Inherited Bone Marrow Failure Syndromes Research Articles

Haematopoietic cell transplantation for 106 infants and preschoolers with acquired and inherited bone marrow failures.

Aplastic anaemia in infants and young children presents unique challenges due to high prevalence of inherited bone marrow failure syndromes (IBMFS) in this age group. The objective of this study is assessing clinical characteristics and outcomes of haematopoietic cell transplantation in children ≤5 years with bone marrow failure syndromes. We analysied 106 patients (66% males), median age 4.6 years, including 40 with Fanconi anaemia (FA), 32 with Acquired Severe Aplastic anaemia (aSAA), 15 with Diamond-Blackfan Anaemia, 11 with Amegakaryocytic Purpura and 8 with other IBMFS. Molecular testing was limited (39%), with 25.4% confirmed genetically. Retrospective longitudinal study across three paediatric transplantation centres (1982-2020). Overall survival (OS) was 76.4% over a median 10-year follow-up. OS rates were similar between aSAA and IBMFS (FA 77.5%, other IBMFS 76.5%). Transplant-related mortality (TRM) was lower in aSAA (9.4%) compared with IBMFS (16.2%). Recent years showed improved outcomes, with TRM declining post-2010. Choice of stem cell source impacted OS, favouring bone marrow over umbilical cord, but showing encouraging results with haploidentical. Late complications were common, including endocrine-metabolic issues and delayed neuropsychomotor development. Diagnosing and managing bone marrow failures in young children pose significant challenges. Despite advancements in transplant practices, ongoing vigilance and comprehensive care are necessary to improve long-term survival rates.

Genotype‐phenotype associations in individuals with Diamond Blackfan anaemia

AbstractIntroductionDiamond Blackfan anaemia (DBA) is a rare disorder characterized by failure of red blood cell production, congenital abnormalities and cancer predisposition, primarily caused by pathogenic germline variants in genes encoding ribosomal proteins.MethodsWe conducted a genotype‐phenotype and outcome study of 121 patients with DBA spanning the 20‐year history of the National Cancer Institute's Inherited Bone Marrow Failure Syndromes study. Patient phenotypes were compared by large versus small ribosomal protein genes, across genes with >5 cases (RPS19, RPS29, RPS26 and RPL35A) and by type of pathogenic variants (hypomorphic versus null, large deletions versus others).ResultsA pathogenic germline variant was identified in 71% of patients (n = 86/121) from 54 families. After adjusting for multiple testing, we found that patients with RPS29 variants were least likely to need treatment for anaemia while those with large ribosomal protein subunit variants had a higher proportion of intellectual disability and gastrointestinal abnormalities compared with small ribosomal protein subunit variants (p < 3.5 × 10−4). There were no statistically significant differences in overall survival or cancer incidence among patients with large or small ribosomal subunit genes.ConclusionThis detailed genotype‐phenotype study of DBA improves our understanding of the role of germline genetics in the clinical manifestations that may help guide the management of people with DBA.

Outcomes of patients undergoing allogeneic haematopoietic stem cell transplantation for congenital amegakaryocytic thrombocytopenia; a study on behalf of the PDWP of the EBMT.

Congenital amegakaryocytic thrombocytopenia is a rare, inherited bone marrow failure syndrome. Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is currently the only curative treatment. In this retrospective study, we analysed 66 patients with allo-HSCT, reported in the European Society for Blood and Marrow Transplantation (EBMT) registry. Bone marrow (BM) was the most widely used stem cell source (n = 40; 61%) followed by peripheral blood (PB) (n = 18; 27%), and unrelated umbilical cord blood (UCB) (n = 8; 12%). Most frequently was a HLA-matched graft from related (n = 26; 39%) and unrelated (n = 15; 23%) donors after a myeloablative busulfan-based conditioning regimen. GvHD prophylaxis was mostly cyclosporine and methotrexate (53%). The 6-year cumulative incidence of graft-failure and second transplant were 25% and 17%, respectively. The 6-year disease-free survival (DFS) and overall survival (OS) were 66.9% and 85.6%, respectively. The 6-year transplant-related mortality (TRM) was 8.0%. In conclusion, most patients with CAMT benefit from allo-HSCT, but with many graft failures.

Comprehensive genetic analysis for identification of monogenic disorders and selection of appropriate treatments in pediatric patients with persistent thrombocytopenia

Persistent thrombocytopenia is caused by various diseases, including immune thrombocytopenia, inherited thrombocytopenia, and inherited bone marrow failure syndromes. Considering the large number of genes responsible for inherited disorders, comprehensive genetic analysis is required to diagnose monogenic disorders. In this study, we enrolled 53 pediatric patients with persistent thrombocytopenia exhibiting visually small or normal-sized platelets. We performed whole-exome sequencing, including 56 genes responsible for inherited thrombocytopenia, and evaluated clinical parameters according to disease type. Among 53 patients, 12 patients (22.6%) were diagnosed with monogenic disorders. Nine patients had a family history of thrombocytopenia. Pathogenic or novel variants of genes responsible for inherited thrombocytopenia were identified in three and six patients, respectively. The variants in genes for inherited thrombocytopenia with large or giant platelets were unexpectedly identified in six patients. Pathogenic variants in genes for inherited bone marrow failure syndromes with systemic features were identified in three patients with atypical symptoms. Since the definitive diagnostic methods for immune thrombocytopenia are limited, and a substantial number of patients with inherited thrombocytopenia are at a high risk of developing malignancies, comprehensive genetic analysis is indispensable for selecting appropriate therapies, avoidance of unnecessary treatments for immune thrombocytopenia, and long-term follow-up of patients with inherited thrombocytopenia.

Germline variants in acquired aplastic anemia: current knowledge and future perspectives.

Aplastic anemia (AA) is a disease characterized by failure of hematopoiesis, bone marrow aplasia, and pancytopenia. It can be inherited or acquired. Although acquired AA is believed to be immune-mediated and random, new evidence suggests an underlying genetic predisposition. Besides confirmed genomic mutations that contribute to inherited AA (such as pathogenic mutations of TERT and TERC), germline variants, often in heterozygous states, also play a not negligible role in the onset and progression of acquired AA. These variants, associated with inherited bone marrow failure syndromes and inborn errors of immunity, contribute to the disease, possibly through mechanisms including gene homeostasis, DNA repair, and immune injury. This article explores the nuanced association between acquired AA and germline variants, detailing the clinical significance of germline variants in diagnosing and managing this condition. More work is encouraged to better understand the role of immunogenic pathogenic variants and whether somatic mutations participate as secondary "hits" in the development of bone marrow failure.

The evolving genetic landscape of telomere biology disorder dyskeratosis congenita

Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by genetic mutations that principally affect telomere biology. Approximately 35% of cases remain uncharacterised at the genetic level. To explore the genetic landscape, we conducted genetic studies on a large collection of clinically diagnosed cases of DC as well as cases exhibiting features resembling DC, referred to as ‘DC-like’ (DCL). This led us to identify several novel pathogenic variants within known genetic loci and in the novel X-linked gene, POLA1. In addition, we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes. Functional characterisation of novel POLA1 and POT1 variants, revealed pathogenic effects on protein-protein interactions with primase, CTC1-STN1-TEN1 (CST) and shelterin subunit complexes, that are critical for telomere maintenance. ZCCHC8 variants demonstrated ZCCHC8 deficiency and signs of pervasive transcription, triggering inflammation in patients’ blood. In conclusion, our studies expand the current genetic architecture and broaden our understanding of disease mechanisms underlying DC and DCL disorders.

Clinical utility of relative telomere length analysis in pediatric bone marrow failure

IntroductionTelomere length related studies are limited in pediatric marrow failure cases due to difficulty in establishing population specific age related normograms. Moreover, there is paucity of data related to clinical relevance of telomere length in idiopathic aplastic anemia (IAA) and non telomere biology inherited bone marrow failure syndrome (IBMFS) cases. Methodology: Hence, in current study we investigated Relative telomere length (RTL) by RQ-PCR in 83 samples as: healthy controls (n = 44), IAA (n = 15) and IBMFS (n = 24). In addition, we performed chromosomal breakage studies and targeted NGS to screen for pathogenic variants. Results & Conclusion: Median RTL was significantly different between control vs. IBMFS (p-0.002), IAA vs. IBMFS (p-0.0075) and DC vs. non-DC IBMFS (p-0.011) but not between control vs. IAA (p-0.46). RTL analysis had clinical utility in differentiating BMF cases as 75 % (9/12) of DC had short/very short telomeres compared to only 17 % (2/12) of non-DC IBMFS, 7 % (1/15) of IAA and 7 % (3/44) of controls (p < 0.001).

Reduced anti-Müllerian hormone levels in males with inherited bone marrow failure syndromes.

Fanconi anemia (FA), dyskeratosis congenita-related telomere biology disorders (DC/TBD), and Diamond-Blackfan anemia (DBA) are inherited bone marrow failure syndromes (IBMFS) with high risks of bone marrow failure, leukemia, and solid tumors. Individuals with FA have reduced fertility. Previously, we showed low levels of anti-Müllerian hormone (AMH), a circulating marker of ovarian reserve, in females with IBMFS. In males, AMH may be a direct marker of Sertoli cell function and an indirect marker of spermatogenesis. In this study, we assessed serum AMH levels in pubertal and postpubertal males with FA, DC/TBD, or DBA and compared this with their unaffected male relatives and unrelated healthy male volunteers. Males with FA had significantly lower levels of AMH (median: 5 ng/mL, range: 1.18-6.75) compared with unaffected male relatives (median: 7.31 ng/mL, range: 3.46-18.82, P = 0.03) or healthy male volunteers (median: 7.66 ng/mL, range: 3.3-14.67, P = 0.008). Males with DC/TBD had lower levels of AMH (median: 3.76 ng/mL, range: 0-8.9) compared with unaffected relatives (median: 5.31 ng/mL, range: 1.2-17.77, P = 0.01) or healthy volunteers (median: 5.995 ng/mL, range: 1.57-14.67, P < 0.001). Males with DBA had similar levels of AMH (median: 3.46 ng/mL, range: 2.32-11.85) as unaffected relatives (median: 4.66 ng/mL, range: 0.09-13.51, P = 0.56) and healthy volunteers (median: 5.81 ng/mL, range: 1.57-14.67, P = 0.10). Our findings suggest a defect in the production of AMH in postpubertal males with FA and DC/TBD, similar to that observed in females. These findings warrant confirmation in larger prospective studies.

Aberrant early hematopoietic progenitor formation marks the onset of hematopoietic defects in Shwachman-Diamond syndrome.

Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure disorder that often presents at infancy. Progress has been made in revealing causal mutated genes (SBDS and others), ribosome defects, and hematopoietic aberrations in SDS. However, the mechanism underlying the hematopoietic failure remained unknown, and treatment options are limited. Herein, we investigated the onset of SDS embryonic hematopoietic impairments. We generated SDS and control human-derived induced pluripotent stem cells (iPSCs). SDS iPSCs recapitulated the SDS hematological phenotype. Detailed stepwise evaluation of definitive hematopoiesis revealed defects that started at the early emerging hematopoietic progenitor (EHP) stage after mesoderm and hemogenicendothelium were normally induced. Hematopoietic potential of EHPs was markedly reduced, and the introduction of SBDS in SDS iPSCs improved colony formation. Transcriptome analysis revealed reduced expression of ribosome and oxidative phosphorylation-related genes in undifferentiated and differentiated iPSCs. However, certain pathways (e.g., DNA replication) and genes (e.g., CHCHD2) were exclusively or more severely dysregulated in EHPs compared with earlier and later stages. To our knowledge, this study offers for the first time an insight into the embryonic onset of human hematopoietic defects in an inherited bone marrow failure syndrome and reveals cellular and molecular aberrations at critical stages of hematopoietic development toward EHPs.

Clinical Profile of Adults with Inherited Bone Marrow Failure Syndromes: Results of an Ambispective Clinical Single-Center Study

BACKGROUND. Inherited bone marrow failure syndromes (IBMFS) is a heterogenous group of rare genetically determined diseases with variable hematologic and nonhematologic manifestations. The implementation of highly specific methods of genetic diagnosis advanced the understanding of IBMFS and allowed its application also beyond pediatrics. That presupposes an awareness of clinical features and reference points for recognizing IBMFS in adults. AIM. To describe the clinical profile of adult IBMFS patients. MATERIALS &amp; METHODS. This ambispective single-center study enrolled 35 patients (10 women and 25 men) with IBMFS. Patients were aged 18–51 years (median 26 years). The following IBMFS were identified: congenital dyskeratosis (n = 10; 28 %), Diamond-Blackfan anemia (n = 9; 26 %), Fanconi anemia (n = 7; 20 %), GATA2 deficiency (n = 3; 8 %), Shwachman-Diamond syndrome (n = 1; 3 %), GATA2 deficiency (n = 1; 3 %), amegakaryocytic thrombocytopenia (n = 1; 3 %), bone marrow failure syndrome type 3 (n = 1; 3 %), severe congenital neutropenia (n = 1; 3 %), bone marrow failure with SAMD9 mutation (n = 1; 3 %). These diseases were analyzed in terms of hematologic and nonhematologic manifestations as well as main diagnosis stages and factors that contribute to recognizing IBMFS. RESULTS. Monolinear cytopenia, bilinear cytopenia, and pancytopenia were identified at hematologic onset in 18 (52 %), 6 (17 %), and 11 (31 %) patients, respectively. The median age of patients by hematologic onset was 15 years (range 0–43 years), in 14 (40 %) patients cytopenia was newly diagnosed at the age of &gt; 18 years. In 23 (63 %) patients hypocellular bone marrow was reported, 7 (20 %) and 5 (14 %) patients had pure red cell aplasia and multilineage myelodysplasia, respectively. Chromosomal aberrations were identified in 2 patients. Paroxysmal nocturnal hemoglobinuria clone was detected in none of 27 examined patients. In 12 (34 %) patients, the criteria for non-severe aplastic anemia were met. Temporary partial or complete spontaneous hematologic recovery was observed in 6 (17 %) patients. Abnormalities with partial or complete organ dysfunctions were identified in 14 patients, whereas all patients showed minor congenital defects. All 7 Fanconi anemia patients and 9 out of 10 congenital dyskeratosis patients demonstrated organ damage specific to these diseases. Family history predominantly showing malignant neoplasms in relatives was reported in 15 (43 %) patients. Initial hematological examination yielded suspect of IBMFS in 12 (34 %) patients with the median time to diagnosis of 6 months. In 23 (66 %) patients, hematologic defects with cytopenia were erroneously accounted for by various acquired diseases, which led to a delayed correct diagnosis (median 7 years). The key factors in suspecting IBMFS were organ abnormalities and positive family history. The IBMFS diagnosis was verified by the next-generation sequencing (NGS) in 29 (83 %) patients and by other specific methods in 4 (11 %) patients. In 2 patients, the diagnosis was established on the basis of complete clinical criteria alone. CONCLUSION. IBMFS is a matter of current concern and a difficult-to-recognize clinical challenge in adult hematology patients. Differential diagnosis of acquired and congenital bone marrow failure needs to be performed irrespective of patient’s age. A detailed physical examination of patients, family history, and critical analysis of clinical profile and disease course allow for early suspicion of IBMFS. Suspected IBMFS is an indication for referral of patients to specialized centers and performing genetic diagnostics including NGS.

The CRISPR-Cas System and Clinical Applications of CRISPR-Based Gene Editing in Hematology with a Focus on Inherited Germline Predisposition to Hematologic Malignancies.

Clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing has begun to transform the treatment landscape of genetic diseases. The history of the discovery of CRISPR/CRISPR-associated (Cas) proteins/single-guide RNA (sgRNA)-based gene editing since the first report of repetitive sequences of unknown significance in 1987 is fascinating, highly instructive, and inspiring for future advances in medicine. The recent approval of CRISPR-Cas9-based gene therapy to treat patients with severe sickle cell anemia and transfusion-dependent β-thalassemia has renewed hope for treating other hematologic diseases, including patients with a germline predisposition to hematologic malignancies, who would benefit greatly from the development of CRISPR-inspired gene therapies. The purpose of this paper is three-fold: first, a chronological description of the history of CRISPR-Cas9-sgRNA-based gene editing; second, a brief description of the current state of clinical research in hematologic diseases, including selected applications in treating hematologic diseases with CRISPR-based gene therapy, preceded by a brief description of the current tools being used in clinical genome editing; and third, a presentation of the current progress in gene therapies in inherited hematologic diseases and bone marrow failure syndromes, to hopefully stimulate efforts towards developing these therapies for patients with inherited bone marrow failure syndromes and other inherited conditions with a germline predisposition to hematologic malignancies.

Benign tumors and non-melanoma skin cancers in patients with Fanconi anemia

Fanconi anemia (FA) is an inherited bone marrow failure syndrome (IBMFS) characterized by pathogenic variants in the FA/BRCA DNA repair pathway genes. Individuals with FA have an elevated risk of developing myelodysplastic syndrome, acute myeloid leukemia, and solid tumors. Hematopoietic cell transplantation (HCT) is the most effective treatment for FA related bone marrow failure but can increase the risk of cancer development. Information on benign tumors and NMSC is lacking in patients with FA. Our objective was to characterize patients with FA enrolled in the National Cancer Institute IBMFS Study who have experienced non-melanoma skin cancers (NMSC) and/or benign tumors (BT). A total of 200 patients diagnosed with FA were enrolled in the Institutional Review Board approved study “Etiologic Investigation of Cancer Susceptibility in IBMFS: A Natural History Study” (NCT00027274). Through medical records review, we identified 30 patients with at least one NMSC, either squamous or basal cell carcinoma, or benign tumor. The remaining 170 patients comprised the control group. Out of 200 patients, 12 had NMSC, 25 had benign tumors, with an age range of 11–64 and 0–56 years, respectively. The median age at HCT was 30.5 years for NMSC patients, 9 years for benign tumor patients, and 9.1 years for controls. The most common genotype observed was FANCA, followed by FANCC and FANCI. Benign tumors spanned diverse anatomical locations. Early onset NMSC in patients with FA compared to the general population emphasizes the need for consistent monitoring in patients with FA, while the diverse anatomical locations of benign tumors underscore the importance of comprehensive surveillance for timely interventions in managing symptomatology and heightened cancer risk.

ДИФФЕРЕНЦИАЛЬНАЯ ДИАГНОСТИКА ПРИОБРЕТЕННОЙ АПЛАСТИЧЕСКОЙ АНЕМИИ У ДЕТЕЙ: АНАЛИЗ ДАННЫХ РЕГИСТРОВОГО ИССЛЕДОВАНИЯ

Acquired aplastic anemia (AA) is still the diagnosis of exclusion. The purpose of the research was to identify clinical and laboratory signs that do not correspond to acquired AA allowing to diagnose other diseases accompanied by cytopenia. Materials and methods used: Authors represent the results of diagnostic search in pediatric patients (0 to 18 y/o) with a suspected diagnosis of acquired AA who underwent remote diagnosis in the laboratories of the National Scientific and Practical Center for Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev (Moscow, Russia) as part of the Register Study in Sep. 1, 2017-May 1, 2022. Results: in retrospective analysis of 523 children records, 104 (20%) patients had other diagnoses. In 29 (27.9%) patients were diagnosed with inherited bone marrow failure syndromes (IBMFS), in 11 (10.6%) with myelodysplastic syndrome, in 11 (10.6%) with deficiency anemia, in 10 (9.6%) with congenital unspecified AA, in 7 (6.7%) with immune cytopenia, in 7 (6.7%) with inborn defects of immunity, in 6 (5.8%) with secondary AA, in 6 (5.8%) with acute leukemia, in 2 (1.9%) with paroxysmal nocturnal hemoglobinuria and in 15 (14.4%) cases with other unspecified diseases. Fanconi anemia (n=15/29 patients) was the most common disease in the IBMFS group; this group had also included: dyskeratosis congenita (n=9), Schwachman-Diamond syndrome (n=2), amegakaryocytic thrombocytopenia (n=2), Diamond-Blackfan anemia in combination with congenital neutropenia (n=1). Conclusion: differential diagnosis of acquired AA can be difficult though it is undoubtedly must-do for successful treatment. Verification of other alternative diseases, including genetically determined syndromes, contributes to the choice of optimal patient management tactics.

Therapeutic Nonsense Suppression Modalities: From Small Molecules to Nucleic Acid-Based Approaches.

Nonsense mutations are genetic mutations that create premature termination codons (PTCs), leading to truncated, defective proteins in diseases such as cystic fibrosis, neurofibromatosis type 1, Dravet syndrome, Hurler syndrome, Beta thalassemia, inherited bone marrow failure syndromes, Duchenne muscular dystrophy, and even cancer. These mutations can also trigger a cellular surveillance mechanism known as nonsense-mediated mRNA decay (NMD) that degrades the PTC-containing mRNA. The activation of NMD can attenuate the consequences of truncated, defective, and potentially toxic proteins in the cell. Since approximately 20% of all single-point mutations are disease-causing nonsense mutations, it is not surprising that this field has received significant attention, resulting in a remarkable advancement in recent years. In fact, since our last review on this topic, new examples of nonsense suppression approaches have been reported, namely new ways of promoting the translational readthrough of PTCs or inhibiting the NMD pathway. With this review, we update the state-of-the-art technologies in nonsense suppression, focusing on novel modalities with therapeutic potential, such as small molecules (readthrough agents, NMD inhibitors, and molecular glue degraders); antisense oligonucleotides; tRNA suppressors; ADAR-mediated RNA editing; targeted pseudouridylation; and gene/base editing. While these various modalities have significantly advanced in their development stage since our last review, each has advantages (e.g., ease of delivery and specificity) and disadvantages (manufacturing complexity and off-target effect potential), which we discuss here.

Overexpression of human SAMD9 inhibits protein translation and alters MYC signaling resulting in cell cycle arrest

Inherited bone marrow failure syndromes often result from pathogenic mutations in genes that are important for ribosome function, namely, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and dyskeratosis congenita. Germline mutations in SAMD9 are a frequent genetic lesion resulting in an inherited bone marrow failure syndrome with monosomy 7; some patients have severe multisystem syndromes that include myelodysplasia. The association of germline SAMD9 mutations and bone marrow failure is clear; however, to date, there is no reliable method to predict whether a novel SAMD9 mutation is pathogenic unless it is accompanied by an obvious family history and/or clinical syndrome. The difficulty with pathogenicity prediction is, in part, due to the incomplete understanding of the biological functions of SAMD9. We used a SAMD9-targeted, inducible CRISPRa system and RNA sequencing to better understand the global transcriptional changes that result from transcriptional manipulation of SAMD9. Supporting recent discoveries that SAMD9 acts as a ACNase specific for phenylalanine tRNA (tRNA-Phe), we confirmed with crosslinking and solid-phase purification that SAMD9 is an RNA binding protein and analyzed how overexpression of tRNA-Phe may reverse transcriptomic changes caused by SAMD9 activation. Our data show that overexpression of SAMD9 from the endogenous locus results in decreased cell proliferation, cell cycle progression, and global protein translation. When SAMD9 contains a gain-of-function mutation (p.E1136Q), these functional phenotypes are exacerbated but only partially rescued with tRNA-Phe overexpression, suggesting additional molecular actions of SAMD9. Additionally, we demonstrate that gene expression pathways important for ribosome biogenesis and MYC signaling are the most significantly impacted by SAMD9 overexpression.

Integrated proteogenomic analysis for inherited bone marrow failure syndrome.

Recent advances in in-depth data-independent acquisition proteomic analysis have enabled comprehensive quantitative analysis of >10,000 proteins. Herein, an integrated proteogenomic analysis for inherited bone marrow failure syndrome (IBMFS) was performed to reveal their biological features and to develop a proteomic-based diagnostic assay in the discovery cohort; dyskeratosis congenita (n = 12), Fanconi anemia (n = 11), Diamond-Blackfan anemia (DBA, n = 9), Shwachman-Diamond syndrome (SDS, n = 6), ADH5/ALDH2 deficiency (n = 4), and other IBMFS (n = 18). Unsupervised proteomic clustering identified eight independent clusters (C1-C8), with the ribosomal pathway specifically downregulated in C1 and C2, enriched for DBA and SDS, respectively. Six patients with SDS had significantly decreased SBDS protein expression, with two of these not diagnosed by DNA sequencing alone. Four patients with ADH5/ALDH2 deficiency showed significantly reduced ADH5 protein expression. To perform a large-scale rapid IBMFS screening, targeted proteomic analysis was performed on 417 samples from patients with IBMFS-related hematological disorders (n = 390) and healthy controls (n = 27). SBDS and ADH5 protein expressions were significantly reduced in SDS and ADH5/ALDH2 deficiency, respectively. The clinical application of this first integrated proteogenomic analysis would be useful for the diagnosis and screening of IBMFS, where appropriate clinical screening tests are lacking.

Genomic insights into inherited bone marrow failure syndromes in a Korean population.

Inherited bone marrow failure syndromes (IBMFS) pose significant diagnostic challenges due to overlapping symptoms and variable expressivity, despite evolving genomic insights. The study aimed to elucidate the genomic landscape among 130 Korean patients with IBMFS. We conducted targeted next-generation sequencing (NGS) and clinical exome sequencing (CES) across the cohort, complemented by whole genome sequencing (WGS) and chromosomal microarray (CMA) in 12 and 47 cases, respectively, with negative initial results. Notably, 50% (n = 65) of our cohort achieved a genomic diagnosis. Among these, 35 patients exhibited mutations associated with classic IBMFSs (n = 33) and the recently defined IBMFS, aplastic anaemia, mental retardation and dwarfism syndrome (AmeDS, n = 2). Classic IBMFSs were predominantly detected via targeted NGS (85%, n = 28) and CES (88%, n = 29), whereas AMeDS was exclusively identified through CES. Both CMA and WGS aided in identifying copy number variations (n = 2) and mutations in previously unexplored regions (n = 2). Additionally, 30 patients were diagnosed with other congenital diseases, encompassing 13 distinct entities including inherited thrombocytopenia (n = 12), myeloid neoplasms with germline predisposition (n = 8), congenital immune disorders (n = 7) and miscellaneous genomic conditions (n = 3). CES was particularly effective in revealing these diverse diagnoses. Our findings underscore the significance of comprehensive genomic analysis in IBMFS, highlighting the need for ongoing exploration in this complex field.

Genetic testing by next generation sequencing is essential for accurate identification of inherited bone marrow failure syndromes

Genetic testing by next generation sequencing is essential for accurate identification of inherited bone marrow failure syndromes

Modified Delphi panel consensus recommendations for management of severe aplastic anemia

AbstractSevere aplastic anemia (SAA) is a rare hematologic condition for which there is no clear management algorithm. A panel of 11 experts on adult and pediatric aplastic anemia was assembled and, using the RAND/University of California, Los Angeles modified Delphi panel method, evaluated >600 varying patient care scenarios to develop clinical recommendations for the initial and subsequent management of patients of all ages with SAA. Here, we present the panel’s recommendations to rule out inherited bone marrow failure syndromes, on supportive care before and during first-line therapy, and on first-line (initial management) and second-line (subsequent management) therapy of acquired SAA, focusing on when transplant vs medical therapy is most appropriate. These recommendations represent the consensus of 11 experts informed by published literature and experience. They are intended only as general guidance for experienced clinicians who treat patients with SAA and are in no way intended to supersede individual physician and patient decision making. Current and future research should validate this consensus using clinical data. Once validated, we hope these expert panel recommendations will improve outcomes for patients with SAA.

Mcph1, mutated in primary microcephaly, is also crucial for erythropoiesis.

Microcephaly is a common feature in inherited bone marrow failure syndromes, prompting investigations into shared pathways between neurogenesis and hematopoiesis. To understand this association, we studied the role of the microcephaly gene Mcph1 in hematological development. Our research revealed that Mcph1-knockout mice exhibited congenital macrocytic anemia due to impaired terminal erythroid differentiation during fetal development. Anemia's cause is a failure to complete cell division, evident from tetraploid erythroid progenitors with DNA content exceeding 4n. Gene expression profiling demonstrated activation of the p53 pathway in Mcph1-deficient erythroid precursors, leading to overexpression of Cdkn1a/p21, a major mediator of p53-dependent cell cycle arrest. Surprisingly, fetal brain analysis revealed hypertrophied binucleated neuroprogenitors overexpressing p21 in Mcph1-knockout mice, indicating a shared pathophysiological mechanism underlying both erythroid and neurological defects. However, inactivating p53 in Mcph1-/- mice failed to reverse anemia and microcephaly, suggesting that p53 activation in Mcph1-deficient cells resulted from their proliferation defect rather than causing it. These findings shed new light on Mcph1's function in fetal hematopoietic development, emphasizing the impact of disrupted cell division on neurogenesis and erythropoiesis-a common limiting pathway.