhibits the degradation of WNK. In this report, we identified a novel CUL3 c.1312A>G mutation in familial cases. A mutation prediction software showed that the significance of these mutations was not clear. However, using the Human Splicing Finder 3.1 software, in silico analyses revealed that these mutations induced splicing alterations, which affected the sites of exon 9, altered the balance between predicted exonic splicing enhancers and silencers, and led to the deletions of exon 9. This study presented a novel pathogenic splicing variant to the CUL3 mutation and provided a reference for further research about the mechanisms of splicing. Moreover, it showed that not only amino acid substitution caused by nonsynonymous mutations but also splicing motif changes due to base substitutions have important roles in the pathogenesis of PHA II.

Integrated genetic and epigenetic analysis revealed heterogeneity of acute lymphoblastic leukemia in Down syndrome.

Children with Down syndrome (DS) are at a 20-fold increased risk for acute lymphoblastic leukemia (ALL). Compared to children with ALL and no DS (non-DS-ALL), those with DS and ALL (DS-ALL) harbor uncommon genetic alterations, suggesting DS-ALL could have distinct biological features. Recent studies have implicated several genes on chromosome 21 in DS-ALL, but the precise mechanisms predisposing children with DS to ALL remain unknown. Our integrated genetic/epigenetic analysis revealed that DS-ALL was highly heterogeneous with many subtypes. Although each subtype had genetic/epigenetic profiles similar to those found in non-DS-ALL, the subtype distribution differed significantly between groups. The Philadelphia chromosome-like subtype, a high-risk B-cell lineage variant relatively rare among the entire pediatric ALL population, was the most common form in DS-ALL. Hypermethylation of RUNX1 on chromosome 21 was also found in DS-ALL, but not non-DS-ALL. RUNX1 is essential for differentiation of blood cells, especially B cells; thus, hypermethylation of the RUNX1 promoter in B-cell precursors might be associated with increased incidence of B-cell precursor ALL in DS patients.

A case of malignant rhabdoid tumor mimicking yolk sac tumor.

Malignant rhabdoid tumors (MRTs) are rare, highly aggressive embryonal neoplasms caused by biallelic alterations of the SMARCB1 gene. MRTs may occur in any soft tissue, but extracranial extrarenal MRTs are extremely rare. Diagnosis of MRTs in unusual locations and with an uncharacteristic cytomorphology that mimics other tumors is difficult. This was an atypical case of MRT in a 15-year-old female with tumors that closely resembled yolk sac tumors. It was extremely challenging to diagnose the tumors without confirming the SMARCB1 status.

[Successful management of acute chest syndrome in a patient with sickle cell disease].

Although sickle cell disease (SCD) is common in endemic areas of malaria, it is one of the rare diseases in Japan. Hence, SCD and its complications are not well established in Japan. An 11-year-old girl was referred to the specialized pediatric center of our hospital. She was born in Brazil and diagnosed with SCD after birth. However, she did not have a routine checkup in Japan. Owing to influenza viral infection, she developed vaso-occlusive pain crisis (VPC) and needed hospitalization for pain management. After admission, she developed dyspnea, needing intratracheal intubation and mechanical ventilation. A chest X-ray revealed bilateral pulmonary infiltration, suggesting acute chest syndrome (ACS) complicated with SCD. Intensive care, including transfusion of red blood cells, successfully improved her condition. Reportedly, half cases of VPC develop ACS, and the mortality of ACS is very high. Hence, when managing VPC cases, the prevention of ACS, through transfusion of red blood cells or infectious control, is imperative. Thus, Japanese hematologists and pediatricians should recognize SCD and its complications owing to an anticipated increase of foreign travelers or migrants in the future.

The first nationwide surveillance of antibacterial susceptibility patterns of pathogens isolated from skin and soft-tissue infections in dermatology departments in Japan.

To investigate the trends of antimicrobial resistance in pathogens isolated from skin and soft-tissue infections (SSTI) at dermatology departments in Japan, a Japanese surveillance committee conducted the first nationwide survey in 2013. Three main organisms were collected from SSTI at 30 dermatology departments in medical centers and 10 dermatology clinics. A total of 860 strains - 579 of Staphylococcus aureus, 240 of coagulase-negative Staphylococci, and 41 of Streptococcus pyogenes - were collected and shipped to a central laboratory for antimicrobial susceptibility testing. The patient profiles were also studied. Among all 579 strains of S. aureus, 141 (24.4%) were methicillin-resistant (MRSA). Among 97 Staphylococcus epidermidis strains, 54 (55.7%) were methicillin-resistant (MRSE). MRSA and MRSE were more frequently isolated from inpatients than from outpatients. Furthermore, these methicillin-resistant strains were also isolated more frequently from patients with histories of taking antibiotics within 4 weeks and hospitalization within 1 year compared to those without. However, there were no significant differences in MIC values and susceptibility patterns of the MRSA strains between patients with a history of hospitalization within 1 year and those without. Therefore, most of the isolated MRSA cases at dermatology departments are not healthcare-acquired, but community-acquired MRSA. S. pyogenes strains were susceptible to most antibiotics except macrolides. The information in this study is not only important in terms of local public health but will also contribute to an understanding of epidemic clones of pathogens from SSTI.

Low-grade cylindromatous adnexal carcinoma with unusual histopathological features: report of a case with comparative immunohistochemical study and meta-analysis of the literature.

We present an extremely rare case of low-grade cylindromatous adnexal carcinoma (CAC) on the right chest wall of a 77-year-old man. Histopathologically, the neoplasm was initially diagnosed as a cylindroma that developed over the course of 13 years. A diagnosis of low-grade CAC was rendered after the documentation of a local recurrence and histopathology of the recurrent tumor. To further assess the evolution of low-grade CAC over time, we compared the morphology, mitotic account, proliferative markers and adhesion molecule immunoreactivity among paired primary and recurrent tumors. Unlike those earlier reported, our case showed the maintenance of tumor morphology after a recurrence without areas of obvious malignant transformation or metaplastic change. We showed here for the first time the expression of adhesion molecules of CAC/spiradenoma and a comparison of proliferation indices between a primary tumor and its local recurrence. This peculiar tumor differs from previously reported cases and harbors a malignant potential although the histopathological features of malignancy are subtle. Our meta-analysis of the literature provided background information regarding this rare entity. Alterations of E-cadherin and GCDFP-15 expression may provide additional helpful clues in differential diagnosis and determining the clinical behavior of this unusual neoplasm. Further studies are warranted to confirm the potential discriminative role of these markers.

Ca2+/S100 proteins inhibit the interaction of FKBP38 with Bcl-2 and Hsp90.

FKBP38 (FK506-binding protein 38), a membrane-anchored TPR (tetratricopeptide repeat)-containing immunophilin, regulates signalling pathways such as cell survival, apoptosis, proliferation and metastasis. However, the mechanisms that regulate the activity of FKBP38 are, at present, poorly understood. We previously reported that Ca2+/S100 proteins directly associate with the TPR proteins, such as Hop [Hsp70 (heat-shock protein of 70 kDa)/Hsp90-organizing protein], kinesin-light chain, Tom70 (translocase of outer mitochondrial membrane 70), FKBP52, CyP40 (cyclophilin 40), CHIP (C-terminus of Hsc70-interacting protein) and PP5 (protein phosphatase 5), leading to the dissociation of the interactions of the TPR proteins with their target proteins. Therefore we have hypothesized that Ca2+/S100 proteins can interact with FKBP38 and regulate its function. In vitro binding studies demonstrated that S100A1, S100A2, S100A6, S100B and S100P specifically interact with FKBP38 and inhibit the interaction of FKBP38 with Bcl-2 and Hsp90. Overexpression of permanently active S100P in Huh-7 cells inhibited the interaction of FKBP38 with Bcl-2, resulting in the suppression of Bcl-2 stability. The association of the S100 proteins with FKBP38 provides a Ca2+-dependent regulatory mechanism of the FKBP38-mediated signalling pathways.

Effects of dopamine depletion on LFP oscillations in striatum are task- and learning-dependent and selectively reversed by L-DOPA.

A major physiologic sign in Parkinson disease is the occurrence of abnormal oscillations in cortico-basal ganglia circuits, which can be normalized by L-DOPA therapy. Under normal circumstances, oscillatory activity in these circuits is modulated as behaviors are learned and performed, but how dopamine depletion affects such modulation is not yet known. We here induced unilateral dopamine depletion in the sensorimotor striatum of rats and then recorded local field potential (LFP) activity in the dopamine-depleted region and its contralateral correspondent as we trained the rats on a conditional T-maze task. Unexpectedly, the dopamine depletion had little effect on oscillations recorded in the pretask baseline period. Instead, the depletion amplified oscillations across delta (~3 Hz), theta (~8 Hz), beta (~13 Hz), and low-gamma (~48 Hz) ranges selectively during task performance times when each frequency band was most strongly modulated, and only after extensive training had occurred. High-gamma activity (65-100 Hz), in contrast, was weakened independent of task time or learning stage. The depletion also increased spike-field coupling of fast-spiking interneurons to low-gamma oscillations. L-DOPA therapy normalized all of these effects except those at low gamma. Our findings suggest that the task-related and learning-related dynamics of LFP oscillations are the primary targets of dopamine depletion, resulting in overexpression of behaviorally relevant oscillations. L-DOPA normalizes these dynamics except at low-gamma, linked by spike-field coupling to fast-spiking interneurons, now known to undergo structural changes after dopamine depletion and to lack normalization of spike activity following l-DOPA therapy.

Selective effects of dopamine depletion and L-DOPA therapy on learning-related firing dynamics of striatal neurons.

Despite evidence that dopamine neurotransmission in the striatum is critical for learning as well as for movement control, little is yet known about how the learning-related dynamics of striatal activity are affected by dopamine depletion, a condition faced in Parkinson's disease. We made localized intrastriatal 6-hydroxydopamine lesions in rats and recorded within the dopamine-depleted sensorimotor striatal zone and its contralateral correspondent as the animals learned a conditional maze task. Rather than producing global, nonspecific elevations in firing rate across the task, the dopamine depletion altered striatal projection neuron activity and fast-spiking interneuron activity selectively, with sharply task-specific and cell type-specific effects, and often, with learning-stage selective effects as well. Striatal projection neurons with strong responses during the maze runs had especially elevated responsiveness during the maze runs. Projection neurons that, instead, fired most strongly before maze running showed elevated pre-start firing rates, but not during maze running, as learning progressed. The intrastriatal dopamine depletion severely affected the learning-related patterning of fast-spiking interneuron ensembles, especially during maze running and after extended training. Remarkably, L-DOPA treatment almost entirely reversed the depletion-induced elevations in pre-run firing of the projection neurons, and elevated their responses around start and end of maze runs. By contrast, L-DOPA failed to normalize fast-spiking interneuron activity. Thus the effects of striatal dopamine depletion and restoration on striatal activity are highly dependent not only on cell type, as previously shown, but also on the behavioral activity called for and the state of behavioral learning achieved.

Ca2+/S100 proteins act as upstream regulators of the chaperone-associated ubiquitin ligase CHIP (C terminus of Hsc70-interacting protein).

The U-box E3 ubiquitin ligase CHIP (C terminus of Hsc70-interacting protein) binds Hsp90 and/or Hsp70 via its tetratricopeptide repeat (TPR), facilitating ubiquitination of the chaperone-bound client proteins. Mechanisms that regulate the activity of CHIP are, at present, poorly understood. We previously reported that Ca(2+)/S100 proteins directly associate with the TPR proteins, such as Hsp70/Hsp90-organizing protein (Hop), kinesin light chain, Tom70, FKBP52, CyP40, and protein phosphatase 5 (PP5), leading to the dissociation of the interactions of the TPR proteins with their target proteins. Therefore, we have hypothesized that Ca(2+)/S100 proteins can interact with CHIP and regulate its function. GST pulldown assays indicated that Ca(2+)/S100A2 and S100P bind to the TPR domain and lead to interference with the interactions of CHIP with Hsp70, Hsp90, HSF1, and Smad1. In vitro ubiquitination assays indicated that Ca(2+)/S100A2 and S100P are efficient and specific inhibitors of CHIP-mediated ubiquitination of Hsp70, Hsp90, HSF1, and Smad1. Overexpression of S100A2 and S100P suppressed CHIP-chaperone complex-dependent mutant p53 ubiquitination and degradation in Hep3B cells. The association of the S100 proteins with CHIP provides a Ca(2+)-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway.

Neonatal Kawasaki disease: case report and data from nationwide survey in Japan.

UNLABELLED: Kawasaki disease (KD) is a systemic vasculitis that develops during childhood, with a peak incidence from 6 to 23 months of age. KD also affects younger children, including neonates. We herein describe the case of a 22-day-old patient with incomplete KD. Some characteristics of neonatal KD are also presented with a review of nationwide surveys of KD in Japan involving approximately 130,000 patients during a 12-year period. The surveys identified 23 neonatal cases, accounting for 1/5,500 of patients of all ages with KD. We found that the characteristics of neonatal KD are likely to be incompatible with the classic criteria for KD and that the incidence of coronary disorders in neonatal patients was not statistically higher than that in older patients. These findings are very similar to those of previous reports of neonatal KD. CONCLUSION: Neonatal KD is rare and often presents with only a few features of KD. In addition, both neonatal and older patients with KD are at risk of coronary disorders. These characteristics present a challenge to pediatricians in the diagnosis and treatment of febrile neonates.

Clofarabine-based combination chemotherapy for relapse and refractory childhood acute lymphoblastic leukemia.

Clofarabine, one of the key treatment agents for refractory and relapsed acute lymphoblastic leukemia (ALL), achieves a remission rate of approximately 30% with single-agent clofarabine induction chemotherapy. However, a remission rate of approximately 50% was reported with a combination chemotherapy regimen consisting of clofarabine, etoposide, and cyclophosphamide. We treated two cases with refractory and relapsed ALL with combination chemotherapy including clofarabine; one was an induction failure but the other achieved remission. Both cases developed an infectious complication (NCI-CTCAE grade 3) and body pain with infusion. Prophylactic antibiotic and opioid infusions facilitated avoiding septic shock and pain. Further investigation of such cases is required.

Germline predisposition for clonal hematopoiesis.

Clonal hematopoiesis (CH) is an entity hallmarked by skewed hematopoiesis with persistent overrepresentation of cells from a common stem/progenitor lineage harboring single-nucleotide variants and/or insertions/deletions. CH is a common and age-related phenomenon that is associated with an increased risk of hematological malignancies, cardiovascular disease, and all-cause mortality. While CH is a term of the hematological aspect, there exists a complex interaction with other organ systems, especially the cardiovascular system. The strongest factor in the development of CH is aging, however, other multiple factors also affect the development of CH including lifestyle-related factors and co-morbid diseases. In recent years, germline genetic factors have been linked to CH risk. In this review, we synthesize what is currently known about how genetic variation affects the risk of CH, how this genetic architecture intersects with myeloid neoplasms, and future prospects for CH.