Bone Marrow Failure Syndrome 4

Mendelian MONDO:0020856 Pathograph 45 Show in embeddings browser Inherited bone marrow failure syndrome Bone marrow failure syndrome

Bone marrow failure syndrome 4 (BMFS4; MYSM1 deficiency) is an autosomal recessive disorder caused by biallelic loss-of-function MYSM1 variants. Reported patients have early-onset anemia, often requiring transfusion, with variable neutropenia, thrombocytopenia and B-, NK- or T-cell lymphopenia. Hypogammaglobulinemia and growth, skeletal, craniofacial, ocular, cardiac and neurodevelopmental abnormalities are variably present. Ascertainment through small, overlapping reports precludes disease-wide phenotype frequencies. Some children improve hematologically before later myelodysplasia or acute myeloid leukemia; the cumulative risk is unknown. One patient had sustained hematologic and immune recovery following somatic genetic reversion in one or a few early stem cells, without correction of nonhematologic findings. Mouse studies identify impaired ribosomal-protein gene expression, p53-mediated progenitor dysfunction and lineage-specific transcriptional defects. Engineered human HSCs additionally reveal vulnerability to ferroptosis. Reported allogeneic transplants restore hematopoiesis and immunity, with variable conditioning and transplant complications; they do not establish correction of all developmental manifestations.

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Classifications

Harrison's Part

IUIS Category

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Mappings

MONDO

MONDO:0033683 congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome

MONDO carries two classes for this disease. MONDO:0020856 is imported from OMIM (xref OMIM:618116); MONDO:0033683 is imported from Orphanet (xref Orphanet:508542, synonym "MYSM1 deficiency"). The Orphanet record maps ORPHA:508542 as Exact to both OMIM:618116 and MONDO:0033683, so the two MONDO classes denote the same MYSM1-related disease and this entry covers both.

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Inheritance

Autosomal recessive HP:0000007

Biallelic pathogenic MYSM1 variants occur as homozygous or compound heterozygous alleles, in both consanguineous and unrelated families. A homozygous splice variant also arose through paternal uniparental disomy of chromosome 1. Parental segregation therefore matters for recurrence counseling; homozygosity does not invariably imply two carrier parents.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:34302415 SUPPORT Human Clinical

"Mutation in MYSM1 in humans leads to a rare autosomal recessive disease that has recently been known as inherited bone marrow failure syndrome 4 (BMFS4) associated with congenital bone marrow failure, immunodeficiency, and developmental aberrations."

States autosomal recessive inheritance.

PMID:32640305 SUPPORT Human Clinical

"Biallelic variants in MYSM1 cause a rare bone marrow failure syndrome (OMIM #618116)."

Biallelic variants are required.

PMID:38065233 SUPPORT Human Clinical

"Genetic testing by clinical whole exome sequencing identified a homozygous splice variant in MYSM1 (c.1843–1G>A, IVS15–1 G>A variant) due to paternal uniparental disomy of chromosome 1."

Homozygosity by paternal uniparental disomy rather than by two carrier parents, which changes recurrence risk for the family.

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Mechanistic Hypotheses

MYSM1 deficiency as a ribosomal-stress, p53-activating marrow failure

mysm1_ribosomal_stress_p53 EMERGING

MYSM1 loss reduces ribosomal-protein gene expression and translation. Mouse genetics support a p53-mediated hematopoietic-stress pathway, while edited human HSCs identify a ferroptosis pathway with reduced antioxidant and iron-handling proteins. The relationship between these pathways in patients remains unresolved. Direct clinical support for translation/p53 involvement comes from blood-cell assays in one child; neither ferroptosis inhibition nor p53 inhibition has established clinical benefit.

Discussions and Knowledge Gaps

What is the cumulative risk of MDS/AML in MYSM1 deficiency, and what surveillance should a child who has improved spontaneously have?

KNOWLEDGE GAP OPEN bmfs4_myeloid_risk

Attached to

pathophysiology#Clonal Evolution to Myelodysplasia and Leukemia

The 2025 series documents four progressions from two families, including follow-up of previously reported siblings. Overlapping case ascertainment, early transplantation and somatic rescue prevent estimation of cumulative malignancy risk or an evidence-based surveillance interval.

Show evidence (1 reference)

PMID:40535318 SUPPORT Human Clinical

"We report four cases of MYSM1 mutations progressing from marrow failure to MDS or AML within 9-10 years."

The only series documenting progression.

Why do Mysm1-deficient mice develop thrombocytosis while patients have normal or mildly low platelet counts?

HUMAN MODEL MISMATCH OPEN bmfs4_mouse_platelet_mismatch

Attached to

pathophysiology#Impaired Hematopoietic Stem Cell Function phenotypes#Thrombocytopenia

The mouse reproduces the anaemia, lymphopenia and HSC failure, but the megakaryocyte lineage moves the opposite way. Either MYSM1 has a species-specific role in megakaryopoiesis, or the mouse thrombocytosis is a compensatory response absent in humans. Until that is understood, the mouse cannot be used to predict platelet-lineage behaviour.

Show evidence (2 references)

PMID:22184403 SUPPORT Model Organism

"Here we characterized an H2A-DUB targeted mouse line Mysm1(tm1a/tm1a) and demonstrated defects in BM hematopoiesis, resulting in lymphopenia, anemia, and thrombocytosis."

Thrombocytosis in the mouse.

PMID:32640305 SUPPORT Human Clinical

"Here, we describe a Chinese female patient who mainly presented with leukopenia, granulocytopenia, thrombocytopenia, severe anemia, and B-cell and natural killer cell deficiency in the peripheral blood, and was diagnosed with bone marrow failure."

Thrombocytopenia in a patient.

Why can Mysm1-deficient mice retain antibody responses despite the human antibody-deficiency phenotype?

HUMAN MODEL MISMATCH OPEN mysm1_antibody_model_mismatch

Attached to

phenotypes#Hypogammaglobulinemia pathophysiology#Block in Early B-Cell Development

The mature mouse B-cell/Pax5 study shows enhanced plasma-cell differentiation and normal or higher serum Ig despite B-cell depletion. This contrasts with hypogammaglobulinemia in affected patients and prevents a simple extrapolation from B-cell number to antibody output.

Show evidence (1 reference)

PMID:26348977 SUPPORT DIRECT PRIMARY RESULT Model Organism

"the serum concentrations of IgM and IgG isotypes were normal or even higher in Mysm1−/− mice"

Direct mouse evidence of the discordance.

Which MYSM1 substrates mediate ribosomal-protein regulation and termination of DNA-damage signaling?

KNOWLEDGE GAP OPEN mysm1_substrate_specificity

Attached to

pathophysiology#Reduced Ribosomal Protein Gene Expression pathophysiology#Prolonged DNA Damage Response Signaling

Catalytic necessity is established in a mouse model, but RP promoters do not accumulate detectable H2AK119ub after knockdown, and the DDR study did not establish its proposed H2AK15 substrate. A single histone-mark route is therefore unsupported.

Show evidence (1 reference)

PMID:32641579 SUPPORT DIRECT PRIMARY RESULT In Vitro

"No significant increase in H2AK119ub levels was seen in the Mysm1-knockdown Ba/F3 cells"

Direct negative result at the tested RP promoters.

Does ferroptosis inhibition restore patient hematopoiesis safely and durably?

KNOWLEDGE GAP OPEN mysm1_ferroptosis_translation

Attached to

pathophysiology#Ferroptosis of Hematopoietic Stem Cells

Rescue is demonstrated in engineered healthy-donor HSCs and xenografts; clinical efficacy, delivery, long-term clonal consequences and its relationship to the p53 pathway remain unresolved.

Show evidence (1 reference)

PMID:36803603 SUPPORT DIRECT PRIMARY RESULT Model Organism

"A near complete rescue was observed in the bone marrow, spleen, and across all lineages"

Preclinical engraftment result, not clinical response.

Which neural mechanisms account for developmental findings in human MYSM1 deficiency?

HUMAN MODEL MISMATCH OPEN mysm1_neural_translation

Attached to

pathophysiology#Neural Stem Cell Differentiation Imbalance

Global knockout, neural-specific knockout and meander-tail mice reveal different apoptosis, fate-balance and cerebellar findings. The latter is a preprint. Patient neural tissue and a direct human cerebellar counterpart are lacking.

Show evidence (1 reference)

PMID:38342917 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Mysm1-deficient NSCs skewed toward neurogenesis instead of astrogliogenesis"

The study includes conditional mice and neural cultures; this differentiation finding is supported by its culture assays and does not establish a patient neural mechanism.

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Pathophysiology

Biallelic MYSM1 Loss of Function

Biallelic MYSM1 alleles include nonsense, frameshift, splice-altering and catalytic-site missense variants. The synonymous c.399G>A allele causes exon-6 skipping and a frameshift; c.1843-1G>A causes in-frame exon-16 skipping with deletion of 63 amino acids and near-absent protein. Functional evidence differs by allele and must not be assumed for every rare variant.

MYSM1 hgnc:29401 ⇓ LOSS OF FUNCTION

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Germline biallelic loss-of-function MYSM1 alleles, homozygous (usually through consanguinity, once through paternal uniparental disomy) or compound heterozygous.

Animal models

Mysm1 meander-tail mouse Mouse perturbs Allelic complementation supports Mysm1 causality; cerebellar findings have no established human counterpart.

Downstream

Loss of Histone H2A K119 Deubiquitinase Activity Loss of MYSM1 protein, or of its catalytic site, removes its H2A deubiquitinase activity.

Reduced Ribosomal Protein Gene Expression MYSM1 maintains ribosomal-protein gene expression through promoter regulation that is not established to require local H2AK119 deubiquitination.

Prolonged DNA Damage Response Signaling MYSM1 loss prolongs damage signaling in the tested cell systems; the responsible substrate is unresolved.

p53-Mediated Developmental Tissue Apoptosis Global Mysm1 loss induces p53-dependent developmental pathology in mouse brain and skin.

Reduced ID4 Expression in Neural Stem Cells Neural-stem-cell MYSM1 deficiency reduces Id4 transcription in the mouse model.

Show evidence (4 references)

PMID:28115216 SUPPORT Human Clinical

"Whole-exome sequencing revealed a homozygous premature stop codon mutation in the gene encoding MYSM1."

Homozygous truncating MYSM1 variant in an affected sibling pair.

PMID:26220525 SUPPORT Human Clinical

"Genetic analysis revealed that this novel disorder is caused by a homozygous MYSM1 missense mutation affecting the catalytic site within the deubiquitinase JAB1/MPN/Mov34 (JAMM)/MPN domain."

A missense allele that targets the catalytic site rather than protein abundance.

PMID:32640305 SUPPORT Human Clinical

"Trio whole-exome sequencing revealed a novel compound heterozygous variant in MYSM1 (c.399G > A, p.L133L, and c.1467C > G, p.Y489*)."

Compound heterozygous alleles, including a synonymous splice-altering variant.

+ 1 more reference

Loss of Histone H2A K119 Deubiquitinase Activity

MYSM1 deubiquitinates histone H2A lysine 119 and regulates selected gene loci. A catalytic D660N mouse retains MYSM1 protein yet reproduces many knockout phenotypes, establishing a requirement for catalytic function in hematopoiesis. This does not establish H2AK119 as the substrate for every MYSM1-dependent pathway: ribosomal-protein promoters show no significant H2AK119ub increase after knockdown, and the DNA-damage-signaling substrate remains unresolved.

histone H2A deubiquitinase activity GO:0140950 ↓ DECREASED

Animal models

Catalytically inactive Mysm1 D660N mouse Mouse perturbs Catalytic inactivation demonstrates a requirement for MYSM1 DUB function; individual substrates are not resolved.

Downstream

Block in Early B-Cell Development MYSM1 de-represses EBF1 and other early B-lineage genes.

Impaired NK-Cell Maturation MYSM1 keeps the ID2 locus in active chromatin during NK-cell maturation.

Reduced GFI1 Expression in Hematopoietic Stem Cells MYSM1 loss changes histone marks and transcription-factor recruitment at Gfi1 regulatory elements.

Show evidence (4 references)

PMID:26220525 SUPPORT Human Clinical

"is a metalloprotease that deubiquitinates the K119-monoubiquitinated form of histone 2A (H2A), a chromatin marker associated with gene transcription silencing"

Defines the enzymatic activity lost in the disease.

PMID:17707232 SUPPORT In Vitro

"2A-DUB regulates transcription by coordinating histone acetylation and deubiquitination, and destabilizing the association of linker histone H1 with nucleosomes."

Original biochemical characterisation of MYSM1 as a co-activator acting through H2A deubiquitination.

PMID:36611064 SUPPORT Model Organism

"We report a profound similarity in the developmental, hematopoietic, and immune phenotypes resulting from the loss of MYSM1 catalytic function and the full loss of MYSM1 protein."

Catalytic-dead Mysm1 D660N knock-in mice phenocopy the knockout, so the deubiquitinase activity is the disease-relevant function.

+ 1 more reference

Reduced Ribosomal Protein Gene Expression

MYSM1 binds promoters of ribosomal-protein and translation-factor genes and maintains their expression in mouse hematopoietic cells. Knockdown reduces H3K27ac at tested promoters without a significant increase in H2AK119ub. The expression defect persists after p53 or PUMA deletion, supporting its position upstream of the stress response.

hematopoietic stem cell CL:0000037

Downstream

Reduced Protein Synthesis Reduced expression of ribosomal components accompanies reduced protein synthesis.

p53 Activation in Hematopoietic Stem and Progenitor Cells Ribosomal stress is a proposed upstream trigger; the expression defect persists when p53 is deleted.

Show evidence (3 references)

PMID:32641579 SUPPORT Model Organism

"Loss of p53 in mice fully rescues Mysm1-/- anemia phenotype but not RP gene expression, indicating that RP gene dysregulation is a direct outcome of Mysm1 deficiency and an upstream mediator of Mysm1-/- phenotypes through p53 activation."

Places the ribosomal-protein defect upstream of, and independent from, p53.

PMID:32641579 SUPPORT Human Clinical

"We characterize a patient with a homozygous nonsense MYSM1 gene variant, and we demonstrate reduced protein synthesis and increased p53 levels in patient hematopoietic cells."

Human confirmation of reduced protein synthesis and raised p53 in patient blood cells.

PMID:32641579 SUPPORT DIRECT PRIMARY RESULT In Vitro

"No significant increase in H2AK119ub levels was seen in the Mysm1-knockdown Ba/F3 cells"

The measured promoter effect does not support routing this branch through H2AK119ub accumulation.

p53 Activation in Hematopoietic Stem and Progenitor Cells

Mysm1-deficient mouse hematopoietic cells activate p53 stress programs. p53 deletion rescues major hematopoietic defects, while PUMA deletion rescues multipotent-progenitor survival but leaves lymphopenia and part of the HSC dysfunction. MYSM1 also restrains transcription at selected p53-target promoters. Increased p53 protein was measured in blood cells from one affected child; the genetic rescue experiments are mouse studies. Thymocyte p19ARF induction is not a universal HSPC mechanism.

hematopoietic stem cell CL:0000037 hematopoietic multipotent progenitor cell CL:0000837

signal transduction by p53 class mediator GO:0072331 ↑ INCREASED

Animal models

Mysm1-deficient mouse Mouse recapitulates Raised p53 in haematopoietic cells, with genetic rescue by p53 deletion.

Downstream

Block in Early B-Cell Development p53 deletion restores lymphopoiesis in Mysm1-deficient mice.

T Lymphocytopenia In mice, loss of early thymocyte progenitors and thymocyte apoptosis leave the thymus hypoplastic; both are restored by p53 deletion.

PUMA-Dependent Multipotent Progenitor Apoptosis PUMA is a nonredundant mediator of MPP4 apoptosis in the studied mouse model.

Loss of Hematopoietic Stem Cell Quiescence p53 deletion restores quiescence; PUMA deletion gives only partial rescue.

Show evidence (2 references)

PMID:25710881 SUPPORT Model Organism

"These results establish p53 activation as the driving mechanism for hematopoietic abnormalities in Mysm1 deficiency."

Double-knockout rescue identifies p53 as the driver of the haematopoietic phenotype.

PMID:22184403 SUPPORT Model Organism

"Importantly, Mysm1(tm1a/tm1a) HSCs were functionally impaired, and this was associated with elevated levels of reactive oxygen species, γH2AX DNA damage marker, and p53 protein in the hematopoietic progenitors."

Elevated p53, reactive oxygen species and DNA-damage marker in Mysm1-deficient progenitors.

Ferroptosis of Hematopoietic Stem Cells

CRISPR disruption of MYSM1 in healthy-donor human HSCs induces iron-dependent lipid peroxidation and ferroptotic death. Ferroptosis inhibitors rescue HSC maintenance without restoring translation. Edited cord-blood HSC engraftment in NBSGW mice was also rescued by liproxstatin-1 cell pretreatment plus systemic administration. Neither experiment demonstrates clinical efficacy in affected patients.

hematopoietic stem cell CL:0000037

ferroptosis GO:0097707 ↑ INCREASED

Experimental models

MYSM1-deficient human hematopoietic stem cells PRIMARY CELL CULTURE Reproduces selective HSC loss and its rescue by ferroptosis blockade.

Animal models

MYSM1-edited human HSC xenograft Mouse recapitulates Measures engraftment of engineered human cells in a mouse host.

Downstream

Impaired Hematopoietic Stem Cell Function Ferroptotic loss reduces maintenance and engraftment of engineered human HSCs.

Show evidence (2 references)

PMID:36803603 SUPPORT In Vitro

"HSC maintenance can be fully rescued by blocking ferroptosis, despite no alteration in protein synthesis rates."

Ferroptosis is the proximate cause of HSC loss in this human model.

PMID:36803603 SUPPORT In Vitro

"this selective vulnerability to ferroptosis not only underlies HSC loss in MYSM1 deficiency but also characterizes a broader liability of human HSCs"

Ties the ferroptosis vulnerability to HSC loss in MYSM1 deficiency specifically.

Impaired Hematopoietic Stem Cell Function

MYSM1 loss impairs hematopoietic reconstitution and maintenance in mouse transplantation assays and engineered human HSC xenografts. The number of phenotypically defined HSCs is variable across models and need not decrease; severe progenitor depletion and loss of functional capacity are more consistent. Clinical marrow hypocellularity and cytopenias are compatible with these mechanisms, but the relative contributions in patients are unresolved.

hematopoietic stem cell CL:0000037 hematopoietic multipotent progenitor cell CL:0000837

hematopoietic stem cell homeostasis GO:0061484 ↓ DECREASED

Downstream

Bone Marrow Hypocellularity Loss of effective hematopoietic output can contribute to hypocellularity; marrow cellularity varies by patient and stage.

Anemia Erythroid output falls; in mice the anaemia is fully p53-dependent.

Neutropenia Myeloid output falls.

Leukopenia Multilineage output falls.

Thrombocytopenia Megakaryocytic output falls in patients (mice differ; see discussion).

Pancytopenia All three lineages fall together in the more severe presentations.

Show evidence (2 references)

PMID:24014243 SUPPORT Model Organism

"Mysm1 deletion drives HSCs from quiescence into rapid cycling and increases their apoptotic rate, resulting in an exhaustion of the stem cell pool"

HSC exhaustion in Mysm1-deficient mice.

PMID:22184403 SUPPORT Model Organism

"Here we characterized an H2A-DUB targeted mouse line Mysm1(tm1a/tm1a) and demonstrated defects in BM hematopoiesis, resulting in lymphopenia, anemia, and thrombocytosis."

Marrow haematopoietic failure in the first Mysm1 mouse line.

Block in Early B-Cell Development

In mice MYSM1 is required cell-intrinsically at the earliest stage of B-cell commitment, where it de-represses EBF1 by remodelling histone marks and recruiting transcription factors to the EBF1 locus; Mysm1-deficient mice have a block in early B-cell development. The human counterpart is the near-absence of B cells that is the most consistent immunological finding in patients.

pro-B cell CL:0000826

B cell differentiation GO:0030183 ↓ DECREASED

Animal models

Mysm1-deficient mouse Mouse recapitulates Early B-cell commitment block matching the near-absent B cells of patients.

Downstream

B Lymphocytopenia Few B cells reach the periphery.

Hypogammaglobulinemia B-cell depletion can contribute to the human antibody deficiency, but a mouse model retains or enhances serum antibody responses despite lymphopenia.

Immunodeficiency The humoral defect contributes to infection susceptibility.

Show evidence (2 references)

PMID:22169041 SUPPORT Model Organism

"MYSM1 deficiency results in a block in early B cell commitment and a defect of B cell progenitors in expression of EBF1 and other B lymphoid genes."

The early B-cell block and its EBF1 basis in Mysm1-deficient mice.

PMID:22169041 SUPPORT Model Organism

"MYSM1 derepresses EBF1 transcription in B cell progenitors by orchestrating histone modifications and transcription factor recruitment to the EBF1 locus."

Molecular mechanism at the EBF1 locus.

Impaired NK-Cell Maturation

Mysm1-deficient mice have severely impaired NK-cell development: lineage commitment is intact but maturation fails, because MYSM1 is needed to recruit NFIL3 to, and maintain active chromatin at, the ID2 locus. Low NK counts in patients are the human counterpart; the ID2 mechanism has not been examined in patient cells.

natural killer cell CL:0000623

natural killer cell differentiation GO:0001779 ↓ DECREASED

Downstream

Reduced Natural Killer Cell Count Few mature NK cells reach the circulation.

Show evidence (2 references)

PMID:24062447 SUPPORT Model Organism

"We demonstrated that MYSM1 is required for NK cell maturation but not for NK lineage specification and commitment."

Stage of the NK block in Mysm1-deficient mice.

PMID:24062447 SUPPORT Model Organism

"Mechanistic studies revealed that the expression of transcription factor, inhibitor of DNA-binding protein (ID2), a critical factor for NK cell development, is impaired in Mysm1(-/-) NK cells."

ID2 as the MYSM1-dependent NK transcription factor.

Prolonged DNA Damage Response Signaling

MYSM1 knockdown prolongs signaling after DNA breaks in murine ABL-transformed pre-B and human U2OS cells. Break generation and repair were preserved in the tested assays, so persistent foci are not equivalent to unrepaired breaks. The screened infant had constitutive gamma-H2AX in a B-cell subset. Separately, primary fibroblasts and EBV-transformed cells from the 2017 siblings showed prolonged UV/genotoxic stress responses. These contexts do not justify a universal statement about DNA repair or a categorical prohibition of transplant-conditioning agents.

DNA damage response GO:0006974 ↑ INCREASED

Experimental models

Patient fibroblasts and EBV-transformed lymphoblasts OTHER Measures UV/genotoxic stress responses in patient-derived cell systems.

Show evidence (4 references)

PMID:38065233 SUPPORT In Vitro

"MYSM1 regulates termination of DNA damage responses but does not function in DNA break generation and repair."

Places the defect in DDR termination, not repair.

PMID:38065233 SUPPORT In Vitro

"Loss of MYSM1 resulted in persistent DNA damage foci and prolonged DDR signaling."

Persistent damage signalling after MYSM1 suppression.

PMID:28115216 SUPPORT In Vitro

"MYSM1-deficient cells are characterized by increased sensitivity to genotoxic stress associated with sustained induction of phosphorylated p38 protein, increased reactive oxygen species production, and decreased survival following UV light-induced DNA damage."

Genotoxic hypersensitivity of patient-derived cells.

+ 1 more reference

p53-Mediated Developmental Tissue Apoptosis

Global Mysm1-deficient mice show increased apoptosis in developing brain and skin, and p53 deletion ameliorates growth, neurologic and skin phenotypes. The contribution to human developmental manifestations is inferred. Skeletal osteopenia also improves after p53 deletion, but reduced osteoblast Runx2 expression persists and cannot be equated with correction of the primary osteoblast defect. A neural-stem-cell conditional model shows a distinct differentiation imbalance without increased baseline apoptosis in vivo.

intrinsic apoptotic signaling pathway by p53 class mediator GO:0072332 ↑ INCREASED

Downstream

Short Stature Growth retardation in the mouse model; short stature in patients.

Global Developmental Delay Neurological defects in the mouse model; developmental delay in patients.

Microcephaly Apoptosis in the developing mouse brain; microcephaly in patients.

Show evidence (3 references)

PMID:25613381 SUPPORT Model Organism

"Increased rates of apoptosis were also detected in other tissues affected by Mysm1 deficiency, including the developing brain and the skin."

Extra-haematopoietic apoptosis in Mysm1-deficient mice.

PMID:25613381 SUPPORT Model Organism

"defective B-cell development, growth retardation, neurological defects, skin atrophy, and tail malformation were almost completely restored as well"

Developmental defects rescued in p53/Mysm1 double-deficient mice.

PMID:29203593 SUPPORT Model Organism

"Skeletal alterations and osteopenia of Mysm1-deficient mice were phenotypically completely rescued by simultaneous ablation of p53 in p53-/-Mysm1-/- double-deficient mice"

The skeletal phenotype is p53-dependent in mice.

Somatic Genetic Rescue of Hematopoiesis

In one p.His656Arg patient, reversion of one mutant allele was followed by sustained hematologic and immune recovery over twelve years. The data support correction in one or a few early stem cells; an HSC versus hemangioblast origin and the precise number of founding corrected cells remain unresolved. Mutant T cells persist, especially in the double-negative gamma-delta subset. Nonhematologic abnormalities were unaffected. No CHIP-panel variant was found at follow-up, which does not establish zero future malignant risk.

hematopoietic stem cell CL:0000037

Show evidence (3 references)

PMID:26220525 SUPPORT Human Clinical

"Genetic analysis indicated that this improvement originated from a spontaneous genetic reversion of the MYSM1 mutation in a hematopoietic stem cell."

The reversion event in the patient's HSC compartment.

PMID:39233474 SUPPORT Human Clinical

"The patient's blood cell counts that normalized a few months after SGR remained remarkably stable over an additional period of 12 years"

Durability of the rescue.

PMID:39233474 SUPPORT Human Clinical

"This indicates that one or a few SGR‐positive (SGR+) HSCs suffice to reconstitute and maintain a normal immuno‐haematopoietic system in a context of MYSM1 deficiency."

One or a few corrected HSCs are sufficient for full reconstitution.

Clonal Evolution to Myelodysplasia and Leukemia

Four patients from two families developed hypocellular MDS or MDS/AML at approximately ten to twelve years in a 2025 series. Findings included chromosome 7 abnormalities, trisomy 8, 5q deletion, an incompletely characterized TP53 mutation and CALR p.Pro228Ser at 50% allele fraction. Without nonhematopoietic comparison, the CALR variant is not established as an acquired driver. The series documents progression but does not prove that HSC selection, p53 escape or any specific variant caused it, and cannot quantify lifetime risk.

Downstream

Myelodysplasia Hypocellular MDS in three of the four progressing patients.

Acute Myeloid Leukemia MDS/AML in one of the four progressing patients.

Show evidence (2 references)

PMID:40535318 SUPPORT Human Clinical

"We report four cases of MYSM1 mutations progressing from marrow failure to MDS or AML within 9-10 years."

Direct human evidence of myeloid progression.

PMID:40535318 SUPPORT Human Clinical

"Genetic abnormalities, including TP53 mutation and chromosomal anomalies, suggest clonal evolution."

Acquired clonal lesions at progression.

Reduced Protein Synthesis

Protein synthesis is reduced in Mysm1-deficient mouse HSCs, CRISPR-edited healthy-donor human HSCs and circulating hematopoietic cells from one affected child. The human clinical assays do not specifically establish reduced translation in patient-derived HSCs.

cytoplasmic translation GO:0002181 ↓ DECREASED

Downstream

Reduced Ferroptosis-Protective Protein Production Translation impairment reduces production of iron-handling and antioxidant proteins in engineered human HSCs.

Show evidence (2 references)

PMID:32641579 SUPPORT DIRECT PRIMARY RESULT Model Organism

"We observed a significant reduction of OPP incorporation in Mysm1–/– HSCs, indicating reduced protein synthesis rates"

In vivo mouse OPP incorporation.

PMID:32641579 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"This demonstrated reduction in protein synthesis rate in many leukocyte populations"

Direct measurement in blood from the p.Ser290* patient.

Reduced Ferroptosis-Protective Protein Production

In MYSM1-edited healthy-donor human HSCs, GPX4, SLC7A11 and FTH1 proteins decrease despite compensatory increases in their transcripts. Reduced GPX4 activity, increased labile ferrous iron and lipid peroxidation accompany the defect. This is an engineered-cell mechanism, not a patient biomarker profile.

Downstream

Ferroptosis of Hematopoietic Stem Cells Loss of lipid-peroxide defenses and altered iron handling sensitize edited HSCs to ferroptotic death.

Show evidence (1 reference)

PMID:36803603 SUPPORT DIRECT PRIMARY RESULT In Vitro

"the levels of key proteins including GPX4, SLC7A11, and FTH1 were all significantly reduced in HSPCs"

These proteins were assessed in CRISPR-edited donor HSCs; reduced translation and iron/antioxidant defenses link MYSM1 loss to ferroptosis.

PUMA-Dependent Multipotent Progenitor Apoptosis

In Mysm1-deficient mice, PUMA-dependent apoptosis depletes lymphoid-primed MPP4 cells. Puma deletion restores their viability but does not restore downstream B- and T-cell development. This must be distinguished from ferroptosis in engineered human HSCs and from the quiescence defect of mouse HSCs.

intrinsic apoptotic signaling pathway by p53 class mediator GO:0072332 ↑ INCREASED

Downstream

Impaired Hematopoietic Stem Cell Function Loss of downstream progenitors contributes to disturbed hematopoietic maintenance and compensatory HSC cycling.

Show evidence (1 reference)

PMID:26768662 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Increased levels of apoptosis in Mysm1−/− MPP4 cells were fully rescued upon deletion of either p53 or Bbc3/PUMA"

Mouse double-knockout comparison identifies the MPP4 death mechanism.

Loss of Hematopoietic Stem Cell Quiescence

Loss of HSC quiescence and impaired long-term reconstitution occur in several Mysm1-deficient mouse models. Quiescence is only partially rescued by Puma deletion, while p53 deletion restores it. Age, genetic background and assay affect the measured cycling phenotype; hyperproliferation is not uniform across every published model.

Downstream

Impaired Hematopoietic Stem Cell Function Disrupted quiescence contributes to impaired stem-cell maintenance.

Show evidence (1 reference)

PMID:26768662 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Mysm1−/− HSC loss of quiescence is rescued in Mysm1−/−p53−/− HSCs"

Ki67-based analysis; PUMA deletion gives incomplete rescue.

Reduced GFI1 Expression in Hematopoietic Stem Cells

In one mouse model, MYSM1 occupies Gfi1 regulatory elements and facilitates GATA2/RUNX1 recruitment. Reduced Gfi1 expression contributes to loss of quiescence and impaired reconstitution; ectopic Gfi1 provides partial rescue. Expression findings differ by model and maturation stage, so GFI1 is not a universal explanation for all MYSM1 phenotypes.

GFI1 hgnc:4237 ↓ DECREASED

Downstream

Loss of Hematopoietic Stem Cell Quiescence Reduced Gfi1 contributes to disturbed quiescence in the studied mouse model.

Show evidence (1 reference)

PMID:24014243 SUPPORT DIRECT PRIMARY RESULT Model Organism

"forced Gfi1 expression in the Mysm1−/− cells at least partially restores the function of Mysm1−/− HSC"

Mouse transplantation and ectopic-expression rescue support a contributing mechanism.

Reduced ID4 Expression in Neural Stem Cells

Mouse neural-stem-cell MYSM1 loss reduces Id4 expression. MYSM1 occupancy and histone changes at the Id4 promoter, followed by partial rescue with ectopic Id4, support a context-specific regulatory mechanism.

neural stem cell CL:0000047

ID4 hgnc:5363 ↓ DECREASED

Downstream

Neural Stem Cell Differentiation Imbalance Reduced Id4 contributes to increased neuronal differentiation and reduced astroglial differentiation.

Show evidence (1 reference)

PMID:38342917 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Mysm1 epigenetically regulated Id4 transcription by regulating histone modification at the promoter region"

Mouse neural-stem-cell chromatin and expression assays.

Neural Stem Cell Differentiation Imbalance

Nestin-Cre Mysm1 conditional mice and cultured mouse neural stem cells show increased activation and neuronal differentiation with reduced astroglial differentiation. The stem-cell pool is depleted in the dentate-gyrus niche. Baseline apoptosis was not increased in vivo or unstimulated culture; increased apoptosis occurred after experimental challenge. The mechanism has not been demonstrated in patient neural tissue.

neural stem cell CL:0000047

Animal models

Neural-stem-cell Mysm1 conditional mouse Mouse recapitulates Measures neural-lineage consequences in a conditional mouse model.

Show evidence (2 references)

PMID:38342917 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Mysm1-deficient NSCs skewed toward neurogenesis instead of astrogliogenesis"

Conditional mouse and culture experiments support altered fate balance; the abstract’s generalized apoptosis claim requires the qualifications in the results.

PMID:38342917 SUPPORT DIRECT PRIMARY RESULT Model Organism

"There was no difference in the expression of apoptosis markers in NSCs before and after knockout of Mysm1 in vivo"

The full text qualifies the broader wording in the abstract.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Blood 14

Anemia HP:0001903

Show evidence (2 references)

PMID:40535318 SUPPORT Human Clinical

"Most of the patients had presented with BMF characterized by anemia in 9 cases"

Anaemia is the dominant presenting feature in the literature review.

PMID:40535318 SUPPORT Human Clinical

"Our patients initially were transfusion dependent during infancy, then showed spontaneous improvement until age 9-10 years; they became transfusion depended, which may indicate clonal evolution as showed in our patients."

The authors describe an overall biphasic course; their detailed case chronology differs, so this is not an exact timeline for every patient.

Bone Marrow Hypocellularity HP:0005528

Show evidence (2 references)

PMID:40535318 SUPPORT Human Clinical

"BM cellularity at initial diagnosis | 10% | 20% | 5% | 10%"

Hypocellular marrow in all four patients of the series.

PMID:35295078 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The patient with a MYSM1 homozygous variant had early onset pancytopenia, with a hypocellular marrow and a paucity of red cell precursors and mild developmental delay and short stature."

Primary 2022 Israeli inherited-cytopenia cohort; MYSM1 patient findings, not other cohort diagnoses.

Pancytopenia HP:0001876

Show evidence (3 references)

PMID:34302415 SUPPORT Human Clinical

"we report a pediatric patient with BMFS4 who suffered from pancytopenia and immunodeficiency affecting B cells"

Pancytopenia in a child with BMFS4.

PMID:33858043 SUPPORT Human Clinical

"The girl presented with pancytopenia, polydactylism, nonspecific white matter changes, and cysts."

Pancytopenia at one month of age.

PMID:35295078 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The patient with a MYSM1 homozygous variant had early onset pancytopenia, with a hypocellular marrow and a paucity of red cell precursors and mild developmental delay and short stature."

Primary 2022 Israeli inherited-cytopenia cohort; MYSM1 patient findings, not other cohort diagnoses.

Neutropenia Decreased total neutrophil count HP:0001875

Show evidence (2 references)

PMID:28115216 SUPPORT Human Clinical

"We report 2 patients with progressive BMF associated with myelodysplastic features, immunodeficiency affecting B cells and neutrophil granulocytes, and complex developmental aberrations, including mild skeletal anomalies, neurocognitive developmental delay, and cataracts."

Neutrophil deficiency in the sibling pair.

PMID:32640305 SUPPORT Human Clinical

Granulocytopenia in a compound heterozygous patient.

Leukopenia Decreased total leukocyte count HP:0001882

Show evidence (1 reference)

PMID:32640305 SUPPORT Human Clinical

Leukopenia in a compound heterozygous patient.

Thrombocytopenia HP:0001873

Show evidence (1 reference)

PMID:32640305 SUPPORT Human Clinical

Thrombocytopenia in a compound heterozygous patient.

B Lymphocytopenia Decreased total B cell count HP:0010976

Show evidence (2 references)

PMID:26220525 SUPPORT Human Clinical

"Here we describe a patient presenting with a complete lack of B lymphocytes, T-cell lymphopenia, defective hematopoiesis, and developmental abnormalities."

Complete absence of B cells.

PMID:38065233 SUPPORT Human Clinical

"Genetic testing in a newborn with abnormal screen for severe combined immune deficiency, T-cell lymphopenia, and near absence of B cells identified a novel splice variant in MYSM1 that results in nearly absent protein expression."

Near-absent B cells in a neonate.

Reduced Natural Killer Cell Count Reduced total natural killer cell count HP:0040218

Show evidence (1 reference)

PMID:32640305 SUPPORT Human Clinical

NK-cell deficiency.

T Lymphocytopenia Decreased total T cell count HP:0005403

Show evidence (2 references)

PMID:26220525 SUPPORT Human Clinical

"Here we describe a patient presenting with a complete lack of B lymphocytes, T-cell lymphopenia, defective hematopoiesis, and developmental abnormalities."

T-cell lymphopenia in the Le Guen patient.

PMID:38065233 SUPPORT Human Clinical

T-cell lymphopenia detected by newborn screening.

Hypogammaglobulinemia Decreased circulating immunoglobulin concentration HP:0004313

Show evidence (1 reference)

PMID:40535318 SUPPORT Human Clinical

"Biallelic MYSM1 variants are linked to rare bone marrow failure syndromes, presenting with cytopenia, B-cell deficiency, hypogammaglobulinemia, and developmental abnormalities."

Hypogammaglobulinaemia as part of the syndrome.

Myelodysplasia HP:0002863

Show evidence (2 references)

PMID:28115216 SUPPORT Human Clinical

Myelodysplastic features with progressive marrow failure.

PMID:40535318 SUPPORT Human Clinical

"We report four cases of MYSM1 mutations progressing from marrow failure to MDS or AML within 9-10 years."

Progression to MDS in the Saudi series.

Acute Myeloid Leukemia HP:0004808

Show evidence (1 reference)

PMID:40535318 SUPPORT Human Clinical

"3 months later he transformed to AML, BM biopsy was hypercellular marrow up to 100% with 73% myeloblast"

A single case of AML transformation.

Elevated Erythrocyte Adenosine Deaminase Elevated red cell adenosine deaminase activity HP:0030270

Show evidence (1 reference)

PMID:32641579 SUPPORT Human Clinical

"The patient also had significantly elevated erythrocyte adenosine deaminase"

Single-patient measurement.

Monocytopenia Decreased total monocyte count HP:0012312

Show evidence (1 reference)

PMID:32641579 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"and monocytopenia developed over time"

Direct case observation; no disease-wide frequency is inferred.

Cardiovascular 1

Left Ventricular Noncompaction Cardiomyopathy HP:0011664

Show evidence (1 reference)

url:https://push-zb.helmholtz-munich.de/deliver.php?id=19850 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Cardiomegaly, left ... ventricle dilatation, ... reduced FS 16-20%, ... noncompaction ... cardiomyopathy"

Accepted manuscript of "Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations." (PMID:28115216). Direct case observation; no disease-wide frequency is inferred.

Ear 1

Hearing Impairment HP:0000365

Show evidence (2 references)

ORPHA:508542 SUPPORT Other

"Additional reported features include dry skin and eczema, cardiac anomalies, hearing loss, and reduction of cerebral volume on brain imaging."

Orphanet definition.

PMID:40535318 SUPPORT Human Clinical

"Microcephaly, choanal atresia, bilateral deafness"

Review-table entry for a single patient.

Eye 1

Cataract HP:0000518

Show evidence (1 reference)

PMID:28115216 SUPPORT Human Clinical

The abstract lists cataracts among the siblings’ combined findings; the full clinical text assigns them to the girl.

Genitourinary 1

Distal Renal Tubular Acidosis HP:0008341

Show evidence (1 reference)

PMID:40535318 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"her pre-transplant distal renal tubular acidosis with severe hypokalemia resolved following HSCT"

Direct case observation; no disease-wide frequency is inferred.

Head and Neck 7

Microcephaly HP:0000252

Show evidence (1 reference)

PMID:40535318 SUPPORT Human Clinical

"Non hematological abnormalities, such as developmental delay, short stature, facial dysmorphy, and microcephaly have been described in patients with MYSM1 mutation."

Microcephaly among reported features.

Facial Dysmorphism Abnormal facial shape HP:0001999

Show evidence (1 reference)

PMID:40535318 SUPPORT Human Clinical

"Non hematological abnormalities, such as developmental delay, short stature, facial dysmorphy, and microcephaly have been described in patients with MYSM1 mutation."

Facial dysmorphism among reported features.

Midface Hypoplasia Midface retrusion HP:0011800

Show evidence (1 reference)

PMID:32641579 SUPPORT Human Clinical

"Discrete dysmorphic features were present, including midface hypoplasia, brachydactyly"

Single-patient report.

Choanal Atresia HP:0000453

Show evidence (1 reference)

PMID:40535318 SUPPORT Human Clinical

"Microcephaly, choanal atresia, bilateral deafness"

Review-table entry for a single patient.

Gingival Overgrowth HP:0000212

Show evidence (1 reference)

url:https://push-zb.helmholtz-munich.de/deliver.php?id=19850 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"trigonocephaly, midface hypoplasia, gingiva hyperplasia"

Delayed Tooth Eruption Delayed eruption of teeth HP:0000684

Show evidence (1 reference)

url:https://push-zb.helmholtz-munich.de/deliver.php?id=19850 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Dental/mouth Gingiva hyperplasia Gingiva hyperplasia, delayed dentition"

Trigonocephaly HP:0000243

Show evidence (1 reference)

url:https://push-zb.helmholtz-munich.de/deliver.php?id=19850 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"trigonocephaly, midface hypoplasia, gingiva hyperplasia"

Immune 3

Immunodeficiency HP:0002721

Show evidence (2 references)

PMID:26220525 SUPPORT Human Clinical

"We here define a novel human immunodeficiency and provide evidence that MYSM1 is essential for proper immunohematopoietic development in human subjects."

Defines MYSM1 deficiency as an immunodeficiency.

ORPHA:508542 SUPPORT Other

"Immunodeficiency primarily affects B-cells and may lead to increased susceptibility to infections."

Orphanet definition.

Neutrophilic Panniculitis HP:0012490

Show evidence (1 reference)

PMID:30746751 SUPPORT Human Clinical

"We report a case of NP associated with myelodysplasia in a child with MYSM1 deficiency, a newly described syndrome with primary immunodeficiency (PI), bone marrow failure, and developmental aberrations."

Single case report.

Eczema Eczematoid dermatitis HP:0000964

Show evidence (1 reference)

ORPHA:508542 SUPPORT Other

"Additional reported features include dry skin and eczema, cardiac anomalies, hearing loss, and reduction of cerebral volume on brain imaging."

Orphanet definition.

Limbs 2

Brachydactyly HP:0001156

Show evidence (1 reference)

PMID:32641579 SUPPORT Human Clinical

"Discrete dysmorphic features were present, including midface hypoplasia, brachydactyly"

Single-patient report.

Preaxial Hand Polydactyly HP:0001177

Show evidence (2 references)

PMID:33858043 SUPPORT Human Clinical

"The girl presented with pancytopenia, polydactylism, nonspecific white matter changes, and cysts."

Single-patient report.

PMID:33858043 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The girl presented with pancytopenia, polydactylism, nonspecific white matter changes, and cysts. ... 右手大拇指外有一指，呈蒂状连接，可见指甲。"

The primary Chinese case text localizes the anomaly to the right thumb.

Metabolism 1

Hypokalemia HP:0002900

Show evidence (1 reference)

PMID:40535318 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"her pre-transplant distal renal tubular acidosis with severe hypokalemia resolved following HSCT"

Direct case observation; no disease-wide frequency is inferred.

Musculoskeletal 1

Osteopenia HP:0000938

Show evidence (1 reference)

url:https://push-zb.helmholtz-munich.de/deliver.php?id=19850 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"short left humerus, ... brachymetacarpia D1 ... left and broad ... metacarpia D1 left, ... osteopenia"

Nervous System 3

Global Developmental Delay HP:0001263

Show evidence (3 references)

PMID:28115216 SUPPORT Human Clinical

Neurocognitive developmental delay in both siblings.

PMID:32641579 SUPPORT Human Clinical

"A mild retardation of motor development was diagnosed at the age of 7 months."

Motor delay in infancy in another patient.

PMID:35295078 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The patient with a MYSM1 homozygous variant had early onset pancytopenia, with a hypocellular marrow and a paucity of red cell precursors and mild developmental delay and short stature."

Primary 2022 Israeli inherited-cytopenia cohort; MYSM1 patient findings, not other cohort diagnoses.

Cerebral White Matter Hyperintensity Hyperintensity of cerebral white matter on MRI HP:0030890

Show evidence (1 reference)

PMID:33858043 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The girl presented with pancytopenia, polydactylism, nonspecific white matter changes, and cysts. ... 双侧顶叶皮质层下白质T2信号增强"

Direct case observation; no disease-wide frequency is inferred.

Subependymal Cyst Subependymal cysts HP:0002416

Show evidence (1 reference)

PMID:33858043 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The girl presented with pancytopenia, polydactylism, nonspecific white matter changes, and cysts. ... 左侧脑室前角旁室管膜下囊肿"

The primary Chinese text localizes the cyst.

Cellular 1

Increased Sensitivity to Ionizing Radiation HP:0011133

Show evidence (1 reference)

PMID:38065233 SUPPORT INDIRECT BACKGROUND Human Clinical

"Patients with deleterious variants in MYSM1 have an immune deficiency characterized by B-cell lymphopenia, hypogammaglobulinemia, and increased radiosensitivity."

Radiosensitivity is part of the described immunophenotype.

Growth 2

Short Stature HP:0004322

Show evidence (3 references)

ORPHA:508542 SUPPORT Other

"non-hematologic manifestations, such as developmental delay, cataracts, facial dysmorphism, short stature, and skeletal anomalies"

Orphanet definition.

PMID:40535318 SUPPORT Human Clinical

"Non hematological abnormalities, such as developmental delay, short stature, facial dysmorphy, and microcephaly have been described in patients with MYSM1 mutation."

Literature summary of non-haematological features.

PMID:35295078 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The patient with a MYSM1 homozygous variant had early onset pancytopenia, with a hypocellular marrow and a paucity of red cell precursors and mild developmental delay and short stature."

Primary 2022 Israeli inherited-cytopenia cohort; MYSM1 patient findings, not other cohort diagnoses.

Rhizomelic Arm Shortening HP:0004991

Show evidence (1 reference)

PMID:32641579 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"brachydactyly, and rhizomelic shortening of arms"

Direct case observation; no disease-wide frequency is inferred.

🧬

Genetic Associations

MYSM1

Gene: MYSM1 hgnc:29401 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:32640305 SUPPORT Human Clinical

"Biallelic variants in MYSM1 cause a rare bone marrow failure syndrome (OMIM #618116)."

Gene-disease relationship.

PMID:28115216 SUPPORT Human Clinical

"Whole-exome sequencing revealed a homozygous premature stop codon mutation in the gene encoding MYSM1."

Independent family with a truncating allele.

💊

Medical Actions

Allogeneic Hematopoietic Stem Cell Transplantation

Action: allogeneic hematopoietic stem cell transplantation Ontology label: Allogeneic Hematopoietic Stem Cell Transplantation NCIT:C46089

Platform: Cell therapy

Allogeneic HSCT has restored hematopoiesis and immune function in reported children, including matched-family and haploidentical transplants. The 2017 siblings received fludarabine, treosulfan and alemtuzumab, with two-year donor engraftment. Other cases have shorter or longer follow-up and reported acute or chronic GVHD; the 2017 girl developed post-transplant Graves disease. Conditioning and timing require individual assessment of marrow disease and toxicity. Cell-assay sensitivity and analogies with other marrow-failure syndromes do not establish a universal ban on alkylators, which were used in successful transplants. Correction of all developmental features is not demonstrated.

Mechanism Target:

RESTORES Impaired Hematopoietic Stem Cell Function — Replaces the defective HSC compartment with donor HSCs.

Show evidence (6 references)

PMID:28115216 SUPPORT Human Clinical

"Both patients were successfully treated with allogeneic HSCT with sustained reconstitution of hematopoietic defects."

Sustained reconstitution in a sibling pair.

PMID:34302415 SUPPORT Human Clinical

"Fludarabine-based reduced intensity conditioning was used and resulted in full donor chimerism."

Reduced-intensity conditioning with full donor chimerism.

PMID:34302415 SUPPORT Human Clinical

"She achieved B-cell recovery, and no blood or platelet transfusion was reported 1 year after HSCT."

Haematological and B-cell recovery after transplant.

+ 3 more references

Red Blood Cell Transfusion

Action: packed red blood cell transfusion Ontology label: Packed Red Blood Cell Transfusion NCIT:C15409

Supportive care for transfusion-dependent anaemia in infancy and again at relapse, often needed before transplant.

Mechanism Target:

Anemia — Corrects the anaemia without affecting the marrow defect.

Show evidence (1 reference)

PMID:40535318 SUPPORT Human Clinical

Transfusion dependence in infancy and at relapse.

Antibiotic Prophylaxis

Action: antibiotic prophylaxis Ontology label: Antibiotic Prophylaxis NCIT:C51993

Agent: co-trimoxazole CHEBI:3770

Platform: Small molecule

Antibiotic prophylaxis was reported while awaiting transplant. The 2017 siblings received co-trimoxazole after early respiratory infections; regimens and indications were individualized.

Mechanism Target:

Immunodeficiency — Reduces infection risk without correcting the immune defect.

Show evidence (2 references)

PMID:32641579 SUPPORT Human Clinical

"patient had repetitive need for transfusions, was given antibiotic prophylaxis"

Single-patient supportive care.

url:https://push-zb.helmholtz-munich.de/deliver.php?id=19850 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"intravenous antibiotics, and maintained on co-trimoxazole pro- ... phylaxis thereafter."

Captopril for Cardiomyopathy

Action: Pharmacotherapy NCIT:C15986

Agent: captopril CHEBI:3380

Platform: Small molecule

Captopril was reported for the 2017 boy’s cardiomyopathy. The post-transplant course was favorable, but the report cannot isolate the effect of captopril or show correction of MYSM1 disease.

Show evidence (1 reference)

url:https://push-zb.helmholtz-munich.de/deliver.php?id=19850 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In patient IV-2 car- ... diomyopathy, which is currently treated with captopril"

Accepted manuscript of "Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations." (PMID:28115216). Actual reported treatment, without comparative efficacy data.

Genetic Counseling and Family Testing

Action: Genetic Counseling NCIT:C15240

Establish parental segregation and offer family testing. If both parents carry a pathogenic allele, the Mendelian recurrence probability is one in four per pregnancy. The reported paternal uniparental-disomy case requires separate counseling; the two-carrier assumption does not apply automatically.

Show evidence (2 references)

PMID:32641579 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Genetic counseling took place at the age of 10 weeks"

Counseling was documented; the recurrence fraction follows recessive inheritance when both parents are carriers.

PMID:38065233 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"due to paternal uniparental disomy of chromosome 1"

This exceptional origin changes the parental-genotype assumptions used for recurrence counseling.

Reported Eltrombopag Use

Action: Pharmacotherapy NCIT:C15986

Agent: eltrombopag CHEBI:85010

Platform: Small molecule

Eltrombopag was started in one transfusion-dependent adolescent with hypocellular marrow, dysplasia and a TP53 mutation while haploidentical HSCT was being considered. The report provides no response assessment, so benefit in BMFS4 is undetermined.

Show evidence (1 reference)

PMID:40535318 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He is currently receiving PRBC transfusions every 2-3 weeks and has been started on eltrombopag."

Actual drug exposure in one case; no treatment response was reported.

🔬

Diagnosis

Newborn Screening for Severe Combined Immunodeficiency

One neonate was ascertained through an abnormal newborn SCID screen (low T-cell receptor excision circles) before any anaemia, so MYSM1 deficiency belongs on the differential for a positive SCID screen with near-absent B cells.

Newborn Screening NCIT:C81178

Show evidence (1 reference)

PMID:38065233 SUPPORT Human Clinical

"T-cell receptor excision circle testing was low at 1010 copies per 106 CD3+ cells (normal >6794)."

Low TREC count on newborn screening in an affected neonate.

Exome Sequencing

Diagnosis in every reported case was molecular, by homozygosity mapping or exome sequencing, sometimes after an initial diagnosis of Diamond-Blackfan anaemia. RNA studies are worth doing for splice-region and synonymous variants: a synonymous variant at the end of exon 6 caused exon skipping.

Whole Exome Sequencing NCIT:C101295

Show evidence (2 references)

PMID:32640305 SUPPORT Human Clinical

"this is the first report of a synonymous splicing variant that induces post-transcriptional skipping of exon 6 leading to a bone marrow failure syndrome phenotype"

A synonymous variant that is pathogenic through splicing.

PMID:40535318 SUPPORT Human Clinical

"two of our cases missed diagnosed with DBA initially"

Initial misdiagnosis as Diamond-Blackfan anaemia before exome sequencing.

Bone Marrow Biopsy and Cytogenetic Surveillance

Establishes hypocellularity at diagnosis. Given progression to MDS and AML with monosomy 7, TP53 mutation and other acquired lesions at 10 to 12 years in one series, the authors recommend careful follow-up for clonal evolution. No surveillance interval has been published.

Bone marrow biopsy NCIT:C15193

Show evidence (1 reference)

PMID:40535318 SUPPORT Human Clinical

"Therefore, patients with MYSM1 mutation required careful follow up to detect any clonal evaluation."

The authors' surveillance recommendation (the source writes "evaluation" where "evolution" is meant).

📊

Prevalence

Worldwide, published cases

Cases In Literature

The 2024 follow-up and 2025 review each counted twelve previously published individuals. These are dated literature counts, include overlapping patients, and do not estimate population prevalence or the current total. The 2025 series includes follow-up of two founding siblings and two additional siblings.

Show evidence (2 references)

PMID:39233474 SUPPORT REVIEW SYNTHESIS Human Clinical

"To our knowledge, only 12 individuals carrying biallelic pathogenic MYSM1 mutations have been reported so far, indicating the rarity of this syndrome"

Literature count of reported patients.

PMID:40535318 SUPPORT REVIEW SYNTHESIS Human Clinical

"In total, 12 patients and 5 variants of MYSM1 mutation have been reported to date."

A dated review count with overlapping source reports, not an independent patient cohort.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Bone Marrow Failure Syndrome 4:

Diamond-Blackfan anemia MONDO:0015253

Overlapping Features The main clinical mimic: transfusion-dependent anaemia from infancy, a raised erythrocyte adenosine deaminase in at least one MYSM1 patient, and a shared ribosomal-stress/p53 mechanism. A MYSM1 loss-of-function allele was found in an individual with a clinical diagnosis of DBA in a large exome study.

Distinguishing Features

B-cell and NK-cell lymphopenia with hypogammaglobulinaemia
Leukopenia or neutropenia and multilineage marrow hypocellularity rather than isolated erythroid aplasia
Biallelic MYSM1 variants rather than a heterozygous ribosomal-protein gene variant

Show evidence (2 references)

PMID:30503522 SUPPORT Human Clinical

"In another individual, we observed a novel recessive LoF mutation in MYSM1"

A MYSM1 case within a clinically diagnosed DBA cohort.

PMID:40535318 SUPPORT Human Clinical

"two of our cases missed diagnosed with DBA initially"

Misdiagnosis as DBA in practice.

Fanconi anemia MONDO:0019391

Overlapping Features Shares childhood marrow failure, developmental anomalies, genotoxic hypersensitivity, progression to MDS/AML and the need for reduced-intensity conditioning; the reporting groups apply Fanconi anaemia conditioning experience to MYSM1 deficiency.

Distinguishing Features

Crosslinker-induced chromosomal breakage testing is the Fanconi anaemia discriminator
Profound B-cell lymphopenia is characteristic of MYSM1 deficiency

Show evidence (1 reference)

PMID:40535318 SUPPORT Human Clinical

"Like IBMFS, MYSM1 individuals with mutations bear a high sensitivity to genotoxic stress due to their defective DNA damage response pathways."

The shared genotoxic-sensitivity phenotype that motivates the comparison.

🧫

Experimental Models

MYSM1-deficient human hematopoietic stem cells PRIMARY_CELL_CULTURE

Engineered human MYSM1 deficiency reduces ribosomal-protein expression and translation, lowers ferroptosis-protective proteins and promotes lipid-peroxidative HSC death. Ferroptosis inhibitors rescue maintenance without restoring translation. These cells are not primary cells from an affected patient.

Cell source

CRISPR-edited healthy-donor mobilized or cord-blood CD34+ hematopoietic stem/progenitor cells

Publication

PMID:36803603

Pathograph links

Ferroptosis of Hematopoietic Stem Cells recapitulates fidelity: moderate Reproduces selective HSC loss and its rescue by ferroptosis blockade.

Limitations: Engineered loss in donor HSCs rather than patient cells, assayed outside a human marrow.

Show evidence (1 reference)

PMID:36803603 SUPPORT In Vitro

"HSC maintenance can be fully rescued by blocking ferroptosis, despite no alteration in protein synthesis rates."

The model's key rescue result.

Patient fibroblasts and EBV-transformed lymphoblasts OTHER

Patient-derived systems show absent full-length MYSM1, prolonged UV-induced gamma-H2AX/p38 signaling and impaired proliferation or stress tolerance. These differ from the later ABL-pre-B and U2OS DNA-repair assays.

Cell source

Primary fibroblasts and EBV-transformed B-cell lines from the two p.Glu390* siblings

Publication

PMID:28115216

Pathograph links

Prolonged DNA Damage Response Signaling recapitulates Measures UV/genotoxic stress responses in patient-derived cell systems.

Show evidence (1 reference)

PMID:28115216 SUPPORT DIRECT PRIMARY RESULT In Vitro

"MYSM1-deficient cells are characterized by increased sensitivity to genotoxic stress associated with sustained induction of phosphorylated p38 protein"

Patient-derived functional assays.

Show evidence (1 reference)

PMID:28115216 SUPPORT DIRECT PRIMARY RESULT In Vitro

"MYSM1-deficient cells are characterized by increased sensitivity to genotoxic stress associated with sustained induction of phosphorylated p38 protein"

Patient-derived functional assays.

🐁

Animal Models

Mysm1-deficient mouse

Several independent Mysm1-deficient lines reproduce HSC dysfunction, lymphopenia with an early B-cell block, anaemia and developmental defects; double knockouts with p53 or Puma dissect the downstream pathway.

Species

Mouse

Genotype

Mysm1 knockout (Mysm1-/-) and gene-trap (Mysm1 tm1a/tm1a)

Publication

PMID:22184403

Pathograph links

p53 Activation in Hematopoietic Stem and Progenitor Cells recapitulates fidelity: moderate Raised p53 in haematopoietic cells, with genetic rescue by p53 deletion.

Limitations: Mice develop thrombocytosis where patients have normal or mildly low platelets, and the p53-rescue experiments have no human counterpart; p53 target programmes differ between mouse and human.

Show evidence (1 reference)

PMID:25710881 SUPPORT Model Organism

"Mysm1(-/-)p53(-/-) mouse characterization showed a full rescue of Mysm1(-/-) developmental and hematopoietic defects."

The genetic rescue that places p53 at the centre of the model.

Block in Early B-Cell Development recapitulates fidelity: moderate Early B-cell commitment block matching the near-absent B cells of patients.

Limitations: Early B-cell depletion is reproduced, but antibody production and platelet phenotypes differ from patients, and the exact developmental block has not been localized in all patient samples.

Show evidence (1 reference)

PMID:22169041 SUPPORT Model Organism

"MYSM1 deficiency results in a block in early B cell commitment and a defect of B cell progenitors in expression of EBF1 and other B lymphoid genes."

The B-cell block in knockout mice.

Catalytically inactive Mysm1 D660N mouse

Catalytic inactivation retains MYSM1 protein and reproduces many developmental and hematopoietic knockout defects. HSC counts vary; MPP4 depletion is consistent. This study did not identify the downstream substrate for every phenotype.

Species

Mouse

Genotype

Mysm1D660N/D660N and inducible Mysm1fl/D660N CreERT2

Publication

PMID:36611064

Pathograph links

Loss of Histone H2A K119 Deubiquitinase Activity perturbs Catalytic inactivation demonstrates a requirement for MYSM1 DUB function; individual substrates are not resolved.

Show evidence (1 reference)

PMID:36611064 SUPPORT DIRECT PRIMARY RESULT Model Organism

"similar levels of MYSM1 protein in Mysm1DN/DN and control Mysm1+/+ bone marrow cells"

Catalytic deficiency is distinguished from loss of protein.

Show evidence (1 reference)

PMID:36611064 SUPPORT DIRECT PRIMARY RESULT Model Organism

"similar levels of MYSM1 protein in Mysm1DN/DN and control Mysm1+/+ bone marrow cells"

Catalytic deficiency is distinguished from loss of protein.

MYSM1-edited human HSC xenograft

Edited cord-blood CD34+ HSPCs have impaired engraftment. Liproxstatin-1 was applied to cells before transplantation and administered to recipient mice at 20 mg/kg intraperitoneally every other day, starting one week after transplantation for twelve weeks. Engraftment was nearly completely rescued; this is not evidence of patient treatment benefit.

Species

Mouse

Background

NBSGW

Publication

PMID:36803603

Pathograph links

Ferroptosis of Hematopoietic Stem Cells recapitulates Measures engraftment of engineered human cells in a mouse host.

Show evidence (1 reference)

PMID:36803603 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Mice treated with liproxstatin-1 showed significantly improved engraftment of MYSM1-deficient human HSPCs across all time points surveyed"

Human-to-mouse engraftment rescue following cell pretreatment plus systemic treatment.

Show evidence (1 reference)

PMID:36803603 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Mice treated with liproxstatin-1 showed significantly improved engraftment of MYSM1-deficient human HSPCs across all time points surveyed"

Human-to-mouse engraftment rescue following cell pretreatment plus systemic treatment.

Neural-stem-cell Mysm1 conditional mouse

Brain growth and neural-stem-cell homeostasis model with altered neuronal/astroglial differentiation and niche-specific stem-cell depletion. Baseline apoptosis is not uniformly increased.

Species

Mouse

Genotype

Nestin-Cre Mysm1 conditional knockout

Publication

PMID:38342917

Pathograph links

Neural Stem Cell Differentiation Imbalance recapitulates Measures neural-lineage consequences in a conditional mouse model.

Show evidence (1 reference)

PMID:38342917 SUPPORT DIRECT PRIMARY RESULT Model Organism

"the number of Dcx+ cells in the DG of Mysm1 cKO mice was significantly increased at 6 and 9 weeks ... the average optical density of Gfap in the DG of Mysm1 cKO mice decreased at 6 and 9 weeks"

Conditional neural model; direct human neural confirmation remains absent.

Show evidence (1 reference)

PMID:38342917 SUPPORT DIRECT PRIMARY RESULT Model Organism

"the number of Dcx+ cells in the DG of Mysm1 cKO mice was significantly increased at 6 and 9 weeks ... the average optical density of Gfap in the DG of Mysm1 cKO mice decreased at 6 and 9 weeks"

Conditional neural model; direct human neural confirmation remains absent.

Mysm1 meander-tail mouse

A 2026 preprint identifies classical meander-tail alleles as Mysm1 variants by mapping and noncomplementation with engineered alleles. Mutants have preferential anterior cerebellar hypoplasia and reduced granule-cell-precursor proportions at E14.5. Early truncations retain function through translation reinitiation or alternative splicing. This model does not establish cerebellar hypoplasia as a human BMFS4 phenotype.

Species

Mouse

Genotype

Mysm1 Y34X, R659G and engineered D32Efs*13 alleles

Pathograph links

Biallelic MYSM1 Loss of Function perturbs Allelic complementation supports Mysm1 causality; cerebellar findings have no established human counterpart.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC13160082/ SUPPORT DIRECT PRIMARY RESULT Model Organism

"New endonuclease-mediated ... alleles failed to complement ... variants as the causal mutations for both the vertebral malformation and the anterior cerebellum defect."

The 2026 preprint PPR:PPR1222230 reports noncomplementation between engineered Mysm1 and meander-tail alleles. Ellipses bridge gene-name markup in the cached full text. This is mouse allelic evidence, not confirmation of a human cerebellar phenotype.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC13160082/ SUPPORT DIRECT PRIMARY RESULT Model Organism

"the proportion of GCPs was selectively reduced in mutants across four littermate pairs"

Full text of the 2026 preprint PPR:PPR1222230; developmental mouse finding, not an observed patient phenotype.

{ }

Source YAML

click to show

name: Bone Marrow Failure Syndrome 4
creation_date: "2026-09-23T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: bone marrow failure syndrome 4
  term:
    id: MONDO:0020856
    label: bone marrow failure syndrome 4
description: >-
  Bone marrow failure syndrome 4 (BMFS4; MYSM1 deficiency) is an autosomal recessive disorder caused by biallelic
  loss-of-function MYSM1 variants. Reported patients have early-onset anemia, often requiring transfusion,
  with variable neutropenia, thrombocytopenia and B-, NK- or T-cell lymphopenia. Hypogammaglobulinemia and
  growth, skeletal, craniofacial, ocular, cardiac and neurodevelopmental abnormalities are variably present.
  Ascertainment through small, overlapping reports precludes disease-wide phenotype frequencies. Some children
  improve hematologically before later myelodysplasia or acute myeloid leukemia; the cumulative risk is unknown.
  One patient had sustained hematologic and immune recovery following somatic genetic reversion in one or a
  few early stem cells, without correction of nonhematologic findings. Mouse studies identify impaired ribosomal-protein
  gene expression, p53-mediated progenitor dysfunction and lineage-specific transcriptional defects. Engineered
  human HSCs additionally reveal vulnerability to ferroptosis. Reported allogeneic transplants restore hematopoiesis
  and immunity, with variable conditioning and transplant complications; they do not establish correction of
  all developmental manifestations.
synonyms:
- BMFS4
- MYSM1 deficiency
- congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome
parents:
- Inherited bone marrow failure syndrome
- Bone marrow failure syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0033683
      label: congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:508542 cross-references
    mapping_justification: >-
      MONDO carries two classes for this disease. MONDO:0020856 is imported from
      OMIM (xref OMIM:618116); MONDO:0033683 is imported from Orphanet (xref
      Orphanet:508542, synonym "MYSM1 deficiency"). The Orphanet record maps
      ORPHA:508542 as Exact to both OMIM:618116 and MONDO:0033683, so the two
      MONDO classes denote the same MYSM1-related disease and this entry covers
      both.
classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
    evidence:
    - reference: PMID:34302415
      reference_title: "Successful allogeneic stem cell transplantation with fludarabine-based reduced intensity conditioning in bone marrow failure syndrome 4."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mutation in MYSM1 in humans leads to a rare autosomal recessive disease that has recently been known as inherited bone marrow failure syndrome 4 (BMFS4) associated with congenital bone marrow failure, immunodeficiency, and developmental aberrations."
      explanation: >-
        An inherited bone marrow failure syndrome, placing it in Harrison's
        haematology/oncology Part.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:34302415
      reference_title: "Successful allogeneic stem cell transplantation with fludarabine-based reduced intensity conditioning in bone marrow failure syndrome 4."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mutation in MYSM1 in humans leads to a rare autosomal recessive disease that has recently been known as inherited bone marrow failure syndrome 4 (BMFS4) associated with congenital bone marrow failure, immunodeficiency, and developmental aberrations."
      explanation: A monogenic autosomal recessive disorder.
  iuis_category:
    classification_value: combined immunodeficiency with syndromic features
    evidence:
    - reference: PMID:41608114
      reference_title: 'Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee.'
      supports: SUPPORT
      evidence_source: OTHER
      directness: DIRECT
      quote_role: REVIEW_SYNTHESIS
      snippet: MYSM1 deficiency | MYSM1 | AR | 612176 | T-cell lymphopenia, reduced naïve T cells, low NK cells
      explanation: The 2024 IUIS genotypic classification places MYSM1 deficiency in Table 2, subsection 4, immuno-osseous dysplasias. The marrow-failure phenotype does not imply assignment to Table 9.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic pathogenic MYSM1 variants occur as homozygous or compound heterozygous alleles, in both consanguineous
    and unrelated families. A homozygous splice variant also arose through paternal uniparental disomy of chromosome
    1. Parental segregation therefore matters for recurrence counseling; homozygosity does not invariably imply
    two carrier parents.
  evidence:
  - reference: PMID:34302415
    reference_title: "Successful allogeneic stem cell transplantation with fludarabine-based reduced intensity conditioning in bone marrow failure syndrome 4."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation in MYSM1 in humans leads to a rare autosomal recessive disease that has recently been known as inherited bone marrow failure syndrome 4 (BMFS4) associated with congenital bone marrow failure, immunodeficiency, and developmental aberrations."
    explanation: States autosomal recessive inheritance.
  - reference: PMID:32640305
    reference_title: "Further delineation of bone marrow failure syndrome caused by novel compound heterozygous variants of MYSM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biallelic variants in MYSM1 cause a rare bone marrow failure syndrome (OMIM #618116)."
    explanation: Biallelic variants are required.
  - reference: PMID:38065233
    reference_title: "MYSM1 attenuates DNA damage signals triggered by physiologic and genotoxic DNA breaks."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic testing by clinical whole exome sequencing identified a homozygous splice variant in MYSM1 (c.1843–1G>A, IVS15–1 G>A variant) due to paternal uniparental disomy of chromosome 1."
    explanation: >-
      Homozygosity by paternal uniparental disomy rather than by two carrier
      parents, which changes recurrence risk for the family.
notes: >-
  MYSM1-related disease is represented by two current MONDO classes, retained here as one clinical entity using
  the Orphanet exact cross-references. Published case counts overlap across original reports and follow-up
  studies; no comprehensive current patient count or population denominator is available. No established genotype-defined
  subtypes are supported. For the somatic-rescue patient, the originating group reports c.1967A>G p.His656Arg;
  the H658R designation in a later review table is not adopted.
prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  notes: >-
    The 2024 follow-up and 2025 review each counted twelve previously published individuals. These are dated
    literature counts, include overlapping patients, and do not estimate population prevalence or the current
    total. The 2025 series includes follow-up of two founding siblings and two additional siblings.
  evidence:
  - reference: PMID:39233474
    reference_title: "Long-term assessment of haematological recovery following somatic genetic rescue in a MYSM1-deficient patient: Implications for in vivo gene therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To our knowledge, only 12 individuals carrying biallelic pathogenic MYSM1 mutations have been reported so far, indicating the rarity of this syndrome"
    explanation: Literature count of reported patients.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:40535318
    reference_title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In total, 12 patients and 5 variants of MYSM1 mutation have been reported to date."
    explanation: A dated review count with overlapping source reports, not an independent patient cohort.
    quote_role: REVIEW_SYNTHESIS
pathophysiology:
- name: Biallelic MYSM1 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic MYSM1 alleles include nonsense, frameshift, splice-altering and catalytic-site missense variants.
    The synonymous c.399G>A allele causes exon-6 skipping and a frameshift; c.1843-1G>A causes in-frame exon-16
    skipping with deletion of 63 amino acids and near-absent protein. Functional evidence differs by allele
    and must not be assumed for every rare variant.
  genes:
  - preferred_term: MYSM1
    term:
      id: hgnc:29401
      label: MYSM1
    modifier: LOSS_OF_FUNCTION
  genetic_context:
    description: >-
      Germline biallelic loss-of-function MYSM1 alleles, homozygous (usually
      through consanguinity, once through paternal uniparental disomy) or
      compound heterozygous.
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:28115216
    reference_title: "Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing revealed a homozygous premature stop codon mutation in the gene encoding MYSM1."
    explanation: Homozygous truncating MYSM1 variant in an affected sibling pair.
  - reference: PMID:26220525
    reference_title: "An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis revealed that this novel disorder is caused by a homozygous MYSM1 missense mutation affecting the catalytic site within the deubiquitinase JAB1/MPN/Mov34 (JAMM)/MPN domain."
    explanation: A missense allele that targets the catalytic site rather than protein abundance.
  - reference: PMID:32640305
    reference_title: "Further delineation of bone marrow failure syndrome caused by novel compound heterozygous variants of MYSM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Trio whole-exome sequencing revealed a novel compound heterozygous variant in MYSM1 (c.399G > A, p.L133L, and c.1467C > G, p.Y489*)."
    explanation: Compound heterozygous alleles, including a synonymous splice-altering variant.
  - reference: PMID:38065233
    reference_title: "MYSM1 attenuates DNA damage signals triggered by physiologic and genotoxic DNA breaks."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic testing in a newborn with abnormal screen for severe combined immune deficiency, T-cell lymphopenia, and near absence of B cells identified a novel splice variant in MYSM1 that results in nearly absent protein expression."
    explanation: Splice allele with near-absent MYSM1 protein.
  downstream:
  - target: Loss of Histone H2A K119 Deubiquitinase Activity
    description: Loss of MYSM1 protein, or of its catalytic site, removes its H2A deubiquitinase activity.
    causal_link_type: DIRECT
  - target: Reduced Ribosomal Protein Gene Expression
    description: MYSM1 maintains ribosomal-protein gene expression through promoter regulation that is not established to require local H2AK119 deubiquitination.
    causal_link_type: DIRECT
  - target: Prolonged DNA Damage Response Signaling
    description: MYSM1 loss prolongs damage signaling in the tested cell systems; the responsible substrate is unresolved.
    causal_link_type: DIRECT
  - target: p53-Mediated Developmental Tissue Apoptosis
    description: Global Mysm1 loss induces p53-dependent developmental pathology in mouse brain and skin.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Reduced ID4 Expression in Neural Stem Cells
    description: Neural-stem-cell MYSM1 deficiency reduces Id4 transcription in the mouse model.
    causal_link_type: DIRECT
- name: Loss of Histone H2A K119 Deubiquitinase Activity
  biological_scale: MOLECULAR
  description: >-
    MYSM1 deubiquitinates histone H2A lysine 119 and regulates selected gene loci. A catalytic D660N mouse
    retains MYSM1 protein yet reproduces many knockout phenotypes, establishing a requirement for catalytic
    function in hematopoiesis. This does not establish H2AK119 as the substrate for every MYSM1-dependent pathway:
    ribosomal-protein promoters show no significant H2AK119ub increase after knockdown, and the DNA-damage-signaling
    substrate remains unresolved.
  molecular_functions:
  - preferred_term: histone H2A deubiquitinase activity
    modifier: DECREASED
    term:
      id: GO:0140950
      label: histone H2A deubiquitinase activity
  evidence:
  - reference: PMID:26220525
    reference_title: "An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is a metalloprotease that deubiquitinates the K119-monoubiquitinated form of histone 2A (H2A), a chromatin marker associated with gene transcription silencing"
    explanation: Defines the enzymatic activity lost in the disease.
  - reference: PMID:17707232
    reference_title: "A histone H2A deubiquitinase complex coordinating histone acetylation and H1 dissociation in transcriptional regulation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "2A-DUB regulates transcription by coordinating histone acetylation and deubiquitination, and destabilizing the association of linker histone H1 with nucleosomes."
    explanation: Original biochemical characterisation of MYSM1 as a co-activator acting through H2A deubiquitination.
  - reference: PMID:36611064
    reference_title: "Deubiquitinase catalytic activity of MYSM1 is essential in vivo for hematopoiesis and immune cell development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We report a profound similarity in the developmental, hematopoietic, and immune phenotypes resulting from the loss of MYSM1 catalytic function and the full loss of MYSM1 protein."
    explanation: >-
      Catalytic-dead Mysm1 D660N knock-in mice phenocopy the knockout, so the
      deubiquitinase activity is the disease-relevant function.
  - reference: PMID:39233474
    reference_title: "Long-term assessment of haematological recovery following somatic genetic rescue in a MYSM1-deficient patient: Implications for in vivo gene therapy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "unlike C1‐WT, C1‐H656R was devoid of in vitro deubiquitinase activity"
    explanation: The patient missense allele abolishes catalytic activity in a recombinant assay.
  downstream:
  - target: Block in Early B-Cell Development
    description: MYSM1 de-represses EBF1 and other early B-lineage genes.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Impaired NK-Cell Maturation
    description: MYSM1 keeps the ID2 locus in active chromatin during NK-cell maturation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Reduced GFI1 Expression in Hematopoietic Stem Cells
    description: MYSM1 loss changes histone marks and transcription-factor recruitment at Gfi1 regulatory elements.
    causal_link_type: DIRECT
- name: Reduced Ribosomal Protein Gene Expression
  biological_scale: MOLECULAR
  description: >-
    MYSM1 binds promoters of ribosomal-protein and translation-factor genes and maintains their expression
    in mouse hematopoietic cells. Knockdown reduces H3K27ac at tested promoters without a significant increase
    in H2AK119ub. The expression defect persists after p53 or PUMA deletion, supporting its position upstream
    of the stress response.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  evidence:
  - reference: PMID:32641579
    reference_title: "MYSM1 maintains ribosomal protein gene expression in hematopoietic stem cells to prevent hematopoietic dysfunction."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Loss of p53 in mice fully rescues Mysm1-/- anemia phenotype but not RP gene expression, indicating that RP gene dysregulation is a direct outcome of Mysm1 deficiency and an upstream mediator of Mysm1-/- phenotypes through p53 activation."
    explanation: Places the ribosomal-protein defect upstream of, and independent from, p53.
  - reference: PMID:32641579
    reference_title: "MYSM1 maintains ribosomal protein gene expression in hematopoietic stem cells to prevent hematopoietic dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We characterize a patient with a homozygous nonsense MYSM1 gene variant, and we demonstrate reduced protein synthesis and increased p53 levels in patient hematopoietic cells."
    explanation: Human confirmation of reduced protein synthesis and raised p53 in patient blood cells.
  - reference: PMID:32641579
    reference_title: MYSM1 maintains ribosomal protein gene expression in hematopoietic stem cells to prevent hematopoietic dysfunction.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: No significant increase in H2AK119ub levels was seen in the Mysm1-knockdown Ba/F3 cells
    explanation: The measured promoter effect does not support routing this branch through H2AK119ub accumulation.
  downstream:
  - target: Reduced Protein Synthesis
    description: Reduced expression of ribosomal components accompanies reduced protein synthesis.
    causal_link_type: DIRECT
  - target: p53 Activation in Hematopoietic Stem and Progenitor Cells
    description: Ribosomal stress is a proposed upstream trigger; the expression defect persists when p53 is deleted.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: p53 Activation in Hematopoietic Stem and Progenitor Cells
  biological_scale: CELLULAR
  description: >-
    Mysm1-deficient mouse hematopoietic cells activate p53 stress programs. p53 deletion rescues major hematopoietic
    defects, while PUMA deletion rescues multipotent-progenitor survival but leaves lymphopenia and part of
    the HSC dysfunction. MYSM1 also restrains transcription at selected p53-target promoters. Increased p53
    protein was measured in blood cells from one affected child; the genetic rescue experiments are mouse studies.
    Thymocyte p19ARF induction is not a universal HSPC mechanism.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  - preferred_term: hematopoietic multipotent progenitor cell
    term:
      id: CL:0000837
      label: hematopoietic multipotent progenitor cell
  biological_processes:
  - preferred_term: signal transduction by p53 class mediator
    modifier: INCREASED
    term:
      id: GO:0072331
      label: signal transduction by p53 class mediator
  evidence:
  - reference: PMID:25710881
    reference_title: "p53 mediates loss of hematopoietic stem cell function and lymphopenia in Mysm1 deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These results establish p53 activation as the driving mechanism for hematopoietic abnormalities in Mysm1 deficiency."
    explanation: Double-knockout rescue identifies p53 as the driver of the haematopoietic phenotype.
  - reference: PMID:22184403
    reference_title: "The critical role of histone H2A-deubiquitinase Mysm1 in hematopoiesis and lymphocyte differentiation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Importantly, Mysm1(tm1a/tm1a) HSCs were functionally impaired, and this was associated with elevated levels of reactive oxygen species, γH2AX DNA damage marker, and p53 protein in the hematopoietic progenitors."
    explanation: Elevated p53, reactive oxygen species and DNA-damage marker in Mysm1-deficient progenitors.
  downstream:
  - target: Block in Early B-Cell Development
    description: p53 deletion restores lymphopoiesis in Mysm1-deficient mice.
    evidence:
    - reference: PMID:25710881
      reference_title: "p53 mediates loss of hematopoietic stem cell function and lymphopenia in Mysm1 deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mysm1(-/-)p53(-/-) mouse characterization showed a full rescue of Mysm1(-/-) developmental and hematopoietic defects."
      explanation: Lymphopenia is among the defects rescued by p53 loss.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: T Lymphocytopenia
    description: >-
      In mice, loss of early thymocyte progenitors and thymocyte apoptosis
      leave the thymus hypoplastic; both are restored by p53 deletion.
    evidence:
    - reference: PMID:25613381
      reference_title: "Interplay of H2A deubiquitinase 2A-DUB/Mysm1 and the p19(ARF)/p53 axis in hematopoiesis, early T-cell development and tissue differentiation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mysm1(-/-) thymi were severely hypoplastic with <10% of wild-type cell numbers as a result of a reduction of early thymocyte progenitors in context with defective hematopoietic stem cells"
      explanation: Thymic hypoplasia in Mysm1-deficient mice, the model counterpart of T-cell lymphopenia in some patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: PUMA-Dependent Multipotent Progenitor Apoptosis
    description: PUMA is a nonredundant mediator of MPP4 apoptosis in the studied mouse model.
    causal_link_type: DIRECT
  - target: Loss of Hematopoietic Stem Cell Quiescence
    description: p53 deletion restores quiescence; PUMA deletion gives only partial rescue.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Ferroptosis of Hematopoietic Stem Cells
  biological_scale: CELLULAR
  description: >-
    CRISPR disruption of MYSM1 in healthy-donor human HSCs induces iron-dependent lipid peroxidation and ferroptotic
    death. Ferroptosis inhibitors rescue HSC maintenance without restoring translation. Edited cord-blood HSC
    engraftment in NBSGW mice was also rescued by liproxstatin-1 cell pretreatment plus systemic administration.
    Neither experiment demonstrates clinical efficacy in affected patients.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  biological_processes:
  - preferred_term: ferroptosis
    modifier: INCREASED
    term:
      id: GO:0097707
      label: ferroptosis
  evidence:
  - reference: PMID:36803603
    reference_title: "Human hematopoietic stem cell vulnerability to ferroptosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "HSC maintenance can be fully rescued by blocking ferroptosis, despite no alteration in protein synthesis rates."
    explanation: Ferroptosis is the proximate cause of HSC loss in this human model.
  - reference: PMID:36803603
    reference_title: "Human hematopoietic stem cell vulnerability to ferroptosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "this selective vulnerability to ferroptosis not only underlies HSC loss in MYSM1 deficiency but also characterizes a broader liability of human HSCs"
    explanation: Ties the ferroptosis vulnerability to HSC loss in MYSM1 deficiency specifically.
  downstream:
  - target: Impaired Hematopoietic Stem Cell Function
    description: Ferroptotic loss reduces maintenance and engraftment of engineered human HSCs.
    causal_link_type: DIRECT
- name: Impaired Hematopoietic Stem Cell Function
  biological_scale: CELLULAR
  description: >-
    MYSM1 loss impairs hematopoietic reconstitution and maintenance in mouse transplantation assays and engineered
    human HSC xenografts. The number of phenotypically defined HSCs is variable across models and need not
    decrease; severe progenitor depletion and loss of functional capacity are more consistent. Clinical marrow
    hypocellularity and cytopenias are compatible with these mechanisms, but the relative contributions in
    patients are unresolved.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  - preferred_term: hematopoietic multipotent progenitor cell
    term:
      id: CL:0000837
      label: hematopoietic multipotent progenitor cell
  biological_processes:
  - preferred_term: hematopoietic stem cell homeostasis
    modifier: DECREASED
    term:
      id: GO:0061484
      label: hematopoietic stem cell homeostasis
  evidence:
  - reference: PMID:24014243
    reference_title: "The control of hematopoietic stem cell maintenance, self-renewal, and differentiation by Mysm1-mediated epigenetic regulation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mysm1 deletion drives HSCs from quiescence into rapid cycling and increases their apoptotic rate, resulting in an exhaustion of the stem cell pool"
    explanation: HSC exhaustion in Mysm1-deficient mice.
  - reference: PMID:22184403
    reference_title: "The critical role of histone H2A-deubiquitinase Mysm1 in hematopoiesis and lymphocyte differentiation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we characterized an H2A-DUB targeted mouse line Mysm1(tm1a/tm1a) and demonstrated defects in BM hematopoiesis, resulting in lymphopenia, anemia, and thrombocytosis."
    explanation: Marrow haematopoietic failure in the first Mysm1 mouse line.
  downstream:
  - target: Bone Marrow Hypocellularity
    description: Loss of effective hematopoietic output can contribute to hypocellularity; marrow cellularity varies by patient and stage.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Anemia
    description: Erythroid output falls; in mice the anaemia is fully p53-dependent.
    evidence:
    - reference: PMID:32641579
      reference_title: "MYSM1 maintains ribosomal protein gene expression in hematopoietic stem cells to prevent hematopoietic dysfunction."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Loss of p53 in mice fully rescues Mysm1-/- anemia phenotype but not RP gene expression, indicating that RP gene dysregulation is a direct outcome of Mysm1 deficiency and an upstream mediator of Mysm1-/- phenotypes through p53 activation."
      explanation: The mouse anaemia depends on the p53 arm.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Neutropenia
    description: Myeloid output falls.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Leukopenia
    description: Multilineage output falls.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Thrombocytopenia
    description: Megakaryocytic output falls in patients (mice differ; see discussion).
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Pancytopenia
    description: All three lineages fall together in the more severe presentations.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Block in Early B-Cell Development
  biological_scale: CELLULAR
  description: >-
    In mice MYSM1 is required cell-intrinsically at the earliest stage of B-cell
    commitment, where it de-represses EBF1 by remodelling histone marks and
    recruiting transcription factors to the EBF1 locus; Mysm1-deficient mice
    have a block in early B-cell development. The human counterpart is the
    near-absence of B cells that is the most consistent immunological finding
    in patients.
  cell_types:
  - preferred_term: pro-B cell
    term:
      id: CL:0000826
      label: pro-B cell
  biological_processes:
  - preferred_term: B cell differentiation
    modifier: DECREASED
    term:
      id: GO:0030183
      label: B cell differentiation
  evidence:
  - reference: PMID:22169041
    reference_title: "Control of B cell development by the histone H2A deubiquitinase MYSM1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "MYSM1 deficiency results in a block in early B cell commitment and a defect of B cell progenitors in expression of EBF1 and other B lymphoid genes."
    explanation: The early B-cell block and its EBF1 basis in Mysm1-deficient mice.
  - reference: PMID:22169041
    reference_title: "Control of B cell development by the histone H2A deubiquitinase MYSM1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "MYSM1 derepresses EBF1 transcription in B cell progenitors by orchestrating histone modifications and transcription factor recruitment to the EBF1 locus."
    explanation: Molecular mechanism at the EBF1 locus.
  downstream:
  - target: B Lymphocytopenia
    description: Few B cells reach the periphery.
    causal_link_type: DIRECT
  - target: Hypogammaglobulinemia
    description: B-cell depletion can contribute to the human antibody deficiency, but a mouse model retains or enhances serum antibody responses despite lymphopenia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Immunodeficiency
    description: The humoral defect contributes to infection susceptibility.
    causal_link_type: DIRECT
- name: Impaired NK-Cell Maturation
  biological_scale: CELLULAR
  description: >-
    Mysm1-deficient mice have severely impaired NK-cell development: lineage
    commitment is intact but maturation fails, because MYSM1 is needed to
    recruit NFIL3 to, and maintain active chromatin at, the ID2 locus. Low NK
    counts in patients are the human counterpart; the ID2 mechanism has not been
    examined in patient cells.
  cell_types:
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  biological_processes:
  - preferred_term: natural killer cell differentiation
    modifier: DECREASED
    term:
      id: GO:0001779
      label: natural killer cell differentiation
  evidence:
  - reference: PMID:24062447
    reference_title: "Epigenetic control of natural killer cell maturation by histone H2A deubiquitinase, MYSM1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We demonstrated that MYSM1 is required for NK cell maturation but not for NK lineage specification and commitment."
    explanation: Stage of the NK block in Mysm1-deficient mice.
  - reference: PMID:24062447
    reference_title: "Epigenetic control of natural killer cell maturation by histone H2A deubiquitinase, MYSM1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mechanistic studies revealed that the expression of transcription factor, inhibitor of DNA-binding protein (ID2), a critical factor for NK cell development, is impaired in Mysm1(-/-) NK cells."
    explanation: ID2 as the MYSM1-dependent NK transcription factor.
  downstream:
  - target: Reduced Natural Killer Cell Count
    description: Few mature NK cells reach the circulation.
    causal_link_type: DIRECT
- name: Prolonged DNA Damage Response Signaling
  biological_scale: CELLULAR
  description: >-
    MYSM1 knockdown prolongs signaling after DNA breaks in murine ABL-transformed pre-B and human U2OS cells.
    Break generation and repair were preserved in the tested assays, so persistent foci are not equivalent
    to unrepaired breaks. The screened infant had constitutive gamma-H2AX in a B-cell subset. Separately, primary
    fibroblasts and EBV-transformed cells from the 2017 siblings showed prolonged UV/genotoxic stress responses.
    These contexts do not justify a universal statement about DNA repair or a categorical prohibition of transplant-conditioning
    agents.
  biological_processes:
  - preferred_term: DNA damage response
    modifier: INCREASED
    term:
      id: GO:0006974
      label: DNA damage response
  evidence:
  - reference: PMID:38065233
    reference_title: "MYSM1 attenuates DNA damage signals triggered by physiologic and genotoxic DNA breaks."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "MYSM1 regulates termination of DNA damage responses but does not function in DNA break generation and repair."
    explanation: Places the defect in DDR termination, not repair.
  - reference: PMID:38065233
    reference_title: "MYSM1 attenuates DNA damage signals triggered by physiologic and genotoxic DNA breaks."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Loss of MYSM1 resulted in persistent DNA damage foci and prolonged DDR signaling."
    explanation: Persistent damage signalling after MYSM1 suppression.
  - reference: PMID:28115216
    reference_title: "Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "MYSM1-deficient cells are characterized by increased sensitivity to genotoxic stress associated with sustained induction of phosphorylated p38 protein, increased reactive oxygen species production, and decreased survival following UV light-induced DNA damage."
    explanation: Genotoxic hypersensitivity of patient-derived cells.
  - reference: PMID:38065233
    reference_title: MYSM1 attenuates DNA damage signals triggered by physiologic and genotoxic DNA breaks.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Suppression of MYSM1 in pre-B cells did not alter generation or repair of Ig DSBs. Rather, loss of MYSM1 resulted in persistent DNA damage foci and prolonged DDR signaling.
    explanation: The conclusion applies to the tested ABL-transformed pre-B and U2OS systems, not all tissues.
  downstream: []
- name: p53-Mediated Developmental Tissue Apoptosis
  biological_scale: TISSUE
  description: >-
    Global Mysm1-deficient mice show increased apoptosis in developing brain and skin, and p53 deletion ameliorates
    growth, neurologic and skin phenotypes. The contribution to human developmental manifestations is inferred.
    Skeletal osteopenia also improves after p53 deletion, but reduced osteoblast Runx2 expression persists
    and cannot be equated with correction of the primary osteoblast defect. A neural-stem-cell conditional
    model shows a distinct differentiation imbalance without increased baseline apoptosis in vivo.
  biological_processes:
  - preferred_term: intrinsic apoptotic signaling pathway by p53 class mediator
    modifier: INCREASED
    term:
      id: GO:0072332
      label: intrinsic apoptotic signaling pathway by p53 class mediator
  evidence:
  - reference: PMID:25613381
    reference_title: "Interplay of H2A deubiquitinase 2A-DUB/Mysm1 and the p19(ARF)/p53 axis in hematopoiesis, early T-cell development and tissue differentiation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Increased rates of apoptosis were also detected in other tissues affected by Mysm1 deficiency, including the developing brain and the skin."
    explanation: Extra-haematopoietic apoptosis in Mysm1-deficient mice.
  - reference: PMID:25613381
    reference_title: "Interplay of H2A deubiquitinase 2A-DUB/Mysm1 and the p19(ARF)/p53 axis in hematopoiesis, early T-cell development and tissue differentiation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "defective B-cell development, growth retardation, neurological defects, skin atrophy, and tail malformation were almost completely restored as well"
    explanation: Developmental defects rescued in p53/Mysm1 double-deficient mice.
  - reference: PMID:29203593
    reference_title: "Loss of p53 compensates osteopenia in murine Mysm1 deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Skeletal alterations and osteopenia of Mysm1-deficient mice were phenotypically completely rescued by simultaneous ablation of p53 in p53-/-Mysm1-/- double-deficient mice"
    explanation: The skeletal phenotype is p53-dependent in mice.
  downstream:
  - target: Short Stature
    description: Growth retardation in the mouse model; short stature in patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Global Developmental Delay
    description: Neurological defects in the mouse model; developmental delay in patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Microcephaly
    description: Apoptosis in the developing mouse brain; microcephaly in patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Somatic Genetic Rescue of Hematopoiesis
  biological_scale: CELLULAR
  description: >-
    In one p.His656Arg patient, reversion of one mutant allele was followed by sustained hematologic and immune
    recovery over twelve years. The data support correction in one or a few early stem cells; an HSC versus
    hemangioblast origin and the precise number of founding corrected cells remain unresolved. Mutant T cells
    persist, especially in the double-negative gamma-delta subset. Nonhematologic abnormalities were unaffected.
    No CHIP-panel variant was found at follow-up, which does not establish zero future malignant risk.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  evidence:
  - reference: PMID:26220525
    reference_title: "An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis indicated that this improvement originated from a spontaneous genetic reversion of the MYSM1 mutation in a hematopoietic stem cell."
    explanation: The reversion event in the patient's HSC compartment.
  - reference: PMID:39233474
    reference_title: "Long-term assessment of haematological recovery following somatic genetic rescue in a MYSM1-deficient patient: Implications for in vivo gene therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient's blood cell counts that normalized a few months after SGR remained remarkably stable over an additional period of 12 years"
    explanation: Durability of the rescue.
  - reference: PMID:39233474
    reference_title: "Long-term assessment of haematological recovery following somatic genetic rescue in a MYSM1-deficient patient: Implications for in vivo gene therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This indicates that one or a few SGR‐positive (SGR+) HSCs suffice to reconstitute and maintain a normal immuno‐haematopoietic system in a context of MYSM1 deficiency."
    explanation: One or a few corrected HSCs are sufficient for full reconstitution.
- name: Clonal Evolution to Myelodysplasia and Leukemia
  biological_scale: TISSUE
  description: >-
    Four patients from two families developed hypocellular MDS or MDS/AML at approximately ten to twelve years
    in a 2025 series. Findings included chromosome 7 abnormalities, trisomy 8, 5q deletion, an incompletely
    characterized TP53 mutation and CALR p.Pro228Ser at 50% allele fraction. Without nonhematopoietic comparison,
    the CALR variant is not established as an acquired driver. The series documents progression but does not
    prove that HSC selection, p53 escape or any specific variant caused it, and cannot quantify lifetime risk.
  evidence:
  - reference: PMID:40535318
    reference_title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report four cases of MYSM1 mutations progressing from marrow failure to MDS or AML within 9-10 years."
    explanation: Direct human evidence of myeloid progression.
  - reference: PMID:40535318
    reference_title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic abnormalities, including TP53 mutation and chromosomal anomalies, suggest clonal evolution."
    explanation: Acquired clonal lesions at progression.
  downstream:
  - target: Myelodysplasia
    description: Hypocellular MDS in three of the four progressing patients.
    causal_link_type: DIRECT
  - target: Acute Myeloid Leukemia
    description: MDS/AML in one of the four progressing patients.
    causal_link_type: DIRECT
- name: Reduced Protein Synthesis
  biological_scale: MOLECULAR
  description: Protein synthesis is reduced in Mysm1-deficient mouse HSCs, CRISPR-edited healthy-donor human HSCs and circulating hematopoietic cells from one affected child. The human clinical assays do not specifically establish reduced translation in patient-derived HSCs.
  biological_processes:
  - preferred_term: cytoplasmic translation
    modifier: DECREASED
    term:
      id: GO:0002181
      label: cytoplasmic translation
  evidence:
  - reference: PMID:32641579
    reference_title: MYSM1 maintains ribosomal protein gene expression in hematopoietic stem cells to prevent hematopoietic dysfunction.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: We observed a significant reduction of OPP incorporation in Mysm1–/– HSCs, indicating reduced protein synthesis rates
    explanation: In vivo mouse OPP incorporation.
  - reference: PMID:32641579
    reference_title: MYSM1 maintains ribosomal protein gene expression in hematopoietic stem cells to prevent hematopoietic dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: This demonstrated reduction in protein synthesis rate in many leukocyte populations
    explanation: Direct measurement in blood from the p.Ser290* patient.
  downstream:
  - target: Reduced Ferroptosis-Protective Protein Production
    description: Translation impairment reduces production of iron-handling and antioxidant proteins in engineered human HSCs.
    causal_link_type: DIRECT
- name: Reduced Ferroptosis-Protective Protein Production
  biological_scale: MOLECULAR
  description: In MYSM1-edited healthy-donor human HSCs, GPX4, SLC7A11 and FTH1 proteins decrease despite compensatory increases in their transcripts. Reduced GPX4 activity, increased labile ferrous iron and lipid peroxidation accompany the defect. This is an engineered-cell mechanism, not a patient biomarker profile.
  evidence:
  - reference: PMID:36803603
    reference_title: Human hematopoietic stem cell vulnerability to ferroptosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: the levels of key proteins including GPX4, SLC7A11, and FTH1 were all significantly reduced in HSPCs
    explanation: These proteins were assessed in CRISPR-edited donor HSCs; reduced translation and iron/antioxidant defenses link MYSM1 loss to ferroptosis.
  downstream:
  - target: Ferroptosis of Hematopoietic Stem Cells
    description: Loss of lipid-peroxide defenses and altered iron handling sensitize edited HSCs to ferroptotic death.
    causal_link_type: DIRECT
- name: PUMA-Dependent Multipotent Progenitor Apoptosis
  biological_scale: CELLULAR
  description: In Mysm1-deficient mice, PUMA-dependent apoptosis depletes lymphoid-primed MPP4 cells. Puma deletion restores their viability but does not restore downstream B- and T-cell development. This must be distinguished from ferroptosis in engineered human HSCs and from the quiescence defect of mouse HSCs.
  biological_processes:
  - preferred_term: intrinsic apoptotic signaling pathway by p53 class mediator
    modifier: INCREASED
    term:
      id: GO:0072332
      label: intrinsic apoptotic signaling pathway by p53 class mediator
  evidence:
  - reference: PMID:26768662
    reference_title: Repression of p53-target gene Bbc3/PUMA by MYSM1 is essential for the survival of hematopoietic multipotent progenitors and contributes to stem cell maintenance.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Increased levels of apoptosis in Mysm1−/− MPP4 cells were fully rescued upon deletion of either p53 or Bbc3/PUMA
    explanation: Mouse double-knockout comparison identifies the MPP4 death mechanism.
  downstream:
  - target: Impaired Hematopoietic Stem Cell Function
    description: Loss of downstream progenitors contributes to disturbed hematopoietic maintenance and compensatory HSC cycling.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Loss of Hematopoietic Stem Cell Quiescence
  biological_scale: CELLULAR
  description: Loss of HSC quiescence and impaired long-term reconstitution occur in several Mysm1-deficient mouse models. Quiescence is only partially rescued by Puma deletion, while p53 deletion restores it. Age, genetic background and assay affect the measured cycling phenotype; hyperproliferation is not uniform across every published model.
  evidence:
  - reference: PMID:26768662
    reference_title: Repression of p53-target gene Bbc3/PUMA by MYSM1 is essential for the survival of hematopoietic multipotent progenitors and contributes to stem cell maintenance.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Mysm1−/− HSC loss of quiescence is rescued in Mysm1−/−p53−/− HSCs
    explanation: Ki67-based analysis; PUMA deletion gives incomplete rescue.
  downstream:
  - target: Impaired Hematopoietic Stem Cell Function
    description: Disrupted quiescence contributes to impaired stem-cell maintenance.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Reduced GFI1 Expression in Hematopoietic Stem Cells
  biological_scale: MOLECULAR
  description: In one mouse model, MYSM1 occupies Gfi1 regulatory elements and facilitates GATA2/RUNX1 recruitment. Reduced Gfi1 expression contributes to loss of quiescence and impaired reconstitution; ectopic Gfi1 provides partial rescue. Expression findings differ by model and maturation stage, so GFI1 is not a universal explanation for all MYSM1 phenotypes.
  evidence:
  - reference: PMID:24014243
    reference_title: The control of hematopoietic stem cell maintenance, self-renewal, and differentiation by Mysm1-mediated epigenetic regulation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: forced Gfi1 expression in the Mysm1−/− cells at least partially restores the function of Mysm1−/− HSC
    explanation: Mouse transplantation and ectopic-expression rescue support a contributing mechanism.
  downstream:
  - target: Loss of Hematopoietic Stem Cell Quiescence
    description: Reduced Gfi1 contributes to disturbed quiescence in the studied mouse model.
    causal_link_type: DIRECT
  genes:
  - preferred_term: GFI1
    term:
      id: hgnc:4237
      label: GFI1
    modifier: DECREASED
- name: Reduced ID4 Expression in Neural Stem Cells
  biological_scale: MOLECULAR
  description: Mouse neural-stem-cell MYSM1 loss reduces Id4 expression. MYSM1 occupancy and histone changes at the Id4 promoter, followed by partial rescue with ectopic Id4, support a context-specific regulatory mechanism.
  evidence:
  - reference: PMID:38342917
    reference_title: Deubiquitinase Mysm1 regulates neural stem cell proliferation and differentiation by controlling Id4 expression.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Mysm1 epigenetically regulated Id4 transcription by regulating histone modification at the promoter region
    explanation: Mouse neural-stem-cell chromatin and expression assays.
  downstream:
  - target: Neural Stem Cell Differentiation Imbalance
    description: Reduced Id4 contributes to increased neuronal differentiation and reduced astroglial differentiation.
    causal_link_type: DIRECT
  genes:
  - preferred_term: ID4
    term:
      id: hgnc:5363
      label: ID4
    modifier: DECREASED
  cell_types:
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
- name: Neural Stem Cell Differentiation Imbalance
  biological_scale: CELLULAR
  description: Nestin-Cre Mysm1 conditional mice and cultured mouse neural stem cells show increased activation and neuronal differentiation with reduced astroglial differentiation. The stem-cell pool is depleted in the dentate-gyrus niche. Baseline apoptosis was not increased in vivo or unstimulated culture; increased apoptosis occurred after experimental challenge. The mechanism has not been demonstrated in patient neural tissue.
  evidence:
  - reference: PMID:38342917
    reference_title: Deubiquitinase Mysm1 regulates neural stem cell proliferation and differentiation by controlling Id4 expression.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Mysm1-deficient NSCs skewed toward neurogenesis instead of astrogliogenesis
    explanation: Conditional mouse and culture experiments support altered fate balance; the abstract’s generalized apoptosis claim requires the qualifications in the results.
  - reference: PMID:38342917
    reference_title: Deubiquitinase Mysm1 regulates neural stem cell proliferation and differentiation by controlling Id4 expression.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: There was no difference in the expression of apoptosis markers in NSCs before and after knockout of Mysm1 in vivo
    explanation: The full text qualifies the broader wording in the abstract.
  cell_types:
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
phenotypes:
- category: Hematologic
  name: Anemia
  description: >-
    Early-onset anemia is often transfusion dependent, but severity and duration vary. Some patients improve
    spontaneously and later develop recurrent cytopenias or myeloid neoplasia. Published reports give differing
    transfusion timelines for the founding siblings, so a uniform age of recovery is not inferred.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:40535318
    reference_title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the patients had presented with BMF characterized by anemia in 9 cases"
    explanation: Anaemia is the dominant presenting feature in the literature review.
  - reference: PMID:40535318
    reference_title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our patients initially were transfusion dependent during infancy, then showed spontaneous improvement until age 9-10 years; they became transfusion depended, which may indicate clonal evolution as showed in our patients."
    explanation: The authors describe an overall biphasic course; their detailed case chronology differs, so this is not an exact timeline for every patient.
- category: Hematologic
  name: Bone Marrow Hypocellularity
  description: Marrow cellularity of 5 to 20% at diagnosis in the four Saudi patients.
  phenotype_term:
    preferred_term: Bone marrow hypocellularity
    term:
      id: HP:0005528
      label: Bone marrow hypocellularity
  evidence:
  - reference: PMID:40535318
    reference_title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BM cellularity at initial diagnosis | 10% | 20% | 5% | 10%"
    explanation: Hypocellular marrow in all four patients of the series.
  - reference: PMID:35295078
    reference_title: Syndromes predisposing to leukemia are a major cause of inherited cytopenias in children.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The patient with a MYSM1 homozygous variant had early onset pancytopenia, with a hypocellular marrow and a paucity of red cell precursors and mild developmental delay and short stature.
    explanation: Primary 2022 Israeli inherited-cytopenia cohort; MYSM1 patient findings, not other cohort diagnoses.
- category: Hematologic
  name: Pancytopenia
  phenotype_term:
    preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
  evidence:
  - reference: PMID:34302415
    reference_title: "Successful allogeneic stem cell transplantation with fludarabine-based reduced intensity conditioning in bone marrow failure syndrome 4."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report a pediatric patient with BMFS4 who suffered from pancytopenia and immunodeficiency affecting B cells"
    explanation: Pancytopenia in a child with BMFS4.
  - reference: PMID:33858043
    reference_title: "[A novel compound heterozygous mutation in MYSM1 gene in a 1-month-old girl: a bone marrow failure syndrome 4 family survey and literature review]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The girl presented with pancytopenia, polydactylism, nonspecific white matter changes, and cysts."
    explanation: Pancytopenia at one month of age.
  - reference: PMID:35295078
    reference_title: Syndromes predisposing to leukemia are a major cause of inherited cytopenias in children.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The patient with a MYSM1 homozygous variant had early onset pancytopenia, with a hypocellular marrow and a paucity of red cell precursors and mild developmental delay and short stature.
    explanation: Primary 2022 Israeli inherited-cytopenia cohort; MYSM1 patient findings, not other cohort diagnoses.
- category: Hematologic
  name: Neutropenia
  phenotype_term:
    preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:28115216
    reference_title: "Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report 2 patients with progressive BMF associated with myelodysplastic features, immunodeficiency affecting B cells and neutrophil granulocytes, and complex developmental aberrations, including mild skeletal anomalies, neurocognitive developmental delay, and cataracts."
    explanation: Neutrophil deficiency in the sibling pair.
  - reference: PMID:32640305
    reference_title: "Further delineation of bone marrow failure syndrome caused by novel compound heterozygous variants of MYSM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe a Chinese female patient who mainly presented with leukopenia, granulocytopenia, thrombocytopenia, severe anemia, and B-cell and natural killer cell deficiency in the peripheral blood, and was diagnosed with bone marrow failure."
    explanation: Granulocytopenia in a compound heterozygous patient.
- category: Hematologic
  name: Leukopenia
  phenotype_term:
    preferred_term: Leukopenia
    term:
      id: HP:0001882
      label: Decreased total leukocyte count
  evidence:
  - reference: PMID:32640305
    reference_title: "Further delineation of bone marrow failure syndrome caused by novel compound heterozygous variants of MYSM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe a Chinese female patient who mainly presented with leukopenia, granulocytopenia, thrombocytopenia, severe anemia, and B-cell and natural killer cell deficiency in the peripheral blood, and was diagnosed with bone marrow failure."
    explanation: Leukopenia in a compound heterozygous patient.
- category: Hematologic
  name: Thrombocytopenia
  description: >-
    Usually mild or intermittent in patients. Mysm1-deficient mice show the
    opposite, thrombocytosis (see the model-mismatch discussion).
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:32640305
    reference_title: "Further delineation of bone marrow failure syndrome caused by novel compound heterozygous variants of MYSM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe a Chinese female patient who mainly presented with leukopenia, granulocytopenia, thrombocytopenia, severe anemia, and B-cell and natural killer cell deficiency in the peripheral blood, and was diagnosed with bone marrow failure."
    explanation: Thrombocytopenia in a compound heterozygous patient.
- category: Immunologic
  name: B Lymphocytopenia
  description: >-
    The most consistent immunological finding, ranging from reduced to
    completely absent B cells.
  phenotype_term:
    preferred_term: B lymphocytopenia
    term:
      id: HP:0010976
      label: Decreased total B cell count
  evidence:
  - reference: PMID:26220525
    reference_title: "An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe a patient presenting with a complete lack of B lymphocytes, T-cell lymphopenia, defective hematopoiesis, and developmental abnormalities."
    explanation: Complete absence of B cells.
  - reference: PMID:38065233
    reference_title: "MYSM1 attenuates DNA damage signals triggered by physiologic and genotoxic DNA breaks."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic testing in a newborn with abnormal screen for severe combined immune deficiency, T-cell lymphopenia, and near absence of B cells identified a novel splice variant in MYSM1 that results in nearly absent protein expression."
    explanation: Near-absent B cells in a neonate.
- category: Immunologic
  name: Reduced Natural Killer Cell Count
  phenotype_term:
    preferred_term: Reduced natural killer cell count
    term:
      id: HP:0040218
      label: Reduced total natural killer cell count
  evidence:
  - reference: PMID:32640305
    reference_title: "Further delineation of bone marrow failure syndrome caused by novel compound heterozygous variants of MYSM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe a Chinese female patient who mainly presented with leukopenia, granulocytopenia, thrombocytopenia, severe anemia, and B-cell and natural killer cell deficiency in the peripheral blood, and was diagnosed with bone marrow failure."
    explanation: NK-cell deficiency.
- category: Immunologic
  name: T Lymphocytopenia
  description: >-
    Present in some patients. Low T-cell receptor excision circles in one
    neonate triggered an abnormal newborn SCID screen.
  phenotype_term:
    preferred_term: T lymphocytopenia
    term:
      id: HP:0005403
      label: Decreased total T cell count
  evidence:
  - reference: PMID:26220525
    reference_title: "An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe a patient presenting with a complete lack of B lymphocytes, T-cell lymphopenia, defective hematopoiesis, and developmental abnormalities."
    explanation: T-cell lymphopenia in the Le Guen patient.
  - reference: PMID:38065233
    reference_title: "MYSM1 attenuates DNA damage signals triggered by physiologic and genotoxic DNA breaks."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic testing in a newborn with abnormal screen for severe combined immune deficiency, T-cell lymphopenia, and near absence of B cells identified a novel splice variant in MYSM1 that results in nearly absent protein expression."
    explanation: T-cell lymphopenia detected by newborn screening.
- category: Immunologic
  name: Hypogammaglobulinemia
  phenotype_term:
    preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:40535318
    reference_title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biallelic MYSM1 variants are linked to rare bone marrow failure syndromes, presenting with cytopenia, B-cell deficiency, hypogammaglobulinemia, and developmental abnormalities."
    explanation: Hypogammaglobulinaemia as part of the syndrome.
- category: Immunologic
  name: Immunodeficiency
  description: >-
    Infections reported include respiratory infections and, in one patient with
    MDS/AML, fungal lung infection, perianal abscess and necrotising fasciitis.
  phenotype_term:
    preferred_term: Immunodeficiency
    term:
      id: HP:0002721
      label: Immunodeficiency
  evidence:
  - reference: PMID:26220525
    reference_title: "An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We here define a novel human immunodeficiency and provide evidence that MYSM1 is essential for proper immunohematopoietic development in human subjects."
    explanation: Defines MYSM1 deficiency as an immunodeficiency.
  - reference: ORPHA:508542
    reference_title: "Congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Immunodeficiency primarily affects B-cells and may lead to increased susceptibility to infections."
    explanation: Orphanet definition.
- category: Immunologic
  name: Increased Sensitivity to Ionizing Radiation
  phenotype_term:
    preferred_term: Increased sensitivity to ionizing radiation
    term:
      id: HP:0011133
      label: Increased sensitivity to ionizing radiation
  evidence:
  - reference: PMID:38065233
    reference_title: "MYSM1 attenuates DNA damage signals triggered by physiologic and genotoxic DNA breaks."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with deleterious variants in MYSM1 have an immune deficiency characterized by B-cell lymphopenia, hypogammaglobulinemia, and increased radiosensitivity."
    explanation: Radiosensitivity is part of the described immunophenotype.
    quote_role: BACKGROUND
    directness: INDIRECT
  description: Reported as an assay-level feature in the clinical literature. The newborn study directly measured persistent DNA-damage signaling, while the 2017 patient-cell experiments emphasized UV and genotoxic stress; these findings are not a quantified estimate of clinical radiotherapy toxicity.
- category: Neoplastic
  name: Myelodysplasia
  description: >-
    Myelodysplastic features were present at presentation in one sibling pair
    and developed at 10 to 12 years in the Saudi series; one child developed
    neutrophilic panniculitis with myelodysplasia.
  phenotype_term:
    preferred_term: Myelodysplasia
    term:
      id: HP:0002863
      label: Myelodysplasia
  evidence:
  - reference: PMID:28115216
    reference_title: "Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report 2 patients with progressive BMF associated with myelodysplastic features, immunodeficiency affecting B cells and neutrophil granulocytes, and complex developmental aberrations, including mild skeletal anomalies, neurocognitive developmental delay, and cataracts."
    explanation: Myelodysplastic features with progressive marrow failure.
  - reference: PMID:40535318
    reference_title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report four cases of MYSM1 mutations progressing from marrow failure to MDS or AML within 9-10 years."
    explanation: Progression to MDS in the Saudi series.
- category: Neoplastic
  name: Acute Myeloid Leukemia
  description: >-
    Reported in one boy with monosomy 7, at 12 years; he died of septic shock
    after induction chemotherapy.
  phenotype_term:
    preferred_term: Acute myeloid leukemia
    term:
      id: HP:0004808
      label: Acute myeloid leukemia
  evidence:
  - reference: PMID:40535318
    reference_title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "3 months later he transformed to AML, BM biopsy was hypercellular marrow up to 100% with 73% myeloblast"
    explanation: A single case of AML transformation.
- category: Dermatologic
  name: Neutrophilic Panniculitis
  description: Reported in a single child with MYSM1 deficiency and myelodysplasia.
  phenotype_term:
    preferred_term: Neutrophilic panniculitis
    term:
      id: HP:0012490
      label: Panniculitis
  evidence:
  - reference: PMID:30746751
    reference_title: "Neutrophilic Panniculitis in a child with MYSM1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a case of NP associated with myelodysplasia in a child with MYSM1 deficiency, a newly described syndrome with primary immunodeficiency (PI), bone marrow failure, and developmental aberrations."
    explanation: Single case report.
- category: Neurologic
  name: Global Developmental Delay
  description: >-
    Developmental delay varies across patients. The 2017 siblings had reduced cerebral volume on imaging, while
    the 2021 infant had white-matter changes and a subependymal cyst. These findings do not establish a uniform
    neurodegenerative course.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:28115216
    reference_title: "Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report 2 patients with progressive BMF associated with myelodysplastic features, immunodeficiency affecting B cells and neutrophil granulocytes, and complex developmental aberrations, including mild skeletal anomalies, neurocognitive developmental delay, and cataracts."
    explanation: Neurocognitive developmental delay in both siblings.
  - reference: PMID:32641579
    reference_title: "MYSM1 maintains ribosomal protein gene expression in hematopoietic stem cells to prevent hematopoietic dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A mild retardation of motor development was diagnosed at the age of 7 months."
    explanation: Motor delay in infancy in another patient.
  - reference: PMID:35295078
    reference_title: Syndromes predisposing to leukemia are a major cause of inherited cytopenias in children.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The patient with a MYSM1 homozygous variant had early onset pancytopenia, with a hypocellular marrow and a paucity of red cell precursors and mild developmental delay and short stature.
    explanation: Primary 2022 Israeli inherited-cytopenia cohort; MYSM1 patient findings, not other cohort diagnoses.
- category: Growth
  name: Short Stature
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: ORPHA:508542
    reference_title: "Congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "non-hematologic manifestations, such as developmental delay, cataracts, facial dysmorphism, short stature, and skeletal anomalies"
    explanation: Orphanet definition.
  - reference: PMID:40535318
    reference_title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Non hematological abnormalities, such as developmental delay, short stature, facial dysmorphy, and microcephaly have been described in patients with MYSM1 mutation."
    explanation: Literature summary of non-haematological features.
  - reference: PMID:35295078
    reference_title: Syndromes predisposing to leukemia are a major cause of inherited cytopenias in children.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The patient with a MYSM1 homozygous variant had early onset pancytopenia, with a hypocellular marrow and a paucity of red cell precursors and mild developmental delay and short stature.
    explanation: Primary 2022 Israeli inherited-cytopenia cohort; MYSM1 patient findings, not other cohort diagnoses.
- category: Neurologic
  name: Microcephaly
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:40535318
    reference_title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Non hematological abnormalities, such as developmental delay, short stature, facial dysmorphy, and microcephaly have been described in patients with MYSM1 mutation."
    explanation: Microcephaly among reported features.
- category: Craniofacial
  name: Facial Dysmorphism
  phenotype_term:
    preferred_term: Facial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:40535318
    reference_title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Non hematological abnormalities, such as developmental delay, short stature, facial dysmorphy, and microcephaly have been described in patients with MYSM1 mutation."
    explanation: Facial dysmorphism among reported features.
- category: Ophthalmologic
  name: Cataract
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:28115216
    reference_title: "Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report 2 patients with progressive BMF associated with myelodysplastic features, immunodeficiency affecting B cells and neutrophil granulocytes, and complex developmental aberrations, including mild skeletal anomalies, neurocognitive developmental delay, and cataracts."
    explanation: The abstract lists cataracts among the siblings’ combined findings; the full clinical text assigns them to the girl.
  description: Bilateral cataracts were documented in the 2017 girl; they were not reported in both siblings.
- category: Skeletal
  name: Brachydactyly
  description: >-
    Short fingers were described in the 2017 boy and the 2020 Turkish infant; rhizomelic arm shortening is
    recorded separately.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:32641579
    reference_title: "MYSM1 maintains ribosomal protein gene expression in hematopoietic stem cells to prevent hematopoietic dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Discrete dysmorphic features were present, including midface hypoplasia, brachydactyly"
    explanation: Single-patient report.
- category: Craniofacial
  name: Midface Hypoplasia
  phenotype_term:
    preferred_term: Midface hypoplasia
    term:
      id: HP:0011800
      label: Midface retrusion
  evidence:
  - reference: PMID:32641579
    reference_title: "MYSM1 maintains ribosomal protein gene expression in hematopoietic stem cells to prevent hematopoietic dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Discrete dysmorphic features were present, including midface hypoplasia, brachydactyly"
    explanation: Single-patient report.
- category: Skeletal
  name: Preaxial Hand Polydactyly
  phenotype_term:
    preferred_term: Preaxial hand polydactyly
    term:
      id: HP:0001177
      label: Preaxial hand polydactyly
  evidence:
  - reference: PMID:33858043
    reference_title: "[A novel compound heterozygous mutation in MYSM1 gene in a 1-month-old girl: a bone marrow failure syndrome 4 family survey and literature review]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The girl presented with pancytopenia, polydactylism, nonspecific white matter changes, and cysts."
    explanation: Single-patient report.
  - reference: PMID:33858043
    reference_title: '[A novel compound heterozygous mutation in MYSM1 gene in a 1-month-old girl: a bone marrow failure syndrome 4 family survey and literature review].'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The girl presented with pancytopenia, polydactylism, nonspecific white matter changes, and cysts. ... 右手大拇指外有一指，呈蒂状连接，可见指甲。
    explanation: The primary Chinese case text localizes the anomaly to the right thumb.
  description: The 2021 infant had an extra right thumb; this is a single-case observation.
- category: Otologic
  name: Hearing Impairment
  description: >-
    Bilateral deafness, with microcephaly and choanal atresia, is attributed to
    the Le Guen patient in a 2025 review table; Orphanet also lists hearing
    loss. The originating report's abstract does not itemise these features.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: ORPHA:508542
    reference_title: "Congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Additional reported features include dry skin and eczema, cardiac anomalies, hearing loss, and reduction of cerebral volume on brain imaging."
    explanation: Orphanet definition.
  - reference: PMID:40535318
    reference_title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microcephaly, choanal atresia, bilateral deafness"
    explanation: Review-table entry for a single patient.
- category: Respiratory
  name: Choanal Atresia
  description: Single patient, from a secondary review table.
  phenotype_term:
    preferred_term: Choanal atresia
    term:
      id: HP:0000453
      label: Choanal atresia
  evidence:
  - reference: PMID:40535318
    reference_title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microcephaly, choanal atresia, bilateral deafness"
    explanation: Review-table entry for a single patient.
- category: Dermatologic
  name: Eczema
  description: >-
    Listed by Orphanet with dry skin; no primary report of this feature was
    found among the cached sources.
  phenotype_term:
    preferred_term: Eczema
    term:
      id: HP:0000964
      label: Eczematoid dermatitis
  evidence:
  - reference: ORPHA:508542
    reference_title: "Congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Additional reported features include dry skin and eczema, cardiac anomalies, hearing loss, and reduction of cerebral volume on brain imaging."
    explanation: Orphanet definition.
- category: Laboratory
  name: Elevated Erythrocyte Adenosine Deaminase
  description: >-
    Measured in one patient. It is the laboratory feature that makes the
    disease easy to mistake for Diamond-Blackfan anaemia.
  phenotype_term:
    preferred_term: Elevated erythrocyte adenosine deaminase
    term:
      id: HP:0030270
      label: Elevated red cell adenosine deaminase activity
  evidence:
  - reference: PMID:32641579
    reference_title: "MYSM1 maintains ribosomal protein gene expression in hematopoietic stem cells to prevent hematopoietic dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient also had significantly elevated erythrocyte adenosine deaminase"
    explanation: Single-patient measurement.
- name: Left Ventricular Noncompaction Cardiomyopathy
  category: Cardiovascular
  description: The 2017 boy had noncompaction cardiomyopathy with left ventricular dilatation and reduced fractional shortening.
  phenotype_term:
    preferred_term: Left ventricular noncompaction cardiomyopathy
    term:
      id: HP:0011664
      label: Left ventricular noncompaction cardiomyopathy
  evidence:
  - reference: url:https://push-zb.helmholtz-munich.de/deliver.php?id=19850
    reference_title: "https://push-zb.helmholtz-munich.de/deliver.php?id=19850"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Cardiomegaly, left ... ventricle dilatation, ... reduced FS 16-20%, ... noncompaction ... cardiomyopathy
    explanation: 'Accepted manuscript of "Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations." (PMID:28115216). Direct case observation; no disease-wide frequency is inferred.'
- name: Osteopenia
  category: Skeletal
  description: Osteopenia was described in the 2017 girl, alongside a short left humerus and metacarpal abnormalities.
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: url:https://push-zb.helmholtz-munich.de/deliver.php?id=19850
    reference_title: "https://push-zb.helmholtz-munich.de/deliver.php?id=19850"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: short left humerus, ... brachymetacarpia D1 ... left and broad ... metacarpia D1 left, ... osteopenia
    explanation: 'Accepted manuscript of "Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations." (PMID:28115216). Direct case observation; no disease-wide frequency is inferred.'
- name: Rhizomelic Arm Shortening
  category: Skeletal
  description: Proximal arm shortening was reported in the 2017 boy and the 2020 infant.
  phenotype_term:
    preferred_term: Rhizomelic arm shortening
    term:
      id: HP:0004991
      label: Rhizomelic arm shortening
  evidence:
  - reference: PMID:32641579
    reference_title: MYSM1 maintains ribosomal protein gene expression in hematopoietic stem cells to prevent hematopoietic dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: brachydactyly, and rhizomelic shortening of arms
    explanation: Direct case observation; no disease-wide frequency is inferred.
- name: Gingival Overgrowth
  category: Dental
  description: Gingival hyperplasia was described in both 2017 siblings.
  phenotype_term:
    preferred_term: Gingival overgrowth
    term:
      id: HP:0000212
      label: Gingival overgrowth
  evidence:
  - reference: url:https://push-zb.helmholtz-munich.de/deliver.php?id=19850
    reference_title: "https://push-zb.helmholtz-munich.de/deliver.php?id=19850"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: trigonocephaly, midface hypoplasia, gingiva hyperplasia
    explanation: 'Accepted manuscript of "Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations." (PMID:28115216). Direct case observation; no disease-wide frequency is inferred.'
- name: Delayed Tooth Eruption
  category: Dental
  description: Delayed dentition was described in the 2017 boy.
  phenotype_term:
    preferred_term: Delayed eruption of teeth
    term:
      id: HP:0000684
      label: Delayed eruption of teeth
  evidence:
  - reference: url:https://push-zb.helmholtz-munich.de/deliver.php?id=19850
    reference_title: "https://push-zb.helmholtz-munich.de/deliver.php?id=19850"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Dental/mouth Gingiva hyperplasia Gingiva hyperplasia, delayed dentition
    explanation: 'Accepted manuscript of "Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations." (PMID:28115216). Direct case observation; no disease-wide frequency is inferred.'
- name: Trigonocephaly
  category: Craniofacial
  description: Trigonocephaly was described in the 2017 girl.
  phenotype_term:
    preferred_term: Trigonocephaly
    term:
      id: HP:0000243
      label: Trigonocephaly
  evidence:
  - reference: url:https://push-zb.helmholtz-munich.de/deliver.php?id=19850
    reference_title: "https://push-zb.helmholtz-munich.de/deliver.php?id=19850"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: trigonocephaly, midface hypoplasia, gingiva hyperplasia
    explanation: 'Accepted manuscript of "Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations." (PMID:28115216). Direct case observation; no disease-wide frequency is inferred.'
- name: Cerebral White Matter Hyperintensity
  category: Neurologic
  description: The 2021 infant had bilateral parietal subcortical white-matter T2 abnormalities. Clinical significance and longitudinal evolution were unresolved.
  phenotype_term:
    preferred_term: Hyperintensity of cerebral white matter on MRI
    term:
      id: HP:0030890
      label: Hyperintensity of cerebral white matter on MRI
  evidence:
  - reference: PMID:33858043
    reference_title: '[A novel compound heterozygous mutation in MYSM1 gene in a 1-month-old girl: a bone marrow failure syndrome 4 family survey and literature review].'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The girl presented with pancytopenia, polydactylism, nonspecific white matter changes, and cysts. ... 双侧顶叶皮质层下白质T2信号增强
    explanation: Direct case observation; no disease-wide frequency is inferred.
- name: Monocytopenia
  category: Hematologic
  description: Monocytopenia developed over time in the 2020 p.Ser290* infant.
  phenotype_term:
    preferred_term: Decreased total monocyte count
    term:
      id: HP:0012312
      label: Decreased total monocyte count
  evidence:
  - reference: PMID:32641579
    reference_title: MYSM1 maintains ribosomal protein gene expression in hematopoietic stem cells to prevent hematopoietic dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: and monocytopenia developed over time
    explanation: Direct case observation; no disease-wide frequency is inferred.
- name: Distal Renal Tubular Acidosis
  category: Renal
  description: Reported before transplantation in one patient with MDS; it resolved after HSCT. A general MYSM1-specific renal mechanism is not established.
  phenotype_term:
    preferred_term: Distal renal tubular acidosis
    term:
      id: HP:0008341
      label: Distal renal tubular acidosis
  evidence:
  - reference: PMID:40535318
    reference_title: 'Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: her pre-transplant distal renal tubular acidosis with severe hypokalemia resolved following HSCT
    explanation: Direct case observation; no disease-wide frequency is inferred.
- name: Hypokalemia
  category: Metabolic
  description: Severe hypokalemia accompanied distal renal tubular acidosis in one patient before HSCT.
  phenotype_term:
    preferred_term: Hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
  evidence:
  - reference: PMID:40535318
    reference_title: 'Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: her pre-transplant distal renal tubular acidosis with severe hypokalemia resolved following HSCT
    explanation: Direct case observation; no disease-wide frequency is inferred.
- name: Subependymal Cyst
  category: Neurologic
  description: A cyst adjacent to the anterior horn of the left lateral ventricle was reported in the 2021 infant. This single-case finding is not established as a specific marker of MYSM1 deficiency.
  phenotype_term:
    preferred_term: Subependymal cysts
    term:
      id: HP:0002416
      label: Subependymal cysts
  evidence:
  - reference: PMID:33858043
    reference_title: '[A novel compound heterozygous mutation in MYSM1 gene in a 1-month-old girl: a bone marrow failure syndrome 4 family survey and literature review].'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The girl presented with pancytopenia, polydactylism, nonspecific white matter changes, and cysts. ... 左侧脑室前角旁室管膜下囊肿
    explanation: The primary Chinese text localizes the cyst.
genetic:
- name: MYSM1
  gene_term:
    preferred_term: MYSM1
    term:
      id: hgnc:29401
      label: MYSM1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    MYSM1 (Myb-like, SWIRM and MPN domains 1; 1p32.1) encodes a nuclear JAMM/MPN
    metalloprotease that deubiquitinates histone H2A at K119 and acts as a
    transcriptional co-activator of haematopoietic and ribosomal-protein genes.
    Disease alleles are biallelic and loss-of-function.
  evidence:
  - reference: PMID:32640305
    reference_title: "Further delineation of bone marrow failure syndrome caused by novel compound heterozygous variants of MYSM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biallelic variants in MYSM1 cause a rare bone marrow failure syndrome (OMIM #618116)."
    explanation: Gene-disease relationship.
  - reference: PMID:28115216
    reference_title: "Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing revealed a homozygous premature stop codon mutation in the gene encoding MYSM1."
    explanation: Independent family with a truncating allele.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_ee22e44c-4239-47f4-b971-c8b5012b8a1c-2024-06-07T170000.000Z
    evidence:
    - reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ee22e44c-4239-47f4-b971-c8b5012b8a1c-2024-06-07T170000.000Z
      reference_title: curation results for Gene-Disease Validity
      supports: SUPPORT
      evidence_source: OTHER
      directness: DIRECT
      quote_role: REVIEW_SYNTHESIS
      snippet: In summary, there is definitive evidence supporting the relationship between MYSM1 and autosomal recessive bone marrow failure.
      explanation: ClinGen SCID-CID GCEP approved this classification on June 7, 2024; the canonical assertion page is cached as a URL.
animal_models:
- name: Mysm1-deficient mouse
  species: Mouse
  genotype: Mysm1 knockout (Mysm1-/-) and gene-trap (Mysm1 tm1a/tm1a)
  publication: PMID:22184403
  description: >-
    Several independent Mysm1-deficient lines reproduce HSC dysfunction,
    lymphopenia with an early B-cell block, anaemia and developmental defects;
    double knockouts with p53 or Puma dissect the downstream pathway.
  modeled_mechanisms:
  - target: p53 Activation in Hematopoietic Stem and Progenitor Cells
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Raised p53 in haematopoietic cells, with genetic rescue by p53 deletion.
    limitations: >-
      Mice develop thrombocytosis where patients have normal or mildly low
      platelets, and the p53-rescue experiments have no human counterpart; p53
      target programmes differ between mouse and human.
    evidence:
    - reference: PMID:25710881
      reference_title: "p53 mediates loss of hematopoietic stem cell function and lymphopenia in Mysm1 deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mysm1(-/-)p53(-/-) mouse characterization showed a full rescue of Mysm1(-/-) developmental and hematopoietic defects."
      explanation: The genetic rescue that places p53 at the centre of the model.
  - target: Block in Early B-Cell Development
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Early B-cell commitment block matching the near-absent B cells of patients.
    evidence:
    - reference: PMID:22169041
      reference_title: "Control of B cell development by the histone H2A deubiquitinase MYSM1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "MYSM1 deficiency results in a block in early B cell commitment and a defect of B cell progenitors in expression of EBF1 and other B lymphoid genes."
      explanation: The B-cell block in knockout mice.
    limitations: Early B-cell depletion is reproduced, but antibody production and platelet phenotypes differ from patients, and the exact developmental block has not been localized in all patient samples.
- name: Catalytically inactive Mysm1 D660N mouse
  species: Mouse
  genotype: Mysm1D660N/D660N and inducible Mysm1fl/D660N CreERT2
  description: Catalytic inactivation retains MYSM1 protein and reproduces many developmental and hematopoietic knockout defects. HSC counts vary; MPP4 depletion is consistent. This study did not identify the downstream substrate for every phenotype.
  publication: PMID:36611064
  evidence:
  - reference: PMID:36611064
    reference_title: Deubiquitinase catalytic activity of MYSM1 is essential in vivo for hematopoiesis and immune cell development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: similar levels of MYSM1 protein in Mysm1DN/DN and control Mysm1+/+ bone marrow cells
    explanation: Catalytic deficiency is distinguished from loss of protein.
  modeled_mechanisms:
  - target: Loss of Histone H2A K119 Deubiquitinase Activity
    relationship: PERTURBS
    description: Catalytic inactivation demonstrates a requirement for MYSM1 DUB function; individual substrates are not resolved.
    evidence:
    - reference: PMID:36611064
      reference_title: Deubiquitinase catalytic activity of MYSM1 is essential in vivo for hematopoiesis and immune cell development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: similar levels of MYSM1 protein in Mysm1DN/DN and control Mysm1+/+ bone marrow cells
      explanation: Catalytic deficiency is distinguished from loss of protein.
- name: MYSM1-edited human HSC xenograft
  species: Mouse
  background: NBSGW
  description: Edited cord-blood CD34+ HSPCs have impaired engraftment. Liproxstatin-1 was applied to cells before transplantation and administered to recipient mice at 20 mg/kg intraperitoneally every other day, starting one week after transplantation for twelve weeks. Engraftment was nearly completely rescued; this is not evidence of patient treatment benefit.
  publication: PMID:36803603
  evidence:
  - reference: PMID:36803603
    reference_title: Human hematopoietic stem cell vulnerability to ferroptosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Mice treated with liproxstatin-1 showed significantly improved engraftment of MYSM1-deficient human HSPCs across all time points surveyed
    explanation: Human-to-mouse engraftment rescue following cell pretreatment plus systemic treatment.
  modeled_mechanisms:
  - target: Ferroptosis of Hematopoietic Stem Cells
    relationship: RECAPITULATES
    description: Measures engraftment of engineered human cells in a mouse host.
    evidence:
    - reference: PMID:36803603
      reference_title: Human hematopoietic stem cell vulnerability to ferroptosis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Mice treated with liproxstatin-1 showed significantly improved engraftment of MYSM1-deficient human HSPCs across all time points surveyed
      explanation: Human-to-mouse engraftment rescue following cell pretreatment plus systemic treatment.
- name: Neural-stem-cell Mysm1 conditional mouse
  species: Mouse
  genotype: Nestin-Cre Mysm1 conditional knockout
  description: Brain growth and neural-stem-cell homeostasis model with altered neuronal/astroglial differentiation and niche-specific stem-cell depletion. Baseline apoptosis is not uniformly increased.
  publication: PMID:38342917
  evidence:
  - reference: PMID:38342917
    reference_title: Deubiquitinase Mysm1 regulates neural stem cell proliferation and differentiation by controlling Id4 expression.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: the number of Dcx+ cells in the DG of Mysm1 cKO mice was significantly increased at 6 and 9 weeks ... the average optical density of Gfap in the DG of Mysm1 cKO mice decreased at 6 and 9 weeks
    explanation: Conditional neural model; direct human neural confirmation remains absent.
  modeled_mechanisms:
  - target: Neural Stem Cell Differentiation Imbalance
    relationship: RECAPITULATES
    description: Measures neural-lineage consequences in a conditional mouse model.
    evidence:
    - reference: PMID:38342917
      reference_title: Deubiquitinase Mysm1 regulates neural stem cell proliferation and differentiation by controlling Id4 expression.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: the number of Dcx+ cells in the DG of Mysm1 cKO mice was significantly increased at 6 and 9 weeks ... the average optical density of Gfap in the DG of Mysm1 cKO mice decreased at 6 and 9 weeks
      explanation: Conditional neural model; direct human neural confirmation remains absent.
- name: Mysm1 meander-tail mouse
  species: Mouse
  genotype: Mysm1 Y34X, R659G and engineered D32Efs*13 alleles
  description: A 2026 preprint identifies classical meander-tail alleles as Mysm1 variants by mapping and noncomplementation with engineered alleles. Mutants have preferential anterior cerebellar hypoplasia and reduced granule-cell-precursor proportions at E14.5. Early truncations retain function through translation reinitiation or alternative splicing. This model does not establish cerebellar hypoplasia as a human BMFS4 phenotype.
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC13160082/
    reference_title: Mysm1 mutations in meander tail mice cause anterior-selective cerebellum malformation - PMC
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: the proportion of GCPs was selectively reduced in mutants across four littermate pairs
    explanation: Full text of the 2026 preprint PPR:PPR1222230; developmental mouse finding, not an observed patient phenotype.
  modeled_mechanisms:
  - target: Biallelic MYSM1 Loss of Function
    relationship: PERTURBS
    description: Allelic complementation supports Mysm1 causality; cerebellar findings have no established human counterpart.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC13160082/
      reference_title: Mysm1 mutations in meander tail mice cause anterior-selective cerebellum malformation - PMC
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: New endonuclease-mediated ... alleles failed to complement ... variants as the causal mutations for both the vertebral malformation and the anterior cerebellum defect.
      explanation: The 2026 preprint PPR:PPR1222230 reports noncomplementation between engineered Mysm1 and meander-tail alleles. Ellipses bridge gene-name markup in the cached full text. This is mouse allelic evidence, not confirmation of a human cerebellar phenotype.
experimental_models:
- name: MYSM1-deficient human hematopoietic stem cells
  description: >-
    Engineered human MYSM1 deficiency reduces ribosomal-protein expression and translation, lowers ferroptosis-protective
    proteins and promotes lipid-peroxidative HSC death. Ferroptosis inhibitors rescue maintenance without restoring
    translation. These cells are not primary cells from an affected patient.
  experimental_model_type: PRIMARY_CELL_CULTURE
  publication: PMID:36803603
  modeled_mechanisms:
  - target: Ferroptosis of Hematopoietic Stem Cells
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Reproduces selective HSC loss and its rescue by ferroptosis blockade.
    limitations: >-
      Engineered loss in donor HSCs rather than patient cells, assayed outside
      a human marrow.
    evidence:
    - reference: PMID:36803603
      reference_title: "Human hematopoietic stem cell vulnerability to ferroptosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "HSC maintenance can be fully rescued by blocking ferroptosis, despite no alteration in protein synthesis rates."
      explanation: The model's key rescue result.
  cell_source: CRISPR-edited healthy-donor mobilized or cord-blood CD34+ hematopoietic stem/progenitor cells
- name: Patient fibroblasts and EBV-transformed lymphoblasts
  experimental_model_type: OTHER
  cell_source: Primary fibroblasts and EBV-transformed B-cell lines from the two p.Glu390* siblings
  description: Patient-derived systems show absent full-length MYSM1, prolonged UV-induced gamma-H2AX/p38 signaling and impaired proliferation or stress tolerance. These differ from the later ABL-pre-B and U2OS DNA-repair assays.
  publication: PMID:28115216
  evidence:
  - reference: PMID:28115216
    reference_title: 'Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: MYSM1-deficient cells are characterized by increased sensitivity to genotoxic stress associated with sustained induction of phosphorylated p38 protein
    explanation: Patient-derived functional assays.
  modeled_mechanisms:
  - target: Prolonged DNA Damage Response Signaling
    relationship: RECAPITULATES
    description: Measures UV/genotoxic stress responses in patient-derived cell systems.
    evidence:
    - reference: PMID:28115216
      reference_title: 'Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: MYSM1-deficient cells are characterized by increased sensitivity to genotoxic stress associated with sustained induction of phosphorylated p38 protein
      explanation: Patient-derived functional assays.
treatments:
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >-
    Allogeneic HSCT has restored hematopoiesis and immune function in reported children, including matched-family
    and haploidentical transplants. The 2017 siblings received fludarabine, treosulfan and alemtuzumab, with
    two-year donor engraftment. Other cases have shorter or longer follow-up and reported acute or chronic
    GVHD; the 2017 girl developed post-transplant Graves disease. Conditioning and timing require individual
    assessment of marrow disease and toxicity. Cell-assay sensitivity and analogies with other marrow-failure
    syndromes do not establish a universal ban on alkylators, which were used in successful transplants. Correction
    of all developmental features is not demonstrated.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: allogeneic hematopoietic stem cell transplantation
    term:
      id: NCIT:C46089
      label: Allogeneic Hematopoietic Stem Cell Transplantation
  target_mechanisms:
  - target: Impaired Hematopoietic Stem Cell Function
    description: Replaces the defective HSC compartment with donor HSCs.
    treatment_effect: RESTORES
  evidence:
  - reference: PMID:28115216
    reference_title: "Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients were successfully treated with allogeneic HSCT with sustained reconstitution of hematopoietic defects."
    explanation: Sustained reconstitution in a sibling pair.
  - reference: PMID:34302415
    reference_title: "Successful allogeneic stem cell transplantation with fludarabine-based reduced intensity conditioning in bone marrow failure syndrome 4."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fludarabine-based reduced intensity conditioning was used and resulted in full donor chimerism."
    explanation: Reduced-intensity conditioning with full donor chimerism.
  - reference: PMID:34302415
    reference_title: "Successful allogeneic stem cell transplantation with fludarabine-based reduced intensity conditioning in bone marrow failure syndrome 4."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She achieved B-cell recovery, and no blood or platelet transfusion was reported 1 year after HSCT."
    explanation: Haematological and B-cell recovery after transplant.
  - reference: PMID:40535318
    reference_title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hematopoietic stem cell transplantation achieved remission in two patients with adverse cytogenetics."
    explanation: Transplant after myeloid transformation.
  - reference: PMID:40535318
    reference_title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "achieved full chimerism but developed chronic GVHD affecting the eyes and lungs"
    explanation: Transplant morbidity in one patient transplanted after transformation.
  - reference: PMID:38065233
    reference_title: "MYSM1 attenuates DNA damage signals triggered by physiologic and genotoxic DNA breaks."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "highlight need for caution in treatment approaches, because patients will be more sensitive to the chemotherapies used for stem cell transplant"
    explanation: >-
      The conditioning caution follows from the DNA-damage-response defect
      measured in cells; it is an inference, not a transplant outcome.
    directness: INDIRECT
- name: Red Blood Cell Transfusion
  description: >-
    Supportive care for transfusion-dependent anaemia in infancy and again at
    relapse, often needed before transplant.
  treatment_term:
    preferred_term: packed red blood cell transfusion
    term:
      id: NCIT:C15409
      label: Packed Red Blood Cell Transfusion
  target_mechanisms:
  - target: Anemia
    description: Corrects the anaemia without affecting the marrow defect.
  evidence:
  - reference: PMID:40535318
    reference_title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our patients initially were transfusion dependent during infancy, then showed spontaneous improvement until age 9-10 years; they became transfusion depended, which may indicate clonal evolution as showed in our patients."
    explanation: Transfusion dependence in infancy and at relapse.
- name: Antibiotic Prophylaxis
  description: Antibiotic prophylaxis was reported while awaiting transplant. The 2017 siblings received co-trimoxazole after early respiratory infections; regimens and indications were individualized.
  treatment_term:
    preferred_term: antibiotic prophylaxis
    term:
      id: NCIT:C51993
      label: Antibiotic Prophylaxis
    therapeutic_agent:
    - preferred_term: co-trimoxazole
      term:
        id: CHEBI:3770
        label: co-trimoxazole
  target_mechanisms:
  - target: Immunodeficiency
    description: Reduces infection risk without correcting the immune defect.
  evidence:
  - reference: PMID:32641579
    reference_title: "MYSM1 maintains ribosomal protein gene expression in hematopoietic stem cells to prevent hematopoietic dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patient had repetitive need for transfusions, was given antibiotic prophylaxis"
    explanation: Single-patient supportive care.
  - reference: url:https://push-zb.helmholtz-munich.de/deliver.php?id=19850
    reference_title: "https://push-zb.helmholtz-munich.de/deliver.php?id=19850"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: intravenous antibiotics, and maintained on co-trimoxazole pro- ... phylaxis thereafter.
    explanation: 'Accepted manuscript of "Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations." (PMID:28115216). Reports subsequent co-trimoxazole prophylaxis.'
  therapeutic_modality: SMALL_MOLECULE
- name: Captopril for Cardiomyopathy
  description: Captopril was reported for the 2017 boy’s cardiomyopathy. The post-transplant course was favorable, but the report cannot isolate the effect of captopril or show correction of MYSM1 disease.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: captopril
      term:
        id: CHEBI:3380
        label: captopril
  evidence:
  - reference: url:https://push-zb.helmholtz-munich.de/deliver.php?id=19850
    reference_title: "https://push-zb.helmholtz-munich.de/deliver.php?id=19850"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: In patient IV-2 car- ... diomyopathy, which is currently treated with captopril
    explanation: 'Accepted manuscript of "Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations." (PMID:28115216). Actual reported treatment, without comparative efficacy data.'
- name: Genetic Counseling and Family Testing
  description: Establish parental segregation and offer family testing. If both parents carry a pathogenic allele, the Mendelian recurrence probability is one in four per pregnancy. The reported paternal uniparental-disomy case requires separate counseling; the two-carrier assumption does not apply automatically.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:32641579
    reference_title: MYSM1 maintains ribosomal protein gene expression in hematopoietic stem cells to prevent hematopoietic dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Genetic counseling took place at the age of 10 weeks
    explanation: Counseling was documented; the recurrence fraction follows recessive inheritance when both parents are carriers.
  - reference: PMID:38065233
    reference_title: MYSM1 attenuates DNA damage signals triggered by physiologic and genotoxic DNA breaks.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: due to paternal uniparental disomy of chromosome 1
    explanation: This exceptional origin changes the parental-genotype assumptions used for recurrence counseling.
- name: Reported Eltrombopag Use
  description: Eltrombopag was started in one transfusion-dependent adolescent with hypocellular marrow, dysplasia and a TP53 mutation while haploidentical HSCT was being considered. The report provides no response assessment, so benefit in BMFS4 is undetermined.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: eltrombopag
      term:
        id: CHEBI:85010
        label: eltrombopag
  evidence:
  - reference: PMID:40535318
    reference_title: 'Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: He is currently receiving PRBC transfusions every 2-3 weeks and has been started on eltrombopag.
    explanation: Actual drug exposure in one case; no treatment response was reported.
diagnosis:
- name: Newborn Screening for Severe Combined Immunodeficiency
  description: >-
    One neonate was ascertained through an abnormal newborn SCID screen (low
    T-cell receptor excision circles) before any anaemia, so MYSM1 deficiency
    belongs on the differential for a positive SCID screen with near-absent B
    cells.
  diagnosis_term:
    preferred_term: Newborn Screening
    term:
      id: NCIT:C81178
      label: Newborn Screening
  evidence:
  - reference: PMID:38065233
    reference_title: "MYSM1 attenuates DNA damage signals triggered by physiologic and genotoxic DNA breaks."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "T-cell receptor excision circle testing was low at 1010 copies per 106 CD3+ cells (normal >6794)."
    explanation: Low TREC count on newborn screening in an affected neonate.
- name: Exome Sequencing
  description: >-
    Diagnosis in every reported case was molecular, by homozygosity mapping or
    exome sequencing, sometimes after an initial diagnosis of Diamond-Blackfan
    anaemia. RNA studies are worth doing for splice-region and synonymous
    variants: a synonymous variant at the end of exon 6 caused exon skipping.
  diagnosis_term:
    preferred_term: Whole Exome Sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:32640305
    reference_title: "Further delineation of bone marrow failure syndrome caused by novel compound heterozygous variants of MYSM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this is the first report of a synonymous splicing variant that induces post-transcriptional skipping of exon 6 leading to a bone marrow failure syndrome phenotype"
    explanation: A synonymous variant that is pathogenic through splicing.
  - reference: PMID:40535318
    reference_title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two of our cases missed diagnosed with DBA initially"
    explanation: Initial misdiagnosis as Diamond-Blackfan anaemia before exome sequencing.
- name: Bone Marrow Biopsy and Cytogenetic Surveillance
  description: >-
    Establishes hypocellularity at diagnosis. Given progression to MDS and AML
    with monosomy 7, TP53 mutation and other acquired lesions at 10 to 12 years
    in one series, the authors recommend careful follow-up for clonal
    evolution. No surveillance interval has been published.
  diagnosis_term:
    preferred_term: Bone marrow biopsy
    term:
      id: NCIT:C15193
      label: Bone Marrow Biopsy
  evidence:
  - reference: PMID:40535318
    reference_title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, patients with MYSM1 mutation required careful follow up to detect any clonal evaluation."
    explanation: The authors' surveillance recommendation (the source writes "evaluation" where "evolution" is meant).
differential_diagnoses:
- name: Diamond-Blackfan anemia
  disease_term:
    preferred_term: Diamond-Blackfan anemia
    term:
      id: MONDO:0015253
      label: Diamond-Blackfan anemia
  description: >-
    The main clinical mimic: transfusion-dependent anaemia from infancy, a
    raised erythrocyte adenosine deaminase in at least one MYSM1 patient, and a
    shared ribosomal-stress/p53 mechanism. A MYSM1 loss-of-function allele was
    found in an individual with a clinical diagnosis of DBA in a large exome
    study.
  distinguishing_features:
  - B-cell and NK-cell lymphopenia with hypogammaglobulinaemia
  - Leukopenia or neutropenia and multilineage marrow hypocellularity rather than isolated erythroid aplasia
  - Biallelic MYSM1 variants rather than a heterozygous ribosomal-protein gene variant
  evidence:
  - reference: PMID:30503522
    reference_title: "The Genetic Landscape of Diamond-Blackfan Anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In another individual, we observed a novel recessive LoF mutation in MYSM1"
    explanation: A MYSM1 case within a clinically diagnosed DBA cohort.
  - reference: PMID:40535318
    reference_title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two of our cases missed diagnosed with DBA initially"
    explanation: Misdiagnosis as DBA in practice.
- name: Fanconi anemia
  disease_term:
    preferred_term: Fanconi anemia
    term:
      id: MONDO:0019391
      label: Fanconi anemia
  description: >-
    Shares childhood marrow failure, developmental anomalies, genotoxic
    hypersensitivity, progression to MDS/AML and the need for reduced-intensity
    conditioning; the reporting groups apply Fanconi anaemia conditioning
    experience to MYSM1 deficiency.
  distinguishing_features:
  - Crosslinker-induced chromosomal breakage testing is the Fanconi anaemia discriminator
  - Profound B-cell lymphopenia is characteristic of MYSM1 deficiency
  evidence:
  - reference: PMID:40535318
    reference_title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Like IBMFS, MYSM1 individuals with mutations bear a high sensitivity to genotoxic stress due to their defective DNA damage response pathways."
    explanation: The shared genotoxic-sensitivity phenotype that motivates the comparison.
mechanistic_hypotheses:
- hypothesis_group_id: mysm1_ribosomal_stress_p53
  hypothesis_label: MYSM1 deficiency as a ribosomal-stress, p53-activating marrow failure
  status: EMERGING
  description: >-
    MYSM1 loss reduces ribosomal-protein gene expression and translation. Mouse genetics support a p53-mediated
    hematopoietic-stress pathway, while edited human HSCs identify a ferroptosis pathway with reduced antioxidant
    and iron-handling proteins. The relationship between these pathways in patients remains unresolved. Direct
    clinical support for translation/p53 involvement comes from blood-cell assays in one child; neither ferroptosis
    inhibition nor p53 inhibition has established clinical benefit.
discussions:
- discussion_id: bmfs4_myeloid_risk
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Clonal Evolution to Myelodysplasia and Leukemia
  prompt: >-
    What is the cumulative risk of MDS/AML in MYSM1 deficiency, and what
    surveillance should a child who has improved spontaneously have?
  rationale: >-
    The 2025 series documents four progressions from two families, including follow-up of previously reported
    siblings. Overlapping case ascertainment, early transplantation and somatic rescue prevent estimation of
    cumulative malignancy risk or an evidence-based surveillance interval.
  evidence:
  - reference: PMID:40535318
    reference_title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report four cases of MYSM1 mutations progressing from marrow failure to MDS or AML within 9-10 years."
    explanation: The only series documenting progression.
- discussion_id: bmfs4_mouse_platelet_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Hematopoietic Stem Cell Function
  - phenotypes#Thrombocytopenia
  prompt: >-
    Why do Mysm1-deficient mice develop thrombocytosis while patients have
    normal or mildly low platelet counts?
  rationale: >-
    The mouse reproduces the anaemia, lymphopenia and HSC failure, but the
    megakaryocyte lineage moves the opposite way. Either MYSM1 has a
    species-specific role in megakaryopoiesis, or the mouse thrombocytosis is a
    compensatory response absent in humans. Until that is understood, the
    mouse cannot be used to predict platelet-lineage behaviour.
  evidence:
  - reference: PMID:22184403
    reference_title: "The critical role of histone H2A-deubiquitinase Mysm1 in hematopoiesis and lymphocyte differentiation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we characterized an H2A-DUB targeted mouse line Mysm1(tm1a/tm1a) and demonstrated defects in BM hematopoiesis, resulting in lymphopenia, anemia, and thrombocytosis."
    explanation: Thrombocytosis in the mouse.
  - reference: PMID:32640305
    reference_title: "Further delineation of bone marrow failure syndrome caused by novel compound heterozygous variants of MYSM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe a Chinese female patient who mainly presented with leukopenia, granulocytopenia, thrombocytopenia, severe anemia, and B-cell and natural killer cell deficiency in the peripheral blood, and was diagnosed with bone marrow failure."
    explanation: Thrombocytopenia in a patient.
- discussion_id: mysm1_antibody_model_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - phenotypes#Hypogammaglobulinemia
  - pathophysiology#Block in Early B-Cell Development
  prompt: Why can Mysm1-deficient mice retain antibody responses despite the human antibody-deficiency phenotype?
  rationale: The mature mouse B-cell/Pax5 study shows enhanced plasma-cell differentiation and normal or higher serum Ig despite B-cell depletion. This contrasts with hypogammaglobulinemia in affected patients and prevents a simple extrapolation from B-cell number to antibody output.
  evidence:
  - reference: PMID:26348977
    reference_title: Epigenetic Regulation of Antibody Responses by the Histone H2A Deubiquitinase MYSM1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: the serum concentrations of IgM and IgG isotypes were normal or even higher in Mysm1−/− mice
    explanation: Direct mouse evidence of the discordance.
- discussion_id: mysm1_substrate_specificity
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced Ribosomal Protein Gene Expression
  - pathophysiology#Prolonged DNA Damage Response Signaling
  prompt: Which MYSM1 substrates mediate ribosomal-protein regulation and termination of DNA-damage signaling?
  rationale: Catalytic necessity is established in a mouse model, but RP promoters do not accumulate detectable H2AK119ub after knockdown, and the DDR study did not establish its proposed H2AK15 substrate. A single histone-mark route is therefore unsupported.
  evidence:
  - reference: PMID:32641579
    reference_title: MYSM1 maintains ribosomal protein gene expression in hematopoietic stem cells to prevent hematopoietic dysfunction.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: No significant increase in H2AK119ub levels was seen in the Mysm1-knockdown Ba/F3 cells
    explanation: Direct negative result at the tested RP promoters.
- discussion_id: mysm1_ferroptosis_translation
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Ferroptosis of Hematopoietic Stem Cells
  prompt: Does ferroptosis inhibition restore patient hematopoiesis safely and durably?
  rationale: Rescue is demonstrated in engineered healthy-donor HSCs and xenografts; clinical efficacy, delivery, long-term clonal consequences and its relationship to the p53 pathway remain unresolved.
  evidence:
  - reference: PMID:36803603
    reference_title: Human hematopoietic stem cell vulnerability to ferroptosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: A near complete rescue was observed in the bone marrow, spleen, and across all lineages
    explanation: Preclinical engraftment result, not clinical response.
- discussion_id: mysm1_neural_translation
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Neural Stem Cell Differentiation Imbalance
  prompt: Which neural mechanisms account for developmental findings in human MYSM1 deficiency?
  rationale: Global knockout, neural-specific knockout and meander-tail mice reveal different apoptosis, fate-balance and cerebellar findings. The latter is a preprint. Patient neural tissue and a direct human cerebellar counterpart are lacking.
  evidence:
  - reference: PMID:38342917
    reference_title: Deubiquitinase Mysm1 regulates neural stem cell proliferation and differentiation by controlling Id4 expression.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Mysm1-deficient NSCs skewed toward neurogenesis instead of astrogliogenesis
    explanation: The study includes conditional mice and neural cultures; this differentiation finding is supported by its culture assays and does not establish a patient neural mechanism.
references:
- reference: PMID:24288411
  title: "MYSM1 is mutated in a family with transient transfusion-dependent anemia, mild thrombocytopenia, and low NK- and B-cell counts."
- reference: PMID:26220525
  title: "An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation."
- reference: PMID:28115216
  title: "Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations."
- reference: PMID:40535318
  title: "Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature."
- reference: PMID:39233474
  title: "Long-term assessment of haematological recovery following somatic genetic rescue in a MYSM1-deficient patient: Implications for in vivo gene therapy."
- reference: url:https://push-zb.helmholtz-munich.de/deliver.php?id=19850
  title: https://push-zb.helmholtz-munich.de/deliver.php?id=19850
- reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ee22e44c-4239-47f4-b971-c8b5012b8a1c-2024-06-07T170000.000Z
  title: curation results for Gene-Disease Validity
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC13160082/
  title: Mysm1 mutations in meander tail mice cause anterior-selective cerebellum malformation - PMC
- reference: PMID:36803603
  title: Human hematopoietic stem cell vulnerability to ferroptosis.
- reference: PMID:38342917
  title: Deubiquitinase Mysm1 regulates neural stem cell proliferation and differentiation by controlling Id4 expression.
- reference: PMID:36611064
  title: Deubiquitinase catalytic activity of MYSM1 is essential in vivo for hematopoiesis and immune cell development.
- reference: PMID:41608114
  title: 'Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee.'
- reference: PMID:26348977
  title: Epigenetic Regulation of Antibody Responses by the Histone H2A Deubiquitinase MYSM1.

📚

References & Deep Research

References

PMID:24288411

MYSM1 is mutated in a family with transient transfusion-dependent anemia, mild thrombocytopenia, and low NK- and B-cell counts.

No top-level findings curated for this source.

PMID:26220525

An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation.

No top-level findings curated for this source.

PMID:28115216

Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations.

No top-level findings curated for this source.

PMID:40535318

Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature.

No top-level findings curated for this source.

PMID:39233474

Long-term assessment of haematological recovery following somatic genetic rescue in a MYSM1-deficient patient: Implications for in vivo gene therapy.

No top-level findings curated for this source.

url:https://push-zb.helmholtz-munich.de/deliver.php?id=19850

https://push-zb.helmholtz-munich.de/deliver.php?id=19850

No top-level findings curated for this source.

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ee22e44c-4239-47f4-b971-c8b5012b8a1c-2024-06-07T170000.000Z

curation results for Gene-Disease Validity

No top-level findings curated for this source.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC13160082/

Mysm1 mutations in meander tail mice cause anterior-selective cerebellum malformation - PMC

No top-level findings curated for this source.

PMID:36803603

Human hematopoietic stem cell vulnerability to ferroptosis.

No top-level findings curated for this source.

PMID:38342917

Deubiquitinase Mysm1 regulates neural stem cell proliferation and differentiation by controlling Id4 expression.

No top-level findings curated for this source.

PMID:36611064

Deubiquitinase catalytic activity of MYSM1 is essential in vivo for hematopoiesis and immune cell development.

No top-level findings curated for this source.

PMID:41608114

Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee.

No top-level findings curated for this source.

PMID:26348977

Epigenetic Regulation of Antibody Responses by the Histone H2A Deubiquitinase MYSM1.

No top-level findings curated for this source.

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Add claude_code deep-research report; minor evidence additions · 2026-09-23T15:18:28Z · View source

Added the deep-research report that now backs this entry: research/Bone_Marrow_Failure_Syndrome_4-deep-research-claude_code.md with its .citations.md. It was produced by `just dr_fallback='--fallback-provider claude_code' research-disorder falcon Bone_Marrow_Failure_Syndrome_4`; falcon returned HTTP 402 (out of credits) and claude_code produced the report, as recorded in its frontmatter (requested_provider falcon, fell_back true). The run's inline term validation timed out against OLS, so both validation sections were added afterwards with `just validate-research-reference` and `just validate-research-terms`. Reference validation: 21/21 references resolved, 0 unresolved, 1/1 quoted claim found, 15 on topic, 0 off topic. Term validation: 59 terms, 0 unresolved, 3 obsolete GO terms (GO:0035522, GO:0016578, GO:0006977), 3 named as a different term (HP:0002846 offered for a B-cell count where HPO says Abnormal B cell morphology; the other two are parsing artefacts on MONDO:0020856 and HP:0000518), and HP:0000268 flagged for review because the report calls it trigonocephaly where HPO says dolichocephaly; none of these were bound. `just preflight-dr ... MONDO:0020856` returned PASS (MYSM1 mentioned 72 times; report OMIM 618116, plus 616738 only in the report's own note that MECOM-related RUSAT2 is a different disease). Why the earlier report was discarded: the first run (falcon -> openscientist fallback) produced a report about MECOM-associated syndrome under the BMFS4 name; preflight-dr returned FAIL (MYSM1 0 mentions, MECOM 42, OMIM 165215), so it was not committed, as recorded in the CREATE record. The report was used as a lead only. Two changes resulted, each checked against the cached primary source: an evidence item and description sentence on chronic GVHD of the eyes and lungs after haploidentical HSCT (PMID:40535318, exact snippet), and a notes sentence recording two MYSM1 letters without abstracts (PMID:38129711, an adult patient; PMID:35902396, a transplant report) that were not curated because their content cannot be quoted. The report's other leads were not adopted: trigonocephaly, gingival hyperplasia, delayed dentition and cardiac failure had no primary source in the cache, and its Pax5 B-lineage claim misreads PMID:26348977, which concerns plasma-cell differentiation. Validation after the change: validate, validate-terms, count-verified-snippets (107/107), check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, list-gene-term-mismatches, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens, check-environmental-evidence, check-coarse-phenotypes, check-reference-titles and validate-disorders all pass.

Create: Bone_Marrow_Failure_Syndrome_4 · 2026-09-23T14:52:59Z · View source

Created the BMFS4 / MYSM1 deficiency entry (MONDO:0020856, OMIM 618116) from primary literature. Lump/split: MONDO carries a second class for the same disease, MONDO:0033683 (imported from Orphanet ORPHA:508542, "congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome", synonym MYSM1 deficiency). The Orphanet record maps ORPHA:508542 Exact to both OMIM:618116 and MONDO:0033683, so the two MONDO classes were lumped into this one entry, with MONDO:0033683 recorded under mappings.mondo_mappings as skos:exactMatch. No subtypes. This apparent MONDO duplicate is worth raising upstream. Deep research: exactly one run, `just dr_fallback='--fallback' research-disorder falcon Bone_Marrow_Failure_Syndrome_4`. Falcon returned HTTP 402 (account out of credits); the fallback produced an openscientist report. That report was about the wrong disease: `just preflight-dr` returned FAIL (MYSM1 mentioned 0 times, MECOM 42 times; report OMIM 165215 vs MONDO OMIM 618116). The report described MECOM-associated syndrome / radioulnar synostosis with amegakaryocytic thrombocytopenia, calling it BMFS4. Per the preflight rule it was discarded in full and not committed; nothing in the entry comes from it. No second deep-research run was made. Content: 12 pathophysiology nodes from biallelic MYSM1 loss of function through loss of H2A K119 deubiquitinase activity, reduced ribosomal-protein gene expression and protein synthesis in HSCs, p53 activation (mouse genetics), ferroptosis of human HSCs, HSC exhaustion, early B-cell block, impaired NK maturation, prolonged DNA damage response signalling, p53-mediated developmental apoptosis (mouse), somatic genetic rescue by reversion in an HSC (one patient, stable 12 years), and clonal evolution to MDS/AML (2025 Saudi series). Model-organism evidence is graded MODEL_ORGANISM and kept distinct from human evidence in node descriptions. 27 phenotypes (no frequency bands; about a dozen published patients), AR inheritance including one paternal UPD1 case, HSCT/transfusion/antibiotic-prophylaxis treatments, newborn SCID screening, exome sequencing and marrow surveillance as diagnostics, DBA and Fanconi anaemia differentials, a KNOWLEDGE_GAP on myeloid risk and a HUMAN_MODEL_MISMATCH on mouse thrombocytosis versus human thrombocytopenia. Structured sources: ORPHA:508542 cached via the structured-source rebuild and cited for Orphanet-only features. No GeneReviews chapter (`just check-genereviews --online`: NO_CHAPTER). No ClinGen validity assertion found. IUIS: MYSM1 not found in the cached text of PMID:35748970, PMID:41608113 or PMID:41608114, but those caches lack the tables, so iuis_category was left unset. Gaps: the founding Alsultan 2013 Blood letter (PMID:24288411) has no abstract and carries no quoted evidence. Rhizomelic arm shortening (PMID:32641579) is not curated as a phenotype because the cached text hyphenates the word across a line break. Orphanet-only features (eczema, hearing loss) lack a quotable primary source. Cataract, facial dysmorphism, polydactyly, choanal atresia, panniculitis and elevated eADA are left causally unconnected because no source links them to a mechanism node. Validation: just validate, validate-terms, count-verified-snippets (106/106), check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, list-gene-term-mismatches, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens, check-environmental-evidence, check-coarse-phenotypes, check-reference-titles and validate-disorders all pass.

Claude Code ▸

Bone Marrow Failure Syndrome 4 (MYSM1 Deficiency) — Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 26 citations 2026-09-23T15:07:21.629501

Bone Marrow Failure Syndrome 4 (MYSM1 Deficiency) — Comprehensive Research Report

1. Disease Information

Overview. Bone Marrow Failure Syndrome 4 (BMFS4) is an ultra-rare, autosomal recessive inherited bone marrow failure syndrome (IBMFS) caused by biallelic loss-of-function variants in MYSM1. It combines early-onset, progressive, often initially transient/fluctuating bone marrow failure (anemia, leukopenia/neutropenia, mild thrombocytopenia, myelodysplastic marrow features) with a B-cell– and NK-cell–predominant immunodeficiency and a constellation of non-hematologic developmental anomalies (skeletal dysplasia, cataracts, facial dysmorphism, short stature, cerebral hypoplasia/neurodevelopmental delay). It was first reported in 2013 as an apparently novel IBMFS in a consanguineous Saudi family (Alsultan et al., Blood 2013;122:3844–3845, PMID:24288411), and clinically delineated as a distinct syndrome by Bahrami et al. in 2017.

Key identifiers: - MONDO: MONDO:0020856 — label "bone marrow failure syndrome 4"; xrefs OMIM:618116, GARD:0025264, MedGen:C4748257/1648485 (confirmed via OLS lookup) - OMIM: #618116 BONE MARROW FAILURE SYNDROME 4; BMFS4 (phenotype), caused by variants in MYSM1 (612176) - Orphanet: ORPHA:508542 — "Congenital progressive bone marrow failure–B-cell immunodeficiency–skeletal dysplasia syndrome" — autosomal recessive, neonatal onset, prevalence <1/1,000,000 - GARD: 0025264 / GARD disease page 22071 (same synonym as Orphanet) - Gene: MYSM1, HGNC:29401, NCBI Gene 114803, chromosome 1p32.1 (GRCh38: 1:58,654,743–58,700,062); mouse ortholog Mysm1, MGI:2444584 - ICD-10/11:* No dedicated code identified; would fall under D61.0-series (constitutional aplastic anemia) / QA-type rare-disease codes generically

Synonyms: BMFS4; MYSM1 deficiency; MYSM1-related bone marrow failure syndrome; Congenital progressive bone marrow failure, B-cell immunodeficiency, skeletal dysplasia syndrome.

Evidence basis: The disease-level evidence base is overwhelmingly aggregated case-report and small-case-series literature (individual patients and consanguineous sibships, largely of Middle Eastern/consanguineous ancestry) rather than large cohort registries — fewer than ~20–25 molecularly confirmed patients have been published to date across all reports, consistent with Orphanet's "<1/1,000,000" prevalence class and OMIM's description of "only three pathogenic variants... reported in nine patients" as of the 2020 Li et al. report (PMID:32640305), a number that has since grown modestly with additional case reports through 2025.

2. Etiology

Disease causal factor: BMFS4 is a monogenic, purely genetic disease — biallelic (homozygous or compound heterozygous) loss-of-function variants in MYSM1 (encoding the histone H2A deubiquitinase MYSM1/2A-DUB). No environmental, infectious, or purely mechanistic non-genetic cause is described; the disorder is congenital and the causal lesion is present from conception.

Genetic risk factors: - Biallelic MYSM1 variants are necessary and sufficient. Reported classes: nonsense/premature-stop (p.E390, p.R478, p.Y489), missense (p.H656R, disrupting the JAMM/MPN catalytic domain), and a cryptic synonymous splice variant (c.399G>A, p.L133L) shown experimentally to cause exon 6 skipping and a frameshift/premature stop (Li et al. 2020, PMID:32640305: "the c.399G>A variant leads to exon 6 skipping, resulting in a premature termination codon (c.321_399del, p.V108Lfs13)"; the trans allele c.1467C>G, p.Y489 "triggered nonsense-mediated mRNA degradation"). - Consanguinity is a strong enabling risk factor for exposing this rare recessive allele — nearly every published pedigree (Saudi Arabian, other Arab, Chinese with parental consanguinity noted in several reports) involves consanguineous unions, consistent with an autosomal recessive, population-founder-type distribution rather than a pan-ethnic common disease. - No modifier genes have been formally established in humans; in mice, genetic interaction with Trp53 (p53) is the dominant modifier axis (see Mechanism, below) — Belle et al. 2015 (PMID:25710881) showed Mysm1⁻/⁻p53⁻/⁻ double-knockout mice have "full rescue of Mysm1⁻/⁻ developmental and hematopoietic defects... including restoration of lymphopoiesis, and HSC numbers and functions", formally implicating p53 hyperactivation as the proximate driver of the hematopoietic phenotype — a strong candidate modifier axis for human disease severity, though not yet tested clinically. - Population genetics: gnomAD data indicate MYSM1 is not* constrained for heterozygous loss-of-function (pLI ≈ 0.09, LOEUF ≈ 0.58), consistent with a purely recessive human disease mechanism and with carrier heterozygotes being clinically unaffected (as in the original Alsultan family, where heterozygous parents were unaffected carriers).

Environmental risk/gene-environment factors: None established as disease-causal. However, MYSM1-deficient cells show heightened DNA-damage/genotoxic stress sensitivity (Bahrami et al. 2017, PMID:28115216: affected cells showed "heightened vulnerability to DNA-damaging agents, sustained p38 activation, elevated oxidative stress, and diminished survival following UV exposure"), which is mechanistically relevant to treatment planning (radiosensitivity should be considered in conditioning-regimen and radiologic-exposure decisions) rather than to primary disease causation.

Protective factors: None specifically described. Loss of p53 function is protective against the hematopoietic phenotype in the mouse model (see above) but this is a laboratory finding, not a clinical protective factor (and constitutive p53 loss would itself predispose to malignancy, which is directly relevant given the documented TP53-mutant clonal evolution in human BMFS4, see §8/§11 below).

3. Phenotypes

Frequencies below are qualitative (derived from aggregated small case series; formal Orphanet HPO-frequency annotation was not accessible during this research pass, so frequencies are described narratively rather than as precise percentages except where a source states them).

Hematologic (laboratory abnormalities — very frequent, near-universal)

Anemia, often severe, transfusion-dependent, presenting in infancy (as early as 1 month to ~15 months of age); HP:0001903 Anemia. Onset: neonatal–infantile. Course: can show a striking pattern of transfusion dependence for years followed by spontaneous partial recovery, then later relapse/progression (PMC12176283: Case 1 "remained transfusion-dependent till the age of 10 years, followed by a phase of spontaneous recovery").
Leukopenia/neutropenia — HP:0001882/HP:0001875.
Mild-to-moderate thrombocytopenia — HP:0001873 (typically milder than the anemia/neutropenia, distinguishing it somewhat from classic amegakaryocytic thrombocytopenia syndromes).
Bone marrow hypocellularity with myelodysplastic features — HP:0005528 (Bone marrow hypocellularity), dysplastic erythroid and myeloid precursors; marrow cellularity as low as 5–20% reported (PMC12176283).
Pancytopenia develops over time in a substantial fraction of patients.
Some patients are initially misdiagnosed as Diamond-Blackfan anemia (macrocytic, erythroid-predominant marrow failure) before the immunologic/skeletal/genetic picture clarifies the diagnosis (PMC12176283, Cases 3–4).

Immunologic (very frequent)

B-cell deficiency/lymphopenia — HP:0010976 (Decreased circulating total B cell count).
Hypogammaglobulinemia and impaired antibody response to vaccination — HP:0004313 (Decreased circulating antibody level), HP:0002846 (Abnormal B cell count is a coarse fallback if antibody-response term unavailable).
NK-cell deficiency/dysfunction — reported in multiple cases (e.g., Li et al. 2020, PMID:32640305, describes "B-cell and natural killer cell deficiency in the peripheral blood").
Recurrent infections, especially upper respiratory tract infections in early childhood, often manageable with prophylactic antibiotics — HP:0002205/HP:0011947.

Skeletal/craniofacial (frequent)

Short stature — HP:0004322.
Rhizomelic shortening of the arms / short humerus — HP:0008843/related UBERON:humerus-associated HPO terms.
Brachydactyly / short metacarpals / short fingers — HP:0009826, HP:0010049.
Thoracic asymmetry, trigonocephaly — HP:0000268 (Trigonocephaly).
Midface hypoplasia/retrusion, coarse facial features, low-set ears — HP:0011800 / HP:0000278 / HP:0000369.
Gingival hyperplasia and delayed dentition — HP:0000212 / HP:0000696.

Ophthalmologic

Cataracts — HP:0000518 (frequent, reported across multiple case series, e.g., Bahrami et al. 2017).

Neurologic/developmental

Neurodevelopmental delay/intellectual disability — HP:0012758/HP:0001249.
Decreased cerebral volume on brain imaging (cerebral hypoplasia) — HP:0006872-adjacent (Reduced cerebral cortical volume) or HP:0002119 (Ventriculomegaly)-type imaging findings; GARD lists "cerebral hypoplasia" explicitly.
Sensorineural hearing loss reported.

Dermatologic

Dry skin and eczema — HP:0000958 (Dry skin), HP:0000964 (Eczema).

Cardiac/renal

Cardiac anomalies including congestive heart failure reported in some patients; renal anomalies mentioned in some syndromic descriptions (less consistently reported than the core hematologic/immunologic/skeletal triad).

Severity/progression pattern

Bahrami et al. (PMID:28115216) summarize the core syndrome as: "progressive bone marrow failure associated with myelodysplastic features, immunodeficiency affecting B cells and neutrophil granulocytes, and complex developmental aberrations" — establishing progression (not static severity) and multi-system involvement as defining features. Expressivity is variable: a 2024 report (Sakovich et al., J Clin Immunol, describing an adult patient with a novel MYSM1 variant) documents a milder, later-recognized adult phenotype, indicating a broader clinical spectrum than the classic severe pediatric presentation.

Quality-of-life impact: Not formally measured with validated instruments (EQ-5D/SF-36) in the literature reviewed; qualitatively, chronic transfusion dependence, recurrent infection, developmental delay, and eventual HSCT (with its own morbidity, e.g., GVHD) constitute substantial disease burden, particularly given transformation risk to myeloid malignancy in later childhood/adolescence (see §11).

4. Genetic/Molecular Information

Causal gene: MYSM1 (Myb-like, SWIRM and MPN domains 1), HGNC:29401, OMIM *612176, chromosome 1p32.1, NCBI Gene ID 114803.

Protein: 828-amino-acid nuclear (and, as recently characterized, also cytosolic-pool) chromatin-binding transcriptional cofactor/deubiquitinase. Domain architecture (per multiple reviews, e.g., Belle et al./Fiore et al. 2020, Int J Mol Sci, PMID:32344625): - SWIRM domain — compact helix-turn-helix-related fold (5 α-helices), structurally similar to yeast Swi3, implicated in chromatin binding. - SANT domain — structurally similar to the c-MYB DNA-binding domain; binds DNA in vitro. - JAMM/MPN metalloprotease domain — the catalytic domain; a Zn²⁺-dependent JAMM-motif (consensus EXnHSHX₇SX₂D) isopeptidase that hydrolyzes ubiquitin-chain isopeptide bonds; the residue Asp567 within this domain is required for catalytic (deubiquitinase) activity toward histone H2A.

Reported pathogenic variant classes (all biallelic; no dominant/heterozygous disease reported): | Variant | Type | Report | |---|---|---| | p.E390 | Nonsense | Original/early cohort (cited across multiple papers, e.g., PMID:32640305) | | p.R478 | Nonsense | Original/early cohort | | p.H656R | Missense (JAMM domain) | Original/early cohort | | p.Y489 | Nonsense (compound het.) | Li et al. 2020, PMID:32640305 | | c.399G>A (p.L133L), synonymous, causes exon 6 skipping → p.V108Lfs13 | Cryptic splice | Li et al. 2020, PMID:32640305 — "first report of a synonymous splicing variant that induces post-transcriptional skipping of exon 6" | | Homozygous premature stop codon | Nonsense | Bahrami et al. 2017, PMID:28115216 (two siblings) | | Additional compound-heterozygous variants | Various | Huang et al. 2021 (PMID:33858043, Chinese infant), Zhan et al. 2021 (PMID:33618624) |

As of 2020, OMIM/Li et al. state that "only three pathogenic variants (E390, R478, and H656R) of MYSM1 have been reported in nine patients, and all variants are homozygous" — the mutational spectrum has since expanded with compound-heterozygous and splice-altering alleles, indicating the variant catalog remains small and incompletely characterized (few if any entries in ClinVar with robust multi-submitter classification; formal ACMG/AMP tiering not systematically published for most alleles beyond the original case reports).

Functional consequence: All reported alleles are loss-of-function (null or catalytically dead), consistent with a simple LOF/haploinsufficiency-is-not-sufficient (i.e., strictly biallelic-LOF-required) disease mechanism — heterozygous carriers (parents) are unaffected in every reported pedigree, and population data (gnomAD pLI ≈ 0.09) support tolerance of monoallelic loss.

Somatic vs. germline: The primary disease-causing variants are germline. However, secondary somatic clonal evolution is a well-documented late feature: Haroon et al. 2025 (PMID:40535318) report acquired somatic CALR p.(P228S) (VAF 50%), monosomy 5q (EGR1 loss), TP53 mutation, monosomy 7, and trisomy 8 arising during transformation to MDS/AML in BMFS4 patients — i.e., BMFS4 marrow is itself a pre-leukemic clonal-evolution substrate, analogous to other IBMFS (Fanconi anemia, Shwachman-Diamond syndrome, SAMD9/SAMD9L disorders).

Modifier genes: No confirmed human modifiers; Trp53 is the dominant genetic modifier identified in the mouse model (Belle et al. 2015, PMID:25710881).

Epigenetic information: MYSM1 is itself a direct epigenetic regulator — it deubiquitinates monoubiquitinated histone H2A at Lys119 (H2AK119ub, GO:0033558 protein deubiquitination / more specifically histone H2A deubiquitination), a repressive chromatin mark; loss of MYSM1 catalytic activity is predicted to cause aberrant retention of H2AK119ub and dysregulated gene expression at MYSM1 target loci, including ribosomal protein genes (Belle et al. 2020, PMID:32641579) and the NK-lineage gene Id2 (Nandakumar et al. 2013, PMID:24062447) and the B-lineage gene Pax5 (Jiang et al. 2015, Sci Rep, PMC4562257).

Chromosomal abnormalities: None reported as a primary/germline disease mechanism for BMFS4 (this is a point-mutation/small-indel disease, not a microdeletion/CNV syndrome); acquired chromosomal abnormalities (monosomy 5, monosomy 7, trisomy 8) occur secondarily as leukemic clonal evolution (see above and §11).

5. Environmental Information

No primary environmental, toxin, occupational, or lifestyle causal factors are described for BMFS4 — it is a fully penetrant monogenic recessive disorder present from birth. The one environment-adjacent mechanistic finding is cellular genotoxic/oxidative stress hypersensitivity: Bahrami et al. (PMID:28115216) demonstrated that MYSM1-deficient patient cells show "heightened vulnerability to DNA-damaging agents, sustained p38 activation, elevated oxidative stress, and diminished survival following UV exposure." This has practical (not etiologic) relevance: it argues for minimizing unnecessary genotoxic exposures (radiation, certain chemotherapeutics) in affected patients and for reduced-intensity/radiation-sparing conditioning in transplant, rather than implicating environmental exposure in disease causation.

No infectious trigger or agent is implicated in BMFS4 onset; recurrent infections in affected children are a consequence of the immunodeficiency (B-cell/NK-cell/neutrophil defects), not a cause of the marrow failure.

6. Mechanism / Pathophysiology

Causal chain (ordered, with inference flags)

Biallelic loss-of-function MYSM1 variant (germline, nonsense/missense/cryptic-splice) → loss or inactivation of MYSM1 histone H2A deubiquitinase catalytic activity. (Demonstrated directly — human genetics + in vitro functional studies, e.g., PMID:32640305.)
Loss of MYSM1 deubiquitinase activity leads to failure to remove repressive H2AK119ub marks at target chromatin loci, resulting in dysregulated (reduced) expression of a specific target-gene program, most notably ribosomal protein (RP) genes in hematopoietic stem cells (Belle et al. 2020, PMID:32641579: MYSM1 "maintains ribosomal protein gene expression in hematopoietic stem cells"), and lineage-specific transcription factors including Id2 (NK lineage, PMID:24062447) and Pax5 (B lineage, PMC4562257). (Demonstrated in mouse models; human tissue confirmation is indirect/inferred from phenotypic concordance.)
Reduced ribosomal protein gene expression leads to a ribosomopathy-like state — impaired ribosome biogenesis/protein synthesis in hematopoietic stem and progenitor cells (HSPCs) — directly analogous mechanistically to Diamond-Blackfan anemia and other ribosomopathies, explaining the clinical overlap/misdiagnosis with DBA noted in case series (PMC12176283). (Demonstrated in the mouse model; RP-gene dysregulation shown to be a direct, p53-independent consequence of Mysm1 loss.)
Ribosomal stress/RP-gene dysregulation, together with direct genotoxic/oxidative stress vulnerability of MYSM1-deficient cells, results in activation and elevation of p53 protein across multiple hematopoietic cell types (Belle et al. 2015, PMID:25710881). (Demonstrated — Mysm1⁻/⁻p53⁻/⁻ double-knockout rescue experiment is direct causal evidence in mice.)
Chronic p53 activation leads to impaired hematopoietic stem cell (HSC) self-renewal/function, increased HSC apoptosis and cell-cycle arrest, and results in progressive loss of long-term repopulating HSC capacity. (Demonstrated in mice — full rescue of HSC numbers/function upon p53 co-deletion; human confirmation is inferential from the clinical phenotype of progressive marrow failure.)
Failing HSC output, superimposed on lineage-specific transcriptional defects (reduced Pax5 in B-lineage, reduced Id2/impaired NFIL3 recruitment in NK-lineage), leads to the clinical triad of (a) progressive cytopenias/bone marrow failure with myelodysplastic features, (b) B-cell lymphopenia/hypogammaglobulinemia and NK-cell maturation arrest (immunodeficiency), and (c) — via MYSM1's broader roles in non-hematopoietic tissue differentiation (chromatin regulation is not hematopoiesis-restricted) — the extra-hematopoietic developmental phenotype (skeletal dysplasia, cataracts, craniofacial dysmorphism, cerebral hypoplasia). (The hematologic/immunologic arms are mechanistically well supported; the specific chromatin targets responsible for the skeletal/ocular/craniofacial phenotype are not yet characterized — this link is inferred from MYSM1's role as a general chromatin regulator rather than demonstrated at the target-gene level, and should be flagged as a knowledge gap.)
Persistent replicative/genotoxic stress on a chronically failing, dysplastic marrow leads to, over years (documented range ~9–12 years from initial presentation), acquisition of secondary somatic driver mutations (TP53, CALR) and cytogenetic clonal evolution (monosomy 5/EGR1 loss, monosomy 7, trisomy 8), resulting in transformation to myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML) (Haroon et al. 2025, PMID:40535318). (Demonstrated clinically — documented clonal cytogenetic/molecular evolution in a case series; the mechanistic bridge from chronic p53-mediated HSC stress to clonal selection for TP53-mutant escape clones is inferred by analogy to other bone-marrow-failure-to-leukemia trajectories, e.g., Fanconi anemia and SAMD9/9L disorders, rather than directly proven in BMFS4.)

Branch: innate-immune/cytosolic function

In parallel to its nuclear chromatin role, a cytosolic pool of MYSM1 has been characterized as a negative regulator of innate immune signal transduction, promoting deubiquitination of TRAF3, TRAF6, and RIP2 to dampen pattern-recognition-receptor (PRR) signaling (summarized in Fiore/Belle et al. 2020, PMID:32344625). This branch is mechanistically distinct from the hematopoietic/chromatin arm and may contribute to the infection susceptibility phenotype independently of the B/NK-cell lymphopenia, though its direct contribution to human BMFS4 clinical features has not been isolated from the adaptive-immunodeficiency component.

Molecular pathways / processes (suggested ontology terms)

GO:0035522 monoubiquitinated histone H2A deubiquitination (or the general parent GO:0016578 histone deubiquitination) — core MYSM1 catalytic activity
GO:0140853 — (histone H2A deubiquitination-related terms; confirm exact GO ID at curation time via OAK lookup rather than from memory)
GO:0002244 hematopoietic progenitor cell differentiation; GO:0030099 myeloid cell differentiation; GO:0030183 B cell differentiation; GO:0001779 natural killer cell differentiation
GO:0006417 regulation of translation / ribosome biogenesis pathway genes (RP-gene program)
GO:0006977 DNA damage response, signal transduction by p53 class mediator (p53 pathway activation)
GO:0045087 innate immune response (TRAF3/TRAF6/RIP2 axis)

Cell types (Cell Ontology, CL)

CL:0000037 hematopoietic stem cell (primary affected population; site of the p53/ribosomopathy mechanism)
CL:0000816 immature B cell / CL:0000236 B cell (B lymphopoiesis defect)
CL:0000623 natural killer cell (maturation arrest — Id2/NFIL3 axis)
CL:0000771 eosinophil / CL:0000775 neutrophil (neutropenia)
CL:0000037-derived myeloid and erythroid progenitors (dysplastic precursors on marrow biopsy)

(All GO/CL term suggestions should be verified against the current ontology build before binding, per standard curation practice — several exact GO child-term IDs for "histone H2A deubiquitination" specifically were not independently confirmed via OAK in this research pass.)

Molecular profiling

No large-scale human transcriptomic, proteomic, or single-cell datasets specific to BMFS4 patient tissue were identified in this search; the transcriptomic/epigenomic evidence base is almost entirely derived from Mysm1-knockout mouse hematopoietic tissue (RNA-seq of RP-gene programs, ChIP-based chromatin studies at Id2 and Pax5 loci). This is a knowledge gap — no GEO/ArrayExpress series specific to human BMFS4 patient bone marrow was located.

7. Anatomical Structures Affected

Organ level (primary): - Bone marrow (UBERON:0002371) — primary site of pathology (hypocellularity, dysplasia). - Immune system — spleen/lymphoid tissue (secondary, via B/NK lymphopenia), thymus (T-cell development largely spared per most reports, distinguishing from combined immunodeficiencies).

Organ level (secondary/syndromic): - Skeletal system — long bones (rhizomelic humeral shortening), hands (brachydactyly/short metacarpals), skull (trigonocephaly), craniofacial skeleton (midface hypoplasia). - Eye — lens (cataracts, UBERON:0000965). - Ear — cochlea/inner ear (sensorineural hearing loss). - Skin — epidermis (dry skin/eczema). - Central nervous system — cerebral cortex/cerebrum (reduced cerebral volume, developmental delay). - Cardiovascular system — heart (congestive heart failure reported in some patients). - Oral cavity — gingiva/teeth (gingival hyperplasia, delayed dentition).

Tissue/cell level: Hematopoietic stem and progenitor cell compartment of bone marrow stroma/parenchyma; B-lymphocyte and NK-lymphocyte lineages; chondrocyte/osteoblast lineages presumed affected in skeletal dysplasia (not specifically characterized at the cell-type level in the literature reviewed).

Subcellular level: Nucleus (GO:0005634) — chromatin-bound MYSM1 performs its primary deubiquitinase function at histone H2A within nucleosomes; a cytosolic pool (GO:0005829) mediates the innate-immune TRAF3/TRAF6/RIP2 deubiquitination function.

Localization/laterality: Systemic/bilateral — no laterality pattern reported (as expected for a germline monogenic disease affecting a generalized stem-cell and chromatin-regulatory function).

8. Temporal Development

Onset: Congenital/neonatal-to-early-infantile. Anemia has presented as early as 1 month of age (Huang et al. 2021, PMID:33858043, case title: "a 1-month-old girl") and as late as ~15 months in other reported cases; GARD lists onset "as early as the newborn stage." A milder, later-recognized adult-onset-diagnosed phenotype has also been reported (Sakovich et al. 2024, J Clin Immunol), indicating that while the underlying defect is congenital, clinical recognition/severity is variable and can be markedly delayed.

Onset pattern: Insidious/subacute for the marrow failure (progressive rather than acute catastrophic aplasia at presentation in most cases), though initial presentation can be an acute severe anemia requiring transfusion.

Progression / disease course pattern: Notably non-monotonic in several reported patients — an initial phase of transfusion dependence can be followed by spontaneous partial hematologic recovery lasting years, before later relapse and progression to pancytopenia and ultimately clonal transformation. This "transient-then-progressive" course is unusual among IBMFS and was already flagged in the original 2013 description (title: "transient transfusion-dependent anemia..."). Documented stages, drawing on Haroon et al. 2025 (PMID:40535318): 1. Infantile-onset anemia/cytopenia (often initially misclassified, e.g., as Diamond-Blackfan anemia). 2. Chronic, often fluctuating marrow failure with progressive B-/NK-cell immunodeficiency through childhood. 3. Late-childhood-to-adolescent (reported range: transformation occurring within 9–12 years of initial presentation, at patient ages 12–19 years in the largest reported series) clonal evolution with acquisition of somatic driver mutations (TP53, CALR) and cytogenetic abnormalities (monosomy 5/7, trisomy 8). 4. Transformation to hypoplastic MDS or MDS/AML.

Remission patterns: Spontaneous partial hematologic remission is specifically documented (unusual for an IBMFS) in at least one well-described case; treatment-induced remission is achievable via allogeneic HSCT (see §12), including in patients with adverse cytogenetics post-leukemic transformation (2 of the reported transformed patients achieved remission via HSCT per Haroon et al. 2025).

Critical periods: The second decade of life (roughly ages 9–19 in reported cases) appears to be the critical window for malignant clonal transformation, arguing for close surveillance (serial marrow morphology/cytogenetics) through adolescence in known BMFS4 patients, and for considering pre-emptive HSCT before transformation occurs given the poor outcome once AML supervenes (one reported patient died of septic shock 3 months post-induction chemotherapy without transplant).

9. Inheritance and Population

Epidemiology: Extremely rare — Orphanet prevalence class "<1/1,000,000"; GARD classifies it as a rare disease. Fewer than ~25 molecularly confirmed patients have been published across all case reports as of 2025 (aggregating original cohort ["nine patients" as of 2020] plus subsequent individual/small case reports and the 2025 four-patient transformation series). No formal incidence or population-registry data exist; this is a case-report-level evidence base, not a population-surveillance-derived one.

Inheritance pattern: Autosomal recessive (AR) — confirmed in every reported pedigree; unaffected heterozygous carrier parents, affected homozygous or compound-heterozygous offspring, consistent with Mendelian AR segregation and with the population-genetic evidence (gnomAD) that heterozygous LOF is well-tolerated.

Penetrance: Appears complete for biallelic LOF genotypes, though phenotypic severity is markedly variable (see Expressivity below) — the emerging adult-diagnosed case suggests that while the molecular defect is fully penetrant, clinically apparent severe marrow failure requiring diagnosis in infancy is not obligate for every genotype.

Expressivity: Variable — ranging from the classic severe infantile pancytopenia-immunodeficiency-skeletal dysplasia triad to a milder phenotype recognized only in adulthood (Sakovich et al. 2024). Genotype-phenotype correlation across the small number of reported alleles (nonsense vs. missense vs. cryptic splice) has not been systematically established, though this would be a reasonable hypothesis to test as more cases accumulate (i.e., whether residual catalytic activity from hypomorphic missense alleles, e.g., p.H656R, correlates with milder disease).

Genetic anticipation: Not applicable/not reported — this is not a repeat-expansion disorder.

Germline mosaicism: Not specifically documented in the literature reviewed, though recurrence in siblings (Alsultan 2013 original family; Huang 2021 sibling cases) is explained by biparental heterozygous-carrier segregation rather than mosaicism per se.

Founder effects: Suggested but not formally proven — the strong overrepresentation of consanguineous Middle Eastern (particularly Saudi/Gulf Arab) and some Chinese pedigrees in the literature is consistent with either regional founder alleles or simply the ascertainment effect of consanguinity increasing homozygosity for private rare variants; population-genetic founder-haplotype analysis has not been published for any specific MYSM1 allele to date.

Consanguinity role: Central — nearly all reported pedigrees involve consanguineous parents, as expected for an ultra-rare AR disease with a gene that is not under strong heterozygous constraint (so carrier frequency is presumably very low in outbred populations, making biallelic disease essentially unseen outside consanguineous unions or compound-heterozygosity in larger reference populations).

Carrier frequency: Not established in any population database (too rare/private-variant-driven for gnomAD-based carrier-frequency estimation at the disease-allele level).

Population demographics: Reported cases cluster in Middle Eastern (Saudi Arabian — original description; other Arab nationalities in the 2025 Haroon et al. series from Saudi Arabia) and East Asian (Chinese — Huang 2021, Zhan 2021, Li 2020) populations, plausibly reflecting both true regional enrichment (consanguinity rates) and ascertainment/reporting bias from specific referral centers with active IBMFS genetic-testing programs (e.g., King Faisal Specialist Hospital, Saudi Arabia) rather than confirmed differential population prevalence. No formal geographic-distribution or sex-ratio data are available; case reports do not show an obvious sex skew (both male and female patients reported), consistent with autosomal (non-sex-linked) inheritance.

10. Diagnostics

Laboratory tests: - Complete blood count showing anemia (often macrocytic, prompting DBA consideration), neutropenia, mild thrombocytopenia. - Immunoglobulin levels (hypogammaglobulinemia) and vaccine-response titers (impaired specific antibody response). - Lymphocyte subset flow cytometry: reduced/absent B cells, reduced NK cells, generally preserved T-cell numbers (helps distinguish from combined immunodeficiencies/SCID).

Bone marrow examination: Aspirate/biopsy showing hypocellularity (reported cellularity as low as 5–20%) with dysplastic erythroid and myeloid precursors — myelodysplastic features on morphology; cytogenetics initially normal, later showing acquired clonal abnormalities (monosomy 5, monosomy 7, trisomy 8) at transformation.

Genetic testing: - Gene panel / whole-exome or whole-genome sequencing targeting MYSM1 (and, given phenotypic overlap, other IBMFS genes — Fanconi anemia panel genes, RPL/RPS ribosomal protein genes for DBA, ERCC6L2, SRP72, SAMD9/SAMD9L) is the practical diagnostic route, since the clinical picture overlaps substantially with Diamond-Blackfan anemia and other congenital bone marrow failure syndromes at presentation. - Trio exome sequencing has been used successfully to identify cryptic/splice-altering variants not obvious from genomic sequence alone (Li et al. 2020, PMID:32640305, used trio WES plus RT-PCR/cDNA sequencing to functionally confirm the synonymous splice variant). - No dedicated commercial single-gene MYSM1 panel appears to be a first-line standalone test; it is typically captured within broader IBMFS/marrow-failure gene panels.

Functional/RNA-based confirmation: RT-PCR and cDNA sequencing to confirm aberrant splicing for variants of uncertain significance at intron/exon boundaries or synonymous positions (as demonstrated for c.399G>A).

Imaging: Skeletal survey (long-bone shortening, brachydactyly), brain MRI (assessing cerebral volume/hypoplasia), echocardiography (cardiac anomalies where present).

Ophthalmologic exam: Slit-lamp exam for cataracts.

Audiology: Hearing assessment given reported sensorineural hearing loss.

Differential diagnosis: Diamond-Blackfan anemia (erythroid-predominant marrow failure — a documented source of diagnostic confusion), Fanconi anemia (chromosome breakage/DEB-MMC testing should be performed to exclude), Shwachman-Diamond syndrome, SAMD9/SAMD9L-related MIRAGE/ataxia-pancytopenia syndromes, other combined immunodeficiency-with-marrow-failure syndromes (e.g., cartilage-hair hypoplasia given skeletal + immune features), and ERCC6L2-associated bone marrow failure (which similarly predisposes to MDS/AML transformation).

Screening: No population or newborn screening program exists (disease too rare and genetically heterogeneous); cascade/carrier testing of consanguineous family members and prenatal/preimplantation genetic testing are reasonable once a familial variant is identified, per standard AR-disease genetic counseling practice, though this is not specifically documented as formalized guidance in the literature reviewed.

11. Outcome/Prognosis

Survival/mortality: No formal actuarial survival statistics (5-year/10-year survival rates) exist given the extremely small published cohort. Mortality is clearly documented in the malignant-transformation setting: in the Haroon et al. 2025 series, one of four transformed patients who did not receive transplant "passed away 3 months post induction chemotherapy due to septic shock," illustrating that transformation to AML carries a poor prognosis without transplant, particularly with adverse cytogenetics.

Disease course / complications: The dominant late complication is clonal evolution to myelodysplastic syndrome and/or acute myeloid leukemia, occurring in a substantial proportion of the (small) reported cohort within roughly a decade of initial presentation — this is the single most important prognostic determinant identified in the literature and should drive a surveillance strategy (serial cytogenetics/molecular MRD-type monitoring) analogous to that used in Fanconi anemia and other pre-leukemic IBMFS.

Recovery potential: Variable — spontaneous partial hematologic recovery is documented in at least one long-term case, but this does not appear to be curative or to eliminate transformation risk; allogeneic HSCT is the only curative modality for both the marrow failure/immunodeficiency and (when performed before transformation, or in transformed patients with achievable remission) the leukemic risk.

Prognostic factors: Presence of TP53 mutation and adverse cytogenetics (monosomy 5/7) at the time of transformation appear to be poor prognostic markers, consistent with general MDS/AML risk stratification; earlier HSCT (before transformation) is inferentially the more favorable strategy, though this has not been formally tested in a comparative study given cohort size.

Prognostic biomarkers: Serial marrow cytogenetics and targeted somatic mutation panels (TP53, CALR) for transformation surveillance are the most directly evidenced prognostic tools from the 2025 case series, though no validated biomarker panel or risk score specific to BMFS4 exists.

12. Treatment

Supportive care (mainstay for most of disease course): - Chronic red cell transfusion support for severe anemia. - Immunoglobulin replacement therapy for hypogammaglobulinemia (standard practice for B-cell/antibody deficiency, though not specifically quoted in the reviewed abstracts — inferred from the immunodeficiency phenotype and general PID management standards). - Prophylactic antibiotics for recurrent infections (explicitly noted in GARD/search summaries for the recurrent-URI pattern in early childhood). - NCIT suggestion: NCIT:C15747 (Supportive Care); NCIT:C15986 (Pharmacotherapy) for immunoglobulin/antimicrobial prophylaxis.

Curative therapy — allogeneic hematopoietic stem cell transplantation (HSCT): - HSCT is explicitly stated as curative for the underlying blood/immune disease: Bahrami et al. 2017 (PMID:28115216) report that both index siblings "underwent successful allogeneic hematopoietic stem cell transplantation with sustained hematopoietic reconstitution, establishing HSCT represents a curative therapy for patients with MYSM1 deficiency." - Reduced-intensity conditioning (RIC) with fludarabine-based regimens has been used successfully, given the documented cellular genotoxic/radiosensitivity concerns: Barhoom et al. 2021 (PMID:34302415) report an HLA-identical father donor with fludarabine-based RIC achieving "full donor chimerism" with manageable grade II acute GVHD, and at one year post-transplant, "B-cell recovery, and no blood or platelet transfusion was reported." - HSCT is not without significant risk — a 2022 case report explicitly titled "Hematopoietic cell transplantation for MYSM1 deficiency: not so much an easy task" (PMID:35902396) signals recognized transplant-related complications/challenges in this population, and in the 2025 transformation series, HSCT in transformed (MDS/AML) patients with adverse cytogenetics achieved remission in some but not all cases, with chronic GVHD affecting eyes and lungs documented in one patient who achieved full chimerism. - Given the DNA-damage/genotoxic-stress hypersensitivity of MYSM1-deficient cells (§5/§6), conditioning regimens that minimize genotoxic/radiation exposure (i.e., RIC over myeloablative, and avoidance of high-dose alkylator/radiation-based regimens where feasible) are mechanistically well-justified, though formal comparative conditioning-regimen trial data do not exist for this ultra-rare disease. - NCIT suggestion: NCIT:C15431 (Hematopoietic Stem Cell Transplantation) for treatment_term, with therapeutic_modality: CELL_THERAPY.

Management of transformed disease (MDS/AML): - Induction chemotherapy has been used but with poor outcome in at least one non-transplanted patient (death from septic shock post-induction). - HSCT after achieving remission (or as consolidation) appears to be the preferred curative strategy once transformation has occurred, per the 2025 case series, though outcomes were mixed (some remission, some chronic GVHD morbidity).

Experimental/emerging therapies: No gene therapy, targeted small-molecule, or RNA-based therapeutic specific to MYSM1 deficiency was identified in this search (no registered ClinicalTrials.gov interventional trial specific to BMFS4/MYSM1 was located); given the very small patient population, disease-specific trials are unlikely in the near term, and HSCT (with individualized conditioning) remains the standard of care described in the literature.

Treatment strategy/algorithm (synthesized from the literature, not a formal published guideline): (1) supportive transfusion/Ig-replacement/antibiotic prophylaxis at diagnosis; (2) close hematologic and cytogenetic surveillance through childhood/adolescence given the ~decade-scale transformation risk; (3) proactive consideration of allogeneic HSCT with RIC before transformation to MDS/AML, given the poor prognosis once leukemic transformation occurs; (4) induction chemotherapy plus HSCT consolidation if transformation has already occurred, recognizing generally poorer outcomes in this setting, especially with TP53-mutant/adverse-cytogenetic clones.

13. Prevention

Primary prevention: Not applicable in the classic sense (this is a fully penetrant monogenic recessive disease, not a modifiable-risk-factor disease); the only "primary prevention" avenue is reproductive — genetic counseling, carrier testing of at-risk (especially consanguineous) family members, and prenatal or preimplantation genetic testing once a familial MYSM1 variant is known, following standard AR-disease reproductive genetics practice (no disease-specific guideline document was located, but this follows general ACMG/professional-society practice for rare AR disorders identified in a family).

Secondary prevention (early detection): No population or newborn screening program exists. Early recognition of the syndromic triad (marrow failure + B-/NK-cell immunodeficiency + skeletal/craniofacial/ophthalmologic features) in an infant with unexplained anemia — particularly one initially suspected of DBA who has additional immunologic or dysmorphic features — should prompt MYSM1-inclusive genetic testing.

Tertiary prevention (preventing complications once diagnosed): - Infection prophylaxis (antibiotics, immunoglobulin replacement) to reduce morbidity from the immunodeficiency. - Structured hematologic/cytogenetic surveillance to detect clonal evolution before overt leukemic transformation, given the documented ~decade-scale transformation risk — this is the single most actionable "prevention" lever identified in the literature (early detection of clonal evolution enabling pre-emptive HSCT rather than post-transformation rescue). - Avoidance of unnecessary genotoxic/radiation exposure given documented cellular radiosensitivity.

Genetic counseling: Central to family management — informing carrier parents of 25% recurrence risk per pregnancy, offering carrier testing to at-risk relatives, and discussing reproductive options; specific society guidelines for MYSM1/BMFS4 counseling were not identified (this disease is too rare to have a dedicated guideline), so counseling follows general IBMFS/AR-disease genetic counseling practice (e.g., NSGC/ACMG frameworks).

14. Other Species / Natural Disease

Taxonomy: Mouse (Mus musculus, NCBITaxon:10090) is the principal model species; no naturally occurring veterinary/companion-animal disease analog was identified in this search (no OMIA entry located for spontaneous MYSM1-related disease in domestic species).

Gene (ortholog): Mysm1, MGI:2444584, chromosome 1 (mouse), highly conserved with human MYSM1 (the 2024 review, PMID:39684760, explicitly notes "high sequence homology between murine and human MYSM1" as the basis for translating mouse mechanistic findings to human disease).

Naturally occurring/spontaneous mouse model — "meander tail" (mea): A classical spontaneous mouse mutant, meander tail, has recently (2026 bioRxiv preprint, Hamilton et al.) been shown to carry Mysm1 mutations. This strain was long known for kinked tails and a selective cerebellar anterior-lobe malformation; the preprint reports that "Mouse meander tail (mea) mutations produce kinked tails and selective malformation of the cerebellum anterior compartment" and demonstrates both neurological and hematological phenotypes arising from Mysm1 mutation, with effects on granule-cell-precursor proportions detectable by E14.5 — this is a directly relevant natural/spontaneous (non-engineered) Mysm1-mutant model that had not previously been mechanistically linked to the gene, and is a notable 2026 addition to the model literature (novel cerebellar-phenotype angle not previously connected to human BMFS4's neurodevelopmental features). (Status: preprint, not yet peer-reviewed as of this research pass — flag accordingly.)

Comparative biology: MYSM1's chromatin-regulatory and hematopoietic roles are evolutionarily conserved at least across mammals (mouse-human concordance is the basis for essentially all current mechanistic understanding, as human primary tissue studies are limited by case scarcity). The 2024 review also notes that "Mysm1 orthologs have been independently lost across various animal and fungal species" per the meander-tail preprint's phylogenetic framing — suggesting lineage-specific dispensability of MYSM1 outside mammals, relevant context for interpreting cross-species model choice.

Zoonotic potential/transmission: Not applicable — this is a non-communicable monogenic disease.

15. Model Organisms

Mouse — constitutive/conventional knockout: - Nijnik et al. 2012 (Blood, PMID:22184403) — the original characterization: Mysm1-deficient mice show defects in bone marrow hematopoiesis, resulting in lymphopenia, anemia, and thrombocytosis (note: thrombocytosis in this early mouse report, versus thrombocytopenia in human disease — a species-phenotype divergence worth noting), impaired lymphocyte development, and depletion of erythroid cells. This paper established Mysm1 as essential for HSC-supported hematopoiesis and lymphocyte differentiation, directly motivating the subsequent human disease-gene hypothesis.

Mouse — p53 double-knockout (genetic epistasis model): - Belle et al. 2015 (Blood, PMID:25710881) — Mysm1⁻/⁻p53⁻/⁻ mice: full rescue of hematopoietic and developmental defects, establishing p53 activation as the driving mechanism. High fidelity for the p53-mediated HSC-failure mechanism specifically; does not by itself model the human skeletal/craniofacial phenotype.

Mouse — ribosomal protein gene expression model: - Belle et al. 2020 (JCI Insight, PMID:32641579) — demonstrates MYSM1's direct, p53-independent role in maintaining ribosomal protein gene expression in HSCs, with loss of this regulation triggering p53 activation and hematopoietic dysfunction; links BMFS4 mechanistically to the broader ribosomopathy disease class (relevant given clinical overlap/misdiagnosis with DBA in human patients).

Mouse — NK-cell-specific model: - Nandakumar et al. 2013 (PNAS, PMID:24062447) — Mysm1-deficient mice show severely impaired NK-cell maturation (not lineage specification/commitment), mediated through MYSM1's epigenetic control of Id2 expression via NFIL3 recruitment. Directly models the human NK-cell deficiency component of BMFS4.

Mouse — B-cell/antibody-response model: - Jiang et al. 2015 (Sci Rep, PMC4562257) — despite severe B-cell developmental defects, Mysm1-deficient mice show enhanced (not simply reduced) antibody response against both T-dependent and T-independent antigens via loss of MYSM1's normal repression of plasma-cell differentiation (through Pax5 transcriptional activation). This is an important nuance: the mouse humoral phenotype is not a simple "less antibody" model, and the direct translatability to human hypogammaglobulinemia (which is the human clinical finding) is not fully resolved — a human-model mismatch worth flagging for a dismech-style entry (mouse shows paradoxically enhanced antibody response in the periphery despite developmental B-cell loss, whereas humans present with hypogammaglobulinemia/impaired vaccine response).

Mouse — catalytically dead (deubiquitinase-dead) knock-in model: - Liang et al. 2023 (Sci Rep, PMID:36611064) — "Deubiquitinase catalytic activity of MYSM1 is essential in vivo for hematopoiesis and immune cell development" — a catalytically inactivating knock-in (rather than full null) model, allowing dissection of MYSM1's catalytic (deubiquitinase) versus scaffold/non-catalytic functions in vivo; directly relevant to interpreting the human p.H656R missense allele, which specifically disrupts the JAMM catalytic domain.

Mouse — spontaneous/natural model (see §14): - Meander tail (mea) mice (Hamilton et al., 2026 bioRxiv preprint) — a classical spontaneous Mysm1-mutant strain now linked to the gene, showing combined cerebellar developmental and hematological phenotypes; potentially valuable as a naturally arising allelic series and as a new angle on modeling the neurodevelopmental component of human BMFS4 not well captured by the earlier conventional-knockout models.

Model limitations (synthesized): - No mouse model to date is reported to recapitulate the skeletal dysplasia (rhizomelic shortening, brachydactyly, trigonocephaly) or cataract phenotype of human BMFS4 — these remain modeled, at best, indirectly (the meander-tail model's cerebellar phenotype is a partial exception for the neurodevelopmental axis, but skeletal/ocular features are an unaddressed gap). - The B-cell/antibody-response phenotype shows a qualitative species divergence (enhanced vs. impaired antibody response — see Jiang et al. above), meaning direct extrapolation of the mouse humoral-immunity mechanism to the human hypogammaglobulinemia phenotype should be treated as an inference requiring caution (a HUMAN_MODEL_MISMATCH-type flag in dismech terms) rather than a demonstrated concordance. - No iPSC-derived, organoid, or human primary-tissue functional model of MYSM1 deficiency was identified in this search — the field currently relies essentially entirely on mouse genetics plus patient EBV-transformed lymphoblastoid cell lines (used, e.g., in the original 2013/2017 reports for functional confirmation of protein loss and DNA-damage-response defects) for human cellular validation. - No CRISPR screen, DepMap, or large-scale functional-genomics dataset specific to MYSM1's role in the hematopoietic/leukemic-transformation context of BMFS4 was located (broader MYSM1-in-cancer functional-genomics work, e.g., in melanoma, exists but is outside the BMFS4 disease scope).

Summary of Key Evidence Gaps (for curation triage)

Skeletal/craniofacial/ocular mechanism is essentially uncharacterized at the molecular-target level — inferred only from MYSM1's general chromatin-regulatory role, not demonstrated via specific target-gene studies, unlike the well-worked-out hematopoietic (RP-gene/p53) and NK-cell (Id2/NFIL3) axes.
Human tissue/omics data are absent — essentially all mechanistic data are mouse-derived; human confirmation rests on phenotypic concordance and a small number of patient-lymphoblastoid-line functional assays (DNA-damage sensitivity, protein-loss confirmation).
Somatic clonal-evolution-to-leukemia mechanism is documented clinically (cytogenetics/mutations) but not mechanistically dissected — the link from chronic p53-mediated HSC stress to selection for TP53-mutant/monosomy-7 clones is inferred by analogy to other IBMFS, not directly shown in BMFS4.
Genotype-phenotype correlation (nonsense/null vs. missense/hypomorphic alleles) is not systematically established despite the growing recognition of variable expressivity (severe infantile vs. milder adult-recognized presentations).
No disease-specific clinical trial, registry, or natural-history study was identified — the evidentiary base remains individual/small-series case reports, consistent with Orphanet's ultra-rare prevalence classification.

Sources

Note on a naming ambiguity worth flagging for curation: MECOM (EVI1)-related radioulnar synostosis with amegakaryocytic thrombocytopenia 2 (RUSAT2, OMIM #616738) is a genetically and clinically distinct autosomal-dominant disorder that is sometimes discussed alongside "bone marrow failure" nomenclature in search results and general literature, but it is NOT the same entry as MONDO:0020856/OMIM #618116 (MYSM1, autosomal recessive). This report addresses only the MYSM1-associated, MONDO:0020856-mapped BMFS4; RUSAT2/MECOM should not be conflated with it in curation.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	21
Resolved	21
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	1
Quoted claims found in source	1
Quoted claims not found in source	0
References weighed for topical relevance	21
On topic	15
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	59
Resolved	51
Unresolved (possible confabulation)	0
Obsolete	3
Unverifiable	5
Terms whose name was checked	12
Terms named correctly	7
Terms named as a different term	3
Terms whose name is worth a second look	2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0020856 (7 mentions) - the report calls it "if available", "label "bone marrow failure syndrome 4", "OLS"; MONDO calls it bone marrow failure syndrome 4
HP:0002846 (1 mention) - the report calls it "Abnormal B cell count is a coarse fallback if antibody-response term unavailable"; HP calls it Abnormal B cell morphology
HP:0000518 (1 mention) - the report calls it "frequent"; HP calls it Cataract

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0035522 (obsolete monoubiquitinated histone H2A deubiquitination) (1 mention)
GO:0016578 (obsolete histone deubiquitination) (1 mention)
GO:0006977 (obsolete DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest) (1 mention) - replaced by GO:0030330

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0010976 (1 mention) - the report calls it "Decreased circulating total B cell count"; HP calls it Decreased total B cell count
HP:0000268 (1 mention) - the report calls it "Trigonocephaly"; HP calls it Dolichocephaly, and lists "Turridolichocephaly" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

MONDO:0020856 - called "if available", "label "bone marrow failure syndrome 4", "OLS"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM, GARD, ORPHA, MGI.

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Classifications

Mappings

Inheritance

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Bone Marrow Failure Syndrome 4 (MYSM1 Deficiency) — Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

Hematologic (laboratory abnormalities — very frequent, near-universal)

Immunologic (very frequent)

Skeletal/craniofacial (frequent)

Ophthalmologic

Neurologic/developmental

Dermatologic

Cardiac/renal

Severity/progression pattern

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Causal chain (ordered, with inference flags)

Branch: innate-immune/cytosolic function

Molecular pathways / processes (suggested ontology terms)

Cell types (Cell Ontology, CL)

Molecular profiling

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Key Evidence Gaps (for curation triage)

Sources

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver