Immunodeficiency 80 with or without Congenital Cardiomyopathy

Mendelian MONDO:0030266 Pathograph 25 Show in embeddings browser Inborn error of immunity Natural killer cell deficiency

Immunodeficiency 80 with or without congenital cardiomyopathy (IMD80; MCM10 deficiency; OMIM 619313) is an ultra-rare autosomal recessive inborn error of immunity caused by biallelic (compound heterozygous) variants in MCM10, which encodes an essential activator and processivity factor of the eukaryotic CMG (CDC45-MCM2-7-GINS) DNA replicative helicase. Only two unrelated kindreds have been reported. One patient, carrying a hypomorphic missense allele together with a nonsense allele, presented in infancy with a profound natural killer (NK) cell deficiency (absence of terminally mature NK cells) and died in infancy of overwhelming cytomegalovirus (CMV) infection. A second, unrelated family carrying a frameshift allele together with a splice-donor allele had three affected fetuses/siblings with restrictive cardiomyopathy accompanied by hypoplasia of the spleen and thymus (lymphoreticular hypoplasia). Functional studies show that MCM10 deficiency causes chronic replication stress, accumulation of abnormal single-stranded-DNA-rich replication fork intermediates, genomic instability, and accelerated telomere erosion; the authors propose that these biallelic hypomorphic/loss-of-function variants push specific, rapidly proliferating lineages (NK cell precursors during terminal maturation, and cardiac/lymphoreticular progenitors during differentiation) to prematurely arrest, producing the divergent but overlapping NKD and restrictive-cardiomyopathy phenotypes from a single gene. MCM10 joins MCM4, GINS1, and GINS4 as CMG-helicase components in which biallelic hypomorphic variants cause human NK cell deficiency.

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1
Inheritance
4
Pathophys.
18
Phenotypes
1
Gaps
25
Pathograph
1
Genes
1
Medical Actions
2
Models
4
References
1
Deep Research
🏷

Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
IUIS Category
innate immunity defect
👪

Inheritance

1
Autosomal recessive HP:0000007
Both reported kindreds carry compound heterozygous (biallelic) MCM10 variants; unaffected parents/relatives are obligate heterozygous carriers.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:33712616 SUPPORT Human Clinical
"Here, we describe compound heterozygous MCM10 variants in patients with distinctive, but overlapping, clinical phenotypes: natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus."
Both reported clinical phenotypes arise from compound heterozygous (biallelic) MCM10 variants, consistent with autosomal recessive inheritance.
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Discussions and Knowledge Gaps

1
Why does one set of biallelic MCM10 variants (missense + nonsense) selectively arrest NK cell precursors while a different set (frameshift + splice donor) instead arrests cardiac and lymphoreticular progenitors, from the same underlying replication-stress mechanism?
KNOWLEDGE GAP OPEN mcm10_allele_lineage_divergence
Attached to
pathophysiology#Impaired Differentiation of Cardiac and Lymphoreticular Progenitors pathophysiology#Impaired Terminal Maturation of NK Cell Precursors
Only two kindreds, with non-overlapping allele combinations, have been reported, so it is not established whether the divergence reflects allele-specific residual MCM10 activity, lineage-specific proliferation kinetics/replication demand, or another factor. The primary report frames this explicitly as an open mechanistic question rather than a settled finding.
Proposed experiments
Isogenic MCM10 allelic-series comparison across NK and cardiomyocyte differentiation
exp_mcm10_allelic_series_lineage_comparison
Generate isogenic human iPSC lines carrying each reported MCM10 variant combination (NKD alleles vs. RCM alleles), differentiate each line down both NK-cell and cardiomyocyte lineages in parallel, and compare replication stress markers, telomere length, and differentiation efficiency to test whether allele identity or lineage-intrinsic replication demand determines which cell type arrests.
⚙

Pathophysiology

4
Biallelic MCM10 Hypomorphic/Loss-of-Function Variants
Compound heterozygous MCM10 variants reduce functional MCM10 protein below a critical threshold. NK-cell-deficiency-associated alleles are a hypomorphic missense variant (p.R426C) paired with a nonsense variant (p.R582X); restrictive-cardiomyopathy-associated alleles are a frameshift variant (c.236delG) paired with a splice-donor variant (c.764+5G>A). MCM10 is required for activation and processivity of the CMG (CDC45-MCM2-7-GINS) replicative helicase.
DNA replication initiation GO:0006270 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased DNA replication initiation (GO:0006270). GO:0006270 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Chronic Replication Stress and Genomic Instability Reduced MCM10 function impairs CMG helicase-dependent DNA replication.
Show evidence (1 reference)
PMID:33712616 SUPPORT Human Clinical
"Here, we describe compound heterozygous MCM10 variants in patients with distinctive, but overlapping, clinical phenotypes: natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus."
Establishes that biallelic MCM10 variants underlie both the NKD and RCM clinical presentations of this disorder.
Chronic Replication Stress and Genomic Instability
Reduced MCM10 function impairs CMG helicase activity, causing chronic replication stress with accumulation of terminally arrested, single-strand-DNA-enriched replication fork structures. These abnormal forks require endonucleolytic processing by MUS81; in MCM10:MUS81 double-mutant cells, viability falls further and telomere shortening accelerates, indicating that MUS81-dependent fork processing is a downstream node that itself contributes to (rather than merely reads out) the genomic instability.
DNA damage response GO:0006974 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased DNA damage response (GO:0006974). GO:0006974 is a biological process from the Gene Ontology. ↑ INCREASED telomere maintenance GO:0000723 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased telomere maintenance (GO:0000723). GO:0000723 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Terminal Maturation of NK Cell Precursors Proposed lineage-specific consequence of replication stress in the NKD-associated genotype.
Impaired Differentiation of Cardiac and Lymphoreticular Progenitors Proposed lineage-specific consequence of replication stress in the RCM-associated genotype.
Mild T and B Lymphopenia The same replication-stress mechanism is proposed to mildly affect proliferating T and B lymphopoiesis, less severely than the NK lineage, consistent with a graded threshold effect across differentiating hematopoietic lineages rather than an NK-restricted defect.
Show evidence (2 references)
PMID:33712616 SUPPORT In Vitro
"MCM10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion."
Direct experimental demonstration (patient-variant-modeled human cell lines) of the proximate cellular consequence of MCM10 deficiency.
PMID:33712616 SUPPORT In Vitro
"Terminally-arrested replication forks in MCM10-deficient cells require endonucleolytic processing by MUS81, as MCM10:MUS81 double mutants display decreased viability and accelerated telomere shortening."
Identifies MUS81-dependent processing of stalled replication forks as a mechanistic contributor to the telomere erosion and reduced viability caused by MCM10 deficiency.
Impaired Terminal Maturation of NK Cell Precursors
In the NKD-associated genotype, replication-stress-driven genomic instability (including telomere erosion) selectively arrests NK cell precursors during terminal differentiation, producing a profound deficiency of mature, functional NK cells while earlier hematopoietic and lymphoid progenitor stages are comparatively preserved.
natural killer cell CL:0000623 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves decreased natural killer cell (CL:0000623). CL:0000623 is a cell type from the Cell Ontology. ↓ DECREASED CD56dim natural killer cell CL:0000939 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves decreased CD56dim natural killer cell, annotated with CD16-positive, CD56-dim natural killer cell, human (CL:0000939). CL:0000939 is a cell type from the Cell Ontology. ↓ DECREASED
natural killer cell differentiation GO:0001779 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased natural killer cell differentiation (GO:0001779). GO:0001779 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
Patient-derived iPSC-NK cell differentiation (MCM10 R426C/R582X) IPSC DERIVED MODEL Patient-derived iPSC-NK differentiation and MCM10 knockdown in NK cell lines reproduce the terminal NK maturation defect seen in the patient.
MCM10 heterozygous (MCM10+/-) iPSC-NK differentiation IPSC DERIVED MODEL MCM10 haploinsufficiency in iPSCs is sufficient to impair NK-lineage differentiation and block generation of mature NK cells, independently confirming the terminal-maturation defect with a distinct (heterozygous knockout, rather than patient compound-heterozygous) genotype.
Downstream
Severely Decreased Mature NK Cells Loss of terminal NK maturation manifests clinically as NK cell deficiency.
Abnormal CD56bright/CD56dim NK Cell Subset Distribution Selective arrest at the CD56bright-to-CD56dim maturation transition manifests clinically as a skewed NK subset distribution.
Show evidence (3 references)
PMID:32865517 SUPPORT In Vitro
"By modeling MCM10 deficiency in primary NK cell precursors, including patient-derived induced pluripotent stem cells, we further demonstrated that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function."
Directly shows MCM10 requirement for the terminal maturation step of NK cell development using patient-derived iPSC-NK differentiation.
PMID:32865517 SUPPORT Human Clinical
"Decreased frequency of peripheral blood NK cells with overrepresentation of the CD56bright subset"
Directly documents the shift toward the immature CD56bright subset with loss of terminally mature CD56dim NK cells in the index patient's peripheral blood (Figure 1 legend).
PMID:38262603 SUPPORT In Vitro
"MCM10+/- iPSCs displayed defects in NK cell differentiation, exhibiting reduced yields of hematopoietic stem cells (HSCs)."
Independent iPSC-differentiation study confirms that reduced MCM10 dosage impairs the NK-lineage differentiation pathway, with the defect most pronounced at the mature NK cell stage.
Impaired Differentiation of Cardiac and Lymphoreticular Progenitors
In the RCM-associated genotype, the same replication-stress mechanism is proposed to prematurely arrest cardiac and lymphoreticular (splenic and thymic) progenitor lineages during differentiation, rather than NK precursors, illustrating lineage-specific sensitivity to a shared molecular lesion.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Downstream
Restrictive Cardiomyopathy Cardiac progenitor arrest during differentiation manifests as restrictive cardiomyopathy.
Hypoplasia of the Thymus Lymphoreticular progenitor arrest manifests as thymic hypoplasia.
Hypoplastic Spleen Lymphoreticular progenitor arrest manifests as splenic hypoplasia.
Show evidence (1 reference)
PMID:33712616 SUPPORT Human Clinical
"We propose that these bi-allelic variants in MCM10 predispose specific cardiac and immune cell lineages to prematurely arrest during differentiation, causing the clinical phenotypes observed in both NKD and RCM patients."
States the authors' proposed mechanistic link between the shared molecular lesion (MCM10 deficiency) and the two divergent, lineage-specific clinical phenotypes.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Immunodeficiency 80 with or without Congenital Cardiomyopathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

18
Blood 2
Mild T and B Lymphopenia Decreased total lymphocyte count HP:0001888 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mild decreased total lymphocyte count, annotated with Decreased total lymphocyte count (HP:0001888). HP:0001888 is a phenotype from the Human Phenotype Ontology.
Sequelae: Decreased Total B Cell Count Decreased Total T Cell Count
Show evidence (1 reference)
PMID:32865517 SUPPORT Human Clinical
"T and B cell numbers were slightly decreased with reduction in effector and memory T cells."
Directly documents mild, non-NK lymphopenia (both T and B lineages) in the index patient's immunophenotyping panel.
Decreased Circulating IgG Concentration HP:0004315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating IgG concentration (HP:0004315). HP:0004315 is a phenotype from the Human Phenotype Ontology.
Serum IgG of 2.22 g/L against a 3-13.2 g/L reference range is recorded only as a cell in the laboratory table of PMID:32865517; the paper contains no sentence stating the finding. No evidence block is attached rather than quoting a bare table value, per the evidence SOP.
Digestive 1
Diarrhea at Presentation HP:0002014 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Diarrhea (HP:0002014). HP:0002014 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32865517 SUPPORT Human Clinical
"at 16 months of age with fever, organomegaly, diarrhea, and CMV infection (2 × 10 6 copies/mL)"
Documents diarrhea at presentation at 16 months of age, coincident with a high CMV viral load, in the index patient.
Metabolism 3
Fever at Presentation HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fever (HP:0001945). HP:0001945 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32865517 SUPPORT Human Clinical
"at 16 months of age with fever, organomegaly, diarrhea, and CMV infection (2 × 10 6 copies/mL)"
Documents fever at presentation at 16 months of age, coincident with a high CMV viral load, in the index patient.
Hyperferritinemia with Hypofibrinogenemia (HLH-like Picture) Increased circulating ferritin concentration HP:0003281 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperferritinemia, annotated with Increased circulating ferritin concentration (HP:0003281). HP:0003281 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32865517 SUPPORT Human Clinical
"Ferritin 33150 μg/L (15–100 μg/L)"
Reports the index patient's markedly elevated ferritin value from the clinical laboratory table.
PMID:32865517 SUPPORT Human Clinical
"elevated levels of ferritin and triglycerides"
Names ferritin and triglyceride elevation together as prompting HLH consideration during the acute CMV illness.
Hypertriglyceridemia HP:0002155 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertriglyceridemia (HP:0002155). HP:0002155 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32865517 SUPPORT Human Clinical
"Triglycerides 1.7 mmol/L (0.4–1.6 mmol/L)"
Reports the index patient's elevated triglyceride value from the clinical laboratory table.
Other 12
Severely Decreased Mature NK Cells Reduced total natural killer cell count HP:0040218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severely decreased mature natural killer cells, annotated with Reduced total natural killer cell count (HP:0040218). HP:0040218 is a phenotype from the Human Phenotype Ontology.
Sequelae: Severe Cytomegalovirus Infection
Show evidence (1 reference)
PMID:32865517 SUPPORT Human Clinical
"we report a cause of NKD resulting from compound heterozygous mutations in minichromosomal maintenance complex member 10 (MCM10) that impaired NK cell maturation in a child with fatal susceptibility to CMV"
Reports the index patient's NK cell deficiency phenotype resulting from biallelic MCM10 variants.
Abnormal CD56bright/CD56dim NK Cell Subset Distribution Abnormal distribution of CD56 bright/dim natural killer cells HP:0031410 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal CD56bright/CD56dim NK cell subset distribution, annotated with Abnormal distribution of CD56 bright/dim natural killer cells (HP:0031410). HP:0031410 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32865517 SUPPORT Human Clinical
"Decreased frequency of peripheral blood NK cells with overrepresentation of the CD56bright subset"
Figure 1 legend states the finding as a proportional overrepresentation of the CD56bright subset within the reduced NK cell population, not an absolute increase in CD56bright cell count.
PMID:32865517 SUPPORT Human Clinical
"the severely reduced number of NK cells precluded precise quantification"
The source itself qualifies the CD56bright/CD56dim proportion as imprecisely quantifiable given how few residual NK cells were present, so this phenotype is recorded as a qualitative distributional abnormality rather than a precise ratio.
Decreased Total B Cell Count HP:0010976 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased total B cell count (HP:0010976). HP:0010976 is a phenotype from the Human Phenotype Ontology.
Sequelae: Decreased Circulating IgG Concentration Decreased Circulating IgM Concentration
Show evidence (1 reference)
PMID:32865517 SUPPORT Human Clinical
"T and B cell numbers were slightly decreased with reduction in effector and memory T cells."
States that B cell numbers were reduced in the index patient. The accompanying laboratory table records CD19+ 210 cells against a 600-3100 reference range, but that table cell is not quoted here because a bare value carries no propositional content.
Decreased Total T Cell Count HP:0005403 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased total T cell count (HP:0005403). HP:0005403 is a phenotype from the Human Phenotype Ontology.
Sequelae: Impaired Lymphocyte Transformation with Phytohemagglutinin
Show evidence (1 reference)
PMID:32865517 SUPPORT Human Clinical
"T and B cell numbers were slightly decreased with reduction in effector and memory T cells."
States that T cell numbers were reduced in the index patient, with a further reduction in effector and memory subsets. The accompanying laboratory table records CD3+ 1250 cells against a 1400-8000 reference range.
Impaired Lymphocyte Transformation with Phytohemagglutinin Decreased mitogen-induced T-cell proliferation HP:0031381 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Impaired lymphocyte transformation with phytohemagglutinin (PHA), annotated with Decreased mitogen-induced T-cell proliferation (HP:0031381). HP:0031381 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32865517 SUPPORT Human Clinical
"T cell activation in response to phytohemagglutinin was reduced relative to control"
Directly documents the reduced PHA response in the index patient's T cell functional testing.
Decreased Circulating IgM Concentration Decreased circulating total IgM HP:0002850 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating IgM concentration, annotated with Decreased circulating total IgM (HP:0002850). HP:0002850 is a phenotype from the Human Phenotype Ontology.
Serum IgM of 0.45 g/L against a 0.48-2.1 g/L reference range is recorded only as a cell in the laboratory table of PMID:32865517; the paper contains no sentence stating the finding. No evidence block is attached rather than quoting a bare table value, per the evidence SOP.
Severe Cytomegalovirus Infection HP:0031692 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe cytomegalovirus infection (HP:0031692). HP:0031692 is a phenotype from the Human Phenotype Ontology.
Sequelae: Fever at Presentation Organomegaly at Presentation Diarrhea at Presentation Hyperferritinemia with Hypofibrinogenemia (HLH-like Picture) Hypertriglyceridemia Hypofibrinogenemia
Show evidence (1 reference)
PMID:32865517 SUPPORT Human Clinical
"impaired NK cell maturation in a child with fatal susceptibility to CMV"
Directly documents fatal CMV susceptibility as the clinical consequence of MCM10-associated NK cell deficiency in the reported infant.
Organomegaly at Presentation
Deliberately left unbound to an ontology term. HPO has no generic "organomegaly" class, and the cited source (PMID:32865517) states only "organomegaly" — it never mentions liver or spleen enlargement, so the more specific HP:0001433 Hepatosplenomegaly would assert which organs were involved beyond what the evidence supports. Candidate for an HPO new-term request; per the no-term-beats-a-bad-term rule the binding is omitted rather than approximated.
Show evidence (1 reference)
PMID:32865517 SUPPORT Human Clinical
"at 16 months of age with fever, organomegaly, diarrhea, and CMV infection (2 × 10 6 copies/mL)"
Documents organomegaly at presentation at 16 months of age, coincident with a high CMV viral load, in the index patient.
Hypofibrinogenemia HP:0011900 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypofibrinogenemia (HP:0011900). HP:0011900 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32865517 SUPPORT Human Clinical
"Fibrinogen 0.5 g/L (2–4 g/L)"
Reports the index patient's decreased fibrinogen value from the clinical laboratory table.
Restrictive Cardiomyopathy HP:0001723 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Restrictive cardiomyopathy (HP:0001723). HP:0001723 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33712616 SUPPORT Human Clinical
"natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus"
Reports restrictive cardiomyopathy, together with splenic and thymic hypoplasia, in the second (RCM) kindred carrying biallelic MCM10 variants.
Hypoplasia of the Thymus HP:0000778 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of the thymus (HP:0000778). HP:0000778 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33712616 SUPPORT Human Clinical
"natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus"
Directly documents thymic hypoplasia as part of the RCM-associated lymphoreticular hypoplasia phenotype.
Hypoplastic Spleen HP:0006270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplastic spleen (HP:0006270). HP:0006270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33712616 SUPPORT Human Clinical
"natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus"
Directly documents splenic hypoplasia as part of the RCM-associated lymphoreticular hypoplasia phenotype.
🧬

Genetic Associations

1
MCM10
Gene: MCM10 hgnc:18043 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MCM10 (hgnc:18043). hgnc:18043 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:33712616 SUPPORT Human Clinical
"Minichromosome maintenance protein 10 (MCM10) is essential for eukaryotic DNA replication."
States the core molecular function of MCM10, the causal gene for this disorder.
PMID:32865517 SUPPORT Computational
"was predicted to be disease causing by MutationTaster (score 0.99) (34) and likely damaging by PolyPhen2 (score 1.0) (35)"
In silico pathogenicity predictions for the NKD-associated p.R426C missense variant support a damaging/hypomorphic effect.
PMID:32865517 SUPPORT Human Clinical
"The nonsense variant was not found in ExAC"
Documents that the NKD-associated p.R582X nonsense allele is absent from population reference databases, consistent with a very rare autosomal recessive pathogenic allele.
💊

Medical Actions

1
Bone Marrow Transplantation
Action: Hematopoietic Cell TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Hematopoietic Cell Transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. NCIT:C15431
The index NKD patient underwent bone marrow transplantation for suspected primary immunodeficiency, but succumbed to overwhelming pre-existing CMV infection at 24 months of age; transplantation was performed after the CMV infection was already established rather than pre-emptively, so this single case does not demonstrate treatment efficacy and instead illustrates the importance of early recognition before severe viral disease is established.
Target Phenotypes: Severely decreased mature natural killer cells HP:0040218 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Severely decreased mature natural killer cells, annotated with Reduced total natural killer cell count (HP:0040218). HP:0040218 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32865517 SUPPORT Human Clinical
"The patient underwent bone marrow transplantation for suspect"
Documents that bone marrow transplantation was attempted in the index patient for suspected primary immunodeficiency.
PMID:32865517 SUPPORT Human Clinical
"succumbed to overwhelming preexisting CMV at 24 months"
The patient died of pre-existing CMV infection despite transplantation, indicating that transplantation performed after severe viral disease was already established was not able to rescue the patient in this single reported case.
🔬

Diagnosis

2
NK cell immunophenotyping by flow cytometry
Flow cytometric enumeration of peripheral blood NK cells (CD56+CD3-) and subset analysis (CD56bright vs. CD56dim) identified the profound NK cell deficit and the shift toward the immature CD56bright subset in the index patient.
flow cytometry NCIT:C16585 NCI Thesaurus (NCIT)
Results: Profoundly reduced frequency of peripheral blood NK cells with overrepresentation of the immature CD56bright subset.
Show evidence (1 reference)
PMID:32865517 SUPPORT Human Clinical
"flow cytometry of peripheral blood lymphocytes demonstrated profoundly reduced frequency of NK cells"
Documents flow cytometric immunophenotyping as the diagnostic modality that identified the NK cell deficiency in the index patient.
Molecular confirmation by whole exome sequencing
Trio-based whole exome sequencing of the proband and his parents identified the compound heterozygous MCM10 variants segregating with disease, confirming the molecular diagnosis.
whole exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Results: Compound heterozygous MCM10 variants (c.1276C>T, p.R426C and c.1744C>T, p.R582X) that were rare, predicted damaging, and segregated with disease.
Show evidence (1 reference)
PMID:32865517 SUPPORT Human Clinical
"Whole exome sequencing identified compound heterozygous mutations that were rare and predicted to be damaging"
Documents whole exome sequencing as the diagnostic modality that identified and confirmed the causal MCM10 variants in the index patient.
🧫

Experimental Models

2
Patient-derived iPSC-NK cell differentiation (MCM10 R426C/R582X) IPSC_DERIVED_MODEL
iPSCs generated from the NKD proband (compound heterozygous MCM10 p.R426C/p.R582X) and differentiated along the NK-cell lineage, alongside CRISPR-modeled patient variants in fibroblast and NK cell lines.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Patient-derived induced pluripotent stem cells (iPSCs)
Publication
PMID:32865517
Pathograph links
Impaired Terminal Maturation of NK Cell Precursors recapitulates fidelity: high Patient-derived iPSC-NK differentiation and MCM10 knockdown in NK cell lines reproduce the terminal NK maturation defect seen in the patient.
Readouts
NK cell terminal maturation and functional acquisition
Direction: DECREASED
Interpretation: Patient-iPSC-derived and MCM10-knockdown NK cells fail to complete terminal maturation and acquire immunological function.
Show evidence (1 reference)
PMID:32865517 SUPPORT In Vitro
"we further demonstrated that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function"
Directly reports the patient-iPSC-derived NK differentiation readout supporting this mechanism node.
Show evidence (1 reference)
PMID:32865517 SUPPORT In Vitro
"By modeling MCM10 deficiency in primary NK cell precursors, including patient-derived induced pluripotent stem cells, we further demonstrated that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function."
Establishes patient-derived iPSC-NK differentiation as informative for the NK terminal maturation mechanism node.
MCM10 heterozygous (MCM10+/-) iPSC-NK differentiation IPSC_DERIVED_MODEL
CRISPR-engineered MCM10 heterozygous (MCM10+/-) iPSC lines differentiated through hematopoietic stem cell and NK-lineage stages, used to test a gene-dosage threshold model of MCM10-dependent genome stability.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
iPSC (CRISPR-engineered MCM10 heterozygous knockout)
Publication
PMID:38262603
Pathograph links
Impaired Terminal Maturation of NK Cell Precursors recapitulates fidelity: moderate MCM10 haploinsufficiency in iPSCs is sufficient to impair NK-lineage differentiation and block generation of mature NK cells, independently confirming the terminal-maturation defect with a distinct (heterozygous knockout, rather than patient compound-heterozygous) genotype.
Limitations: Models MCM10 haploinsufficiency rather than the patient's specific compound heterozygous missense/nonsense genotype, so it demonstrates a gene-dosage threshold effect rather than reproducing the exact allelic combination.
Readouts
NK-lineage differentiation from hematopoietic progenitors
Direction: DECREASED
Interpretation: MCM10+/- hematopoietic progenitors give rise to lymphoid progenitors but fail to generate mature NK cells, coincident with telomere erosion.
Show evidence (1 reference)
PMID:38262603 SUPPORT In Vitro
"Although MCM10+/- HSCs were able to give rise to lymphoid progenitors, these did not generate mature NK cells."
Directly reports the block at the mature NK cell stage in this model.
Show evidence (1 reference)
PMID:38262603 SUPPORT In Vitro
"MCM10+/- iPSCs displayed defects in NK cell differentiation, exhibiting reduced yields of hematopoietic stem cells (HSCs)."
Establishes the MCM10+/- iPSC-NK differentiation system as informative for the NK terminal maturation mechanism node.
{ }

Source YAML

click to show 
name: Immunodeficiency 80 with or without Congenital Cardiomyopathy
creation_date: "2026-08-17T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: immunodeficiency 80 with or without congenital cardiomyopathy
  term:
    id: MONDO:0030266
    label: immunodeficiency 80 with or without congenital cardiomyopathy
description: >
  Immunodeficiency 80 with or without congenital cardiomyopathy (IMD80; MCM10
  deficiency; OMIM 619313) is an ultra-rare autosomal recessive inborn error of
  immunity caused by biallelic (compound heterozygous) variants in MCM10, which
  encodes an essential activator and processivity factor of the eukaryotic CMG
  (CDC45-MCM2-7-GINS) DNA replicative helicase. Only two unrelated kindreds have
  been reported. One patient, carrying a hypomorphic missense allele together
  with a nonsense allele, presented in infancy with a profound natural killer
  (NK) cell deficiency (absence of terminally mature NK cells) and died in
  infancy of overwhelming cytomegalovirus (CMV) infection. A second, unrelated
  family carrying a frameshift allele together with a splice-donor allele had
  three affected fetuses/siblings with restrictive cardiomyopathy accompanied
  by hypoplasia of the spleen and thymus (lymphoreticular hypoplasia).
  Functional studies show that MCM10 deficiency causes chronic replication
  stress, accumulation of abnormal single-stranded-DNA-rich replication fork
  intermediates, genomic instability, and accelerated telomere erosion; the
  authors propose that these biallelic hypomorphic/loss-of-function variants
  push specific, rapidly proliferating lineages (NK cell precursors during
  terminal maturation, and cardiac/lymphoreticular progenitors during
  differentiation) to prematurely arrest, producing the divergent but
  overlapping NKD and restrictive-cardiomyopathy phenotypes from a single
  gene. MCM10 joins MCM4, GINS1, and GINS4 as CMG-helicase components in which
  biallelic hypomorphic variants cause human NK cell deficiency.

synonyms:
  - IMD80
  - MCM10 deficiency
  - NK cell deficiency with or without restrictive cardiomyopathy

parents:
  - Inborn error of immunity
  - Natural killer cell deficiency

classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    evidence:
    - reference: PMID:36809597
      reference_title: "Unwinding the Role of the CMG Helicase in Inborn Errors of Immunity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Inborn errors of immunity (IEI) are a collection of diseases resulting from genetic causes that impact the immune system through multiple mechanisms. Natural killer cell deficiency (NKD) is one such IEI"
      explanation: >
        MCM10-associated NK cell deficiency is classified as an inborn error
        of immunity, placing it in Harrison's immune/rheumatologic Part.
  - classification_value: CARDIOVASCULAR
    evidence:
    - reference: PMID:33712616
      reference_title: "Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus"
      explanation: >
        The RCM-associated genotype produces a primary cardiomyopathy
        phenotype, placing it in Harrison's cardiovascular Part.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:33712616
      reference_title: "Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Here, we describe compound heterozygous MCM10 variants in patients with distinctive, but overlapping, clinical phenotypes"
      explanation: >
        A biallelic Mendelian disorder caused by compound heterozygous MCM10
        variants, placing it in Harrison's genetics Part.
  iuis_category:
    classification_value: innate immunity defect
    notes: >-
      IUIS Table 6. MCM10 is grouped with MCM4, GINS1, and GINS4 (CMG helicase
      components) as causes of human NK cell deficiency, an innate-immunity
      defect (PMID:36809597); the RCM-predominant genotype is not itself an
      immunodeficiency, so this IUIS placement reflects the NKD-associated
      genotype specifically. The lesion is in the development of an innate
      effector lineage — terminally mature NK cells are absent — and the
      resulting susceptibility is correspondingly narrow (herpesvirus, notably
      CMV) rather than the broad infection burden of a combined
      immunodeficiency.
    evidence:
    - reference: PMID:32865517
      reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Human natural killer cell deficiency (NKD) arises from inborn errors of
        immunity that lead to impaired NK cell development, function, or both.
      explanation: >-
        Frames the disease as an inborn error of immunity acting on the NK cell,
        an innate effector lineage, which is the basis for the IUIS Table 6
        (intrinsic and innate immunity) assignment.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    Both reported kindreds carry compound heterozygous (biallelic) MCM10
    variants; unaffected parents/relatives are obligate heterozygous carriers.
  evidence:
  - reference: PMID:33712616
    reference_title: "Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe compound heterozygous MCM10 variants in patients with distinctive, but overlapping, clinical phenotypes: natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus."
    explanation: >
      Both reported clinical phenotypes arise from compound heterozygous
      (biallelic) MCM10 variants, consistent with autosomal recessive
      inheritance.

notes: >
  Ultra-rare: only two published kindreds (one NKD proband, one three-sibling
  RCM family) as of this curation. The cached reference for PMID:32865517 (the
  NKD proband paper) includes full open-access text (PMC7524476), which
  supplied the detailed clinical vignette, laboratory values, and variant
  pathogenicity scores used throughout this entry. The cached reference for
  PMID:33712616 (the RCM family paper) is shorter and does not include its
  Supplementary Note 1, which is where the RCM family's detailed
  clinical/genetic description (pedigree, exact variant segregation,
  individual fetal/sibling outcomes) is reported; RCM-family claims here are
  therefore limited to what the main-text/abstract-level cached content
  states. HP:0001522 (Death in infancy) is not a valid PhenotypeTerm (it sits
  under the HPO Clinical modifier / Mortality branch, not Phenotypic
  abnormality), so the index patient's fatal outcome is recorded only in this
  description, not as a separate phenotype entry. No GeneReviews chapter
  exists for this disorder (PubMed search for "MCM10[TI] GeneReviews[TI]"
  returned no results, 2026-08-17). `just discover-datasets` for this entry
  returned only GENE_ONLY candidates (generic MCM10 replication-biology GEO
  series in yeast, zebrafish, and unrelated human cell lines) with no
  disease-specific dataset, so no `datasets:` block is populated (see
  CLAUDE.md dataset-curation guidance on GENE_ONLY triage risk). A falcon
  deep-research report (research/Immunodeficiency_80_with_or_without_Congenital_Cardiomyopathy-deep-research-falcon.md)
  was consulted (NEC preflight PASS against MONDO:0030266/MCM10) and its
  detailed clinical/molecular claims were independently re-verified against
  the primary-literature cache before being curated here, rather than
  transcribed from the report directly.

pathophysiology:
- name: Biallelic MCM10 Hypomorphic/Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >
    Compound heterozygous MCM10 variants reduce functional MCM10 protein below
    a critical threshold. NK-cell-deficiency-associated alleles are a
    hypomorphic missense variant (p.R426C) paired with a nonsense variant
    (p.R582X); restrictive-cardiomyopathy-associated alleles are a frameshift
    variant (c.236delG) paired with a splice-donor variant (c.764+5G>A).
    MCM10 is required for activation and processivity of the CMG
    (CDC45-MCM2-7-GINS) replicative helicase.
  biological_processes:
  - preferred_term: DNA replication initiation
    modifier: DECREASED
    term:
      id: GO:0006270
      label: DNA replication initiation
  evidence:
  - reference: PMID:33712616
    reference_title: "Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe compound heterozygous MCM10 variants in patients with distinctive, but overlapping, clinical phenotypes: natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus."
    explanation: >
      Establishes that biallelic MCM10 variants underlie both the NKD and RCM
      clinical presentations of this disorder.
  downstream:
  - target: Chronic Replication Stress and Genomic Instability
    description: Reduced MCM10 function impairs CMG helicase-dependent DNA replication.

- name: Chronic Replication Stress and Genomic Instability
  biological_scale: CELLULAR
  description: >
    Reduced MCM10 function impairs CMG helicase activity, causing chronic
    replication stress with accumulation of terminally arrested,
    single-strand-DNA-enriched replication fork structures. These abnormal
    forks require
    endonucleolytic processing by MUS81; in MCM10:MUS81 double-mutant cells,
    viability falls further and telomere shortening accelerates, indicating
    that MUS81-dependent fork processing is a downstream node that itself
    contributes to (rather than merely reads out) the genomic instability.
  biological_processes:
  - preferred_term: DNA damage response
    modifier: INCREASED
    term:
      id: GO:0006974
      label: DNA damage response
  - preferred_term: telomere maintenance
    modifier: DECREASED
    term:
      id: GO:0000723
      label: telomere maintenance
  evidence:
  - reference: PMID:33712616
    reference_title: "Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "MCM10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion."
    explanation: >
      Direct experimental demonstration (patient-variant-modeled human cell
      lines) of the proximate cellular consequence of MCM10 deficiency.
  - reference: PMID:33712616
    reference_title: "Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Terminally-arrested replication forks in MCM10-deficient cells require endonucleolytic processing by MUS81, as MCM10:MUS81 double mutants display decreased viability and accelerated telomere shortening."
    explanation: >
      Identifies MUS81-dependent processing of stalled replication forks as a
      mechanistic contributor to the telomere erosion and reduced viability
      caused by MCM10 deficiency.
  downstream:
  - target: Impaired Terminal Maturation of NK Cell Precursors
    description: >
      Proposed lineage-specific consequence of replication stress in the
      NKD-associated genotype.
  - target: Impaired Differentiation of Cardiac and Lymphoreticular Progenitors
    description: >
      Proposed lineage-specific consequence of replication stress in the
      RCM-associated genotype.
  - target: Mild T and B Lymphopenia
    description: >
      The same replication-stress mechanism is proposed to mildly affect
      proliferating T and B lymphopoiesis, less severely than the NK
      lineage, consistent with a graded threshold effect across
      differentiating hematopoietic lineages rather than an NK-restricted
      defect.

- name: Impaired Terminal Maturation of NK Cell Precursors
  biological_scale: CELLULAR
  description: >
    In the NKD-associated genotype, replication-stress-driven genomic
    instability (including telomere erosion) selectively arrests NK cell
    precursors during terminal differentiation, producing a profound
    deficiency of mature, functional NK cells while earlier hematopoietic and
    lymphoid progenitor stages are comparatively preserved.
  cell_types:
  - preferred_term: natural killer cell
    modifier: DECREASED
    term:
      id: CL:0000623
      label: natural killer cell
  - preferred_term: CD56dim natural killer cell
    modifier: DECREASED
    term:
      id: CL:0000939
      label: "CD16-positive, CD56-dim natural killer cell, human"
  biological_processes:
  - preferred_term: natural killer cell differentiation
    modifier: DECREASED
    term:
      id: GO:0001779
      label: natural killer cell differentiation
  evidence:
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "By modeling MCM10 deficiency in primary NK cell precursors, including patient-derived induced pluripotent stem cells, we further demonstrated that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function."
    explanation: >
      Directly shows MCM10 requirement for the terminal maturation step of NK
      cell development using patient-derived iPSC-NK differentiation.
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Decreased frequency of peripheral blood NK cells with overrepresentation of the CD56bright subset"
    explanation: >
      Directly documents the shift toward the immature CD56bright subset with
      loss of terminally mature CD56dim NK cells in the index patient's
      peripheral blood (Figure 1 legend).
  - reference: PMID:38262603
    reference_title: "A critical threshold of MCM10 is required to maintain genome stability during differentiation of induced pluripotent stem cells into natural killer cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "MCM10+/- iPSCs displayed defects in NK cell differentiation, exhibiting reduced yields of hematopoietic stem cells (HSCs)."
    explanation: >
      Independent iPSC-differentiation study confirms that reduced MCM10
      dosage impairs the NK-lineage differentiation pathway, with the defect
      most pronounced at the mature NK cell stage.
  downstream:
  - target: Severely Decreased Mature NK Cells
    description: Loss of terminal NK maturation manifests clinically as NK cell deficiency.
  - target: Abnormal CD56bright/CD56dim NK Cell Subset Distribution
    description: >
      Selective arrest at the CD56bright-to-CD56dim maturation transition
      manifests clinically as a skewed NK subset distribution.

- name: Impaired Differentiation of Cardiac and Lymphoreticular Progenitors
  biological_scale: CELLULAR
  description: >
    In the RCM-associated genotype, the same replication-stress mechanism is
    proposed to prematurely arrest cardiac and lymphoreticular (splenic and
    thymic) progenitor lineages during differentiation, rather than NK
    precursors, illustrating lineage-specific sensitivity to a shared
    molecular lesion.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:33712616
    reference_title: "Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We propose that these bi-allelic variants in MCM10 predispose specific cardiac and immune cell lineages to prematurely arrest during differentiation, causing the clinical phenotypes observed in both NKD and RCM patients."
    explanation: >
      States the authors' proposed mechanistic link between the shared
      molecular lesion (MCM10 deficiency) and the two divergent,
      lineage-specific clinical phenotypes.
  downstream:
  - target: Restrictive Cardiomyopathy
    description: Cardiac progenitor arrest during differentiation manifests as restrictive cardiomyopathy.
  - target: Hypoplasia of the Thymus
    description: Lymphoreticular progenitor arrest manifests as thymic hypoplasia.
  - target: Hypoplastic Spleen
    description: Lymphoreticular progenitor arrest manifests as splenic hypoplasia.

discussions:
- discussion_id: mcm10_allele_lineage_divergence
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - "pathophysiology#Impaired Differentiation of Cardiac and Lymphoreticular Progenitors"
  - "pathophysiology#Impaired Terminal Maturation of NK Cell Precursors"
  prompt: >
    Why does one set of biallelic MCM10 variants (missense + nonsense)
    selectively arrest NK cell precursors while a different set (frameshift +
    splice donor) instead arrests cardiac and lymphoreticular progenitors,
    from the same underlying replication-stress mechanism?
  rationale: >
    Only two kindreds, with non-overlapping allele combinations, have been
    reported, so it is not established whether the divergence reflects
    allele-specific residual MCM10 activity, lineage-specific proliferation
    kinetics/replication demand, or another factor. The primary report frames
    this explicitly as an open mechanistic question rather than a settled
    finding.
  proposed_experiments:
  - experiment_id: exp_mcm10_allelic_series_lineage_comparison
    name: Isogenic MCM10 allelic-series comparison across NK and cardiomyocyte differentiation
    description: >
      Generate isogenic human iPSC lines carrying each reported MCM10 variant
      combination (NKD alleles vs. RCM alleles), differentiate each line down
      both NK-cell and cardiomyocyte lineages in parallel, and compare
      replication stress markers, telomere length, and differentiation
      efficiency to test whether allele identity or lineage-intrinsic
      replication demand determines which cell type arrests.

phenotypes:
- name: Severely Decreased Mature NK Cells
  description: >
    Profound deficiency of terminally mature, functional NK cells reported in
    the single published NKD proband.
  phenotype_term:
    preferred_term: Severely decreased mature natural killer cells
    term:
      id: HP:0040218
      label: Reduced total natural killer cell count
  evidence:
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report a cause of NKD resulting from compound heterozygous mutations in minichromosomal maintenance complex member 10 (MCM10) that impaired NK cell maturation in a child with fatal susceptibility to CMV"
    explanation: >
      Reports the index patient's NK cell deficiency phenotype resulting from
      biallelic MCM10 variants.
  sequelae:
  - target: Severe Cytomegalovirus Infection
    description: >
      Loss of NK-cell-mediated antiviral immunity leaves the patient unable
      to control CMV infection.
    evidence:
    - reference: PMID:32865517
      reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "impaired NK cell maturation in a child with fatal susceptibility to CMV"
      explanation: >
        Directly links the NK cell maturation defect to fatal CMV
        susceptibility in the same reported patient.

- name: Abnormal CD56bright/CD56dim NK Cell Subset Distribution
  description: >
    Among the index patient's severely reduced residual NK cells, roughly
    half were the immature CD56bright subset — a proportional skew toward
    the immature subset, not an absolute increase in CD56bright cell number
    (the patient's total NK count was only 1 cell/uL). The source explicitly
    notes that the severely reduced NK cell number precluded precise
    quantification of this distribution.
  phenotype_term:
    preferred_term: Abnormal CD56bright/CD56dim NK cell subset distribution
    term:
      id: HP:0031410
      label: Abnormal distribution of CD56 bright/dim natural killer cells
  evidence:
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Decreased frequency of peripheral blood NK cells with overrepresentation of the CD56bright subset"
    explanation: >
      Figure 1 legend states the finding as a proportional overrepresentation
      of the CD56bright subset within the reduced NK cell population, not an
      absolute increase in CD56bright cell count.
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the severely reduced number of NK cells precluded \nprecise quantification"
    explanation: >
      The source itself qualifies the CD56bright/CD56dim proportion as
      imprecisely quantifiable given how few residual NK cells were present,
      so this phenotype is recorded as a qualitative distributional
      abnormality rather than a precise ratio.

- name: Mild T and B Lymphopenia
  description: >
    Alongside the profound NK cell deficit, the same immunophenotyping panel
    showed milder decreases in total T and B lymphocyte numbers, with a
    reduction in effector and memory T cells. This graded, multilineage
    pattern (severe NK loss with only mild T/B lymphopenia) is consistent
    with a replication-stress threshold model in which the most rapidly
    proliferating/differentiating lineage (terminal NK maturation) is most
    sensitive to reduced MCM10 function, rather than a lineage-restricted
    NK-only defect.
  phenotype_term:
    preferred_term: Mild decreased total lymphocyte count
    term:
      id: HP:0001888
      label: Decreased total lymphocyte count
  evidence:
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "T and B cell numbers were \nslightly decreased with reduction in effector and memory T cells."
    explanation: >
      Directly documents mild, non-NK lymphopenia (both T and B lineages) in
      the index patient's immunophenotyping panel.
  sequelae:
  - target: Decreased Total B Cell Count
    description: >
      The B lineage component of the mild multilineage lymphopenia, resolved
      to the CD19+ B cell subset in the same immunophenotyping panel.
  - target: Decreased Total T Cell Count
    description: >
      The T lineage component of the mild multilineage lymphopenia, resolved
      to the CD3+ T cell subset in the same immunophenotyping panel.

- name: Decreased Total B Cell Count
  description: >
    CD19+ B cell count was below the reference range in the index patient's
    immunophenotyping panel.
  phenotype_term:
    preferred_term: Decreased total B cell count
    term:
      id: HP:0010976
      label: Decreased total B cell count
  evidence:
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "T and B cell numbers were slightly decreased with reduction in effector and memory T cells."
    explanation: >
      States that B cell numbers were reduced in the index patient. The
      accompanying laboratory table records CD19+ 210 cells against a
      600-3100 reference range, but that table cell is not quoted here
      because a bare value carries no propositional content.
  sequelae:
  - target: Decreased Circulating IgG Concentration
    description: >
      Reduced circulating B cell number provides a biologically plausible
      basis for the accompanying mild hypogammaglobulinemia (reduced B cells
      producing less antibody), though the source does not itself state this
      causal link in a quotable sentence.
  - target: Decreased Circulating IgM Concentration
    description: >
      Reduced circulating B cell number provides a biologically plausible
      basis for the accompanying mild reduction in circulating IgM, though
      the source does not itself state this causal link in a quotable
      sentence.

- name: Decreased Total T Cell Count
  description: >
    CD3+ T cell count was below the reference range in the index patient's
    immunophenotyping panel.
  phenotype_term:
    preferred_term: Decreased total T cell count
    term:
      id: HP:0005403
      label: Decreased total T cell count
  evidence:
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "T and B cell numbers were slightly decreased with reduction in effector and memory T cells."
    explanation: >
      States that T cell numbers were reduced in the index patient, with a
      further reduction in effector and memory subsets. The accompanying
      laboratory table records CD3+ 1250 cells against a 1400-8000
      reference range.
  sequelae:
  - target: Impaired Lymphocyte Transformation with Phytohemagglutinin
    description: >
      The same T cell compartment showing reduced total number also showed
      reduced functional response to phytohemagglutinin stimulation, while
      responses to phorbol myristate acetate and CD3 activation were normal.

- name: Impaired Lymphocyte Transformation with Phytohemagglutinin
  description: >
    T cell activation in response to phytohemagglutinin (PHA) was reduced
    relative to control in the index patient, while responses to phorbol
    myristate acetate and CD3 activation were normal, localizing the
    functional defect to PHA-responsive signaling rather than a generic
    T cell activation failure.
  phenotype_term:
    preferred_term: Impaired lymphocyte transformation with phytohemagglutinin (PHA)
    term:
      id: HP:0031381
      label: Decreased mitogen-induced T-cell proliferation
  evidence:
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "T cell activation in \nresponse to phytohemagglutinin was reduced relative to control"
    explanation: >
      Directly documents the reduced PHA response in the index patient's
      T cell functional testing.

- name: Decreased Circulating IgG Concentration
  description: >
    Serum IgG was below the reference range in the index patient, part of a
    mild humoral deficit alongside the profound NK cell defect.
  phenotype_term:
    preferred_term: Decreased circulating IgG concentration
    term:
      id: HP:0004315
      label: Decreased circulating IgG concentration
  notes: >
    Serum IgG of 2.22 g/L against a 3-13.2 g/L reference range is recorded
    only as a cell in the laboratory table of PMID:32865517; the paper
    contains no sentence stating the finding. No evidence block is attached
    rather than quoting a bare table value, per the evidence SOP.

- name: Decreased Circulating IgM Concentration
  description: >
    Serum IgM was below the reference range in the index patient, part of a
    mild humoral deficit alongside the profound NK cell defect.
  phenotype_term:
    preferred_term: Decreased circulating IgM concentration
    term:
      id: HP:0002850
      label: Decreased circulating total IgM
  notes: >
    Serum IgM of 0.45 g/L against a 0.48-2.1 g/L reference range is recorded
    only as a cell in the laboratory table of PMID:32865517; the paper
    contains no sentence stating the finding. No evidence block is attached
    rather than quoting a bare table value, per the evidence SOP.

- name: Severe Cytomegalovirus Infection
  description: >
    Fatal susceptibility to CMV infection in infancy, the presenting and fatal
    complication of the NK cell deficiency in the index patient.
  phenotype_term:
    preferred_term: Severe cytomegalovirus infection
    term:
      id: HP:0031692
      label: Severe cytomegalovirus infection
  evidence:
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "impaired NK cell maturation in a child with fatal susceptibility to CMV"
    explanation: >
      Directly documents fatal CMV susceptibility as the clinical consequence
      of MCM10-associated NK cell deficiency in the reported infant.
  sequelae:
  - target: Fever at Presentation
    description: >
      Fever was part of the presenting clinical picture of the same acute
      CMV illness.
  - target: Organomegaly at Presentation
    description: >
      Organomegaly was part of the presenting clinical picture of the same
      acute CMV illness.
  - target: Diarrhea at Presentation
    description: >
      Diarrhea was part of the presenting clinical picture of the same acute
      CMV illness, consistent with CMV enteric involvement.
  - target: Hyperferritinemia with Hypofibrinogenemia (HLH-like Picture)
    description: >
      The acute CMV illness prompted a reactive, CMV-driven hyperinflammatory
      picture with elevated ferritin and triglycerides.
  - target: Hypertriglyceridemia
    description: >
      The acute CMV illness prompted a reactive, CMV-driven hyperinflammatory
      picture with elevated triglycerides, part of the same HLH-like
      laboratory picture as the ferritin elevation.
  - target: Hypofibrinogenemia
    description: >
      The acute CMV illness was accompanied by decreased fibrinogen, part of
      the same HLH-like laboratory picture.

- name: Fever at Presentation
  description: >
    Fever was part of the presenting clinical picture of the index NKD proband
    at 16 months of age, coincident with a high CMV viral load, before
    immunologic workup identified the underlying NK cell deficiency.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "at 16 months of age with fever, organomegaly, diarrhea, and CMV infection (2 × 10 6 copies/mL)"
    explanation: >
      Documents fever at presentation at 16 months of age, coincident with a
      high CMV viral load, in the index patient.

- name: Organomegaly at Presentation
  description: >
    Organomegaly was part of the presenting clinical picture of the index NKD
    proband at 16 months of age. The source reports only "organomegaly" and
    does not identify which organs were enlarged.
  phenotype_term:
    preferred_term: Organomegaly
  notes: >
    Deliberately left unbound to an ontology term. HPO has no generic
    "organomegaly" class, and the cited source (PMID:32865517) states only
    "organomegaly" — it never mentions liver or spleen enlargement, so the
    more specific HP:0001433 Hepatosplenomegaly would assert which organs
    were involved beyond what the evidence supports. Candidate for an HPO
    new-term request; per the no-term-beats-a-bad-term rule the binding is
    omitted rather than approximated.
  evidence:
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "at 16 months of age with fever, organomegaly, diarrhea, and CMV infection (2 × 10 6 copies/mL)"
    explanation: >
      Documents organomegaly at presentation at 16 months of age, coincident
      with a high CMV viral load, in the index patient.

- name: Diarrhea at Presentation
  description: >
    Diarrhea was part of the presenting clinical picture of the index NKD
    proband at 16 months of age, coincident with a high CMV viral load and
    consistent with CMV enteric involvement.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "at 16 months of age with fever, organomegaly, diarrhea, and CMV infection (2 × 10 6 copies/mL)"
    explanation: >
      Documents diarrhea at presentation at 16 months of age, coincident with
      a high CMV viral load, in the index patient.

- name: Hyperferritinemia with Hypofibrinogenemia (HLH-like Picture)
  description: >
    During the acute CMV illness, the index patient had markedly elevated
    ferritin, elevated triglycerides, and decreased fibrinogen, prompting
    consideration of hemophagocytic lymphohistiocytosis (HLH); SAP, XIAP,
    MHC I/II, and CD3-zeta were normal, arguing against a distinct primary
    HLH-causing defect and favoring a reactive, CMV-driven hyperinflammatory
    picture secondary to the underlying NK cell deficiency.
  phenotype_term:
    preferred_term: Hyperferritinemia
    term:
      id: HP:0003281
      label: Increased circulating ferritin concentration
  evidence:
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ferritin 33150 μg/L (15–100 μg/L)"
    explanation: >
      Reports the index patient's markedly elevated ferritin value from the
      clinical laboratory table.
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "elevated levels of ferritin and triglycerides"
    explanation: >
      Names ferritin and triglyceride elevation together as prompting HLH
      consideration during the acute CMV illness.

- name: Hypofibrinogenemia
  description: >
    Decreased fibrinogen during the acute CMV illness, part of the same
    HLH-like laboratory picture as the ferritin/triglyceride elevation.
  phenotype_term:
    preferred_term: Hypofibrinogenemia
    term:
      id: HP:0011900
      label: Hypofibrinogenemia
  evidence:
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fibrinogen 0.5 g/L (2–4 g/L)"
    explanation: >
      Reports the index patient's decreased fibrinogen value from the
      clinical laboratory table.

- name: Hypertriglyceridemia
  description: >
    Elevated triglycerides during the acute CMV illness, part of the same
    HLH-like laboratory picture as the ferritin elevation and decreased
    fibrinogen.
  phenotype_term:
    preferred_term: Hypertriglyceridemia
    term:
      id: HP:0002155
      label: Hypertriglyceridemia
  evidence:
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Triglycerides 1.7 mmol/L (0.4–1.6 mmol/L)"
    explanation: >
      Reports the index patient's elevated triglyceride value from the
      clinical laboratory table.

- name: Restrictive Cardiomyopathy
  description: >
    Restrictive cardiomyopathy reported in three affected members of a single
    unrelated family carrying a distinct pair of biallelic MCM10 variants
    (frameshift and splice-donor alleles).
  phenotype_term:
    preferred_term: Restrictive cardiomyopathy
    term:
      id: HP:0001723
      label: Restrictive cardiomyopathy
  evidence:
  - reference: PMID:33712616
    reference_title: "Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus"
    explanation: >
      Reports restrictive cardiomyopathy, together with splenic and thymic
      hypoplasia, in the second (RCM) kindred carrying biallelic MCM10
      variants.

- name: Hypoplasia of the Thymus
  description: >
    Thymic hypoplasia reported alongside restrictive cardiomyopathy and
    splenic hypoplasia in the RCM-affected family (lymphoreticular
    hypoplasia).
  phenotype_term:
    preferred_term: Hypoplasia of the thymus
    term:
      id: HP:0000778
      label: Hypoplasia of the thymus
  evidence:
  - reference: PMID:33712616
    reference_title: "Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus"
    explanation: >
      Directly documents thymic hypoplasia as part of the RCM-associated
      lymphoreticular hypoplasia phenotype.

- name: Hypoplastic Spleen
  description: >
    Splenic hypoplasia reported alongside restrictive cardiomyopathy and
    thymic hypoplasia in the RCM-affected family (lymphoreticular hypoplasia).
  phenotype_term:
    preferred_term: Hypoplastic spleen
    term:
      id: HP:0006270
      label: Hypoplastic spleen
  evidence:
  - reference: PMID:33712616
    reference_title: "Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus"
    explanation: >
      Directly documents splenic hypoplasia as part of the RCM-associated
      lymphoreticular hypoplasia phenotype.

experimental_models:
- name: Patient-derived iPSC-NK cell differentiation (MCM10 R426C/R582X)
  experimental_model_type: IPSC_DERIVED_MODEL
  cell_source: Patient-derived induced pluripotent stem cells (iPSCs)
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:32865517
  description: >
    iPSCs generated from the NKD proband (compound heterozygous MCM10
    p.R426C/p.R582X) and differentiated along the NK-cell lineage, alongside
    CRISPR-modeled patient variants in fibroblast and NK cell lines.
  modeled_mechanisms:
  - target: Impaired Terminal Maturation of NK Cell Precursors
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >
      Patient-derived iPSC-NK differentiation and MCM10 knockdown in NK cell
      lines reproduce the terminal NK maturation defect seen in the patient.
    readouts:
    - name: NK cell terminal maturation and functional acquisition
      target: Impaired Terminal Maturation of NK Cell Precursors
      direction: DECREASED
      interpretation: >
        Patient-iPSC-derived and MCM10-knockdown NK cells fail to complete
        terminal maturation and acquire immunological function.
      evidence:
      - reference: PMID:32865517
        reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "we further demonstrated that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function"
        explanation: >
          Directly reports the patient-iPSC-derived NK differentiation
          readout supporting this mechanism node.
    evidence:
    - reference: PMID:32865517
      reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "By modeling MCM10 deficiency in primary NK cell precursors, including patient-derived induced pluripotent stem cells, we further demonstrated that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function."
      explanation: >
        Establishes patient-derived iPSC-NK differentiation as informative
        for the NK terminal maturation mechanism node.

- name: MCM10 heterozygous (MCM10+/-) iPSC-NK differentiation
  experimental_model_type: IPSC_DERIVED_MODEL
  cell_source: iPSC (CRISPR-engineered MCM10 heterozygous knockout)
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:38262603
  description: >
    CRISPR-engineered MCM10 heterozygous (MCM10+/-) iPSC lines differentiated
    through hematopoietic stem cell and NK-lineage stages, used to test a
    gene-dosage threshold model of MCM10-dependent genome stability.
  modeled_mechanisms:
  - target: Impaired Terminal Maturation of NK Cell Precursors
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >
      MCM10 haploinsufficiency in iPSCs is sufficient to impair NK-lineage
      differentiation and block generation of mature NK cells, independently
      confirming the terminal-maturation defect with a distinct
      (heterozygous knockout, rather than patient compound-heterozygous)
      genotype.
    limitations: >-
      Models MCM10 haploinsufficiency rather than the patient's specific
      compound heterozygous missense/nonsense genotype, so it demonstrates a
      gene-dosage threshold effect rather than reproducing the exact allelic
      combination.
    readouts:
    - name: NK-lineage differentiation from hematopoietic progenitors
      target: Impaired Terminal Maturation of NK Cell Precursors
      direction: DECREASED
      interpretation: >
        MCM10+/- hematopoietic progenitors give rise to lymphoid progenitors
        but fail to generate mature NK cells, coincident with telomere
        erosion.
      evidence:
      - reference: PMID:38262603
        reference_title: "A critical threshold of MCM10 is required to maintain genome stability during differentiation of induced pluripotent stem cells into natural killer cells."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Although MCM10+/- HSCs were able to give rise to lymphoid progenitors, these did not generate mature NK cells."
        explanation: >
          Directly reports the block at the mature NK cell stage in this
          model.
    evidence:
    - reference: PMID:38262603
      reference_title: "A critical threshold of MCM10 is required to maintain genome stability during differentiation of induced pluripotent stem cells into natural killer cells."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "MCM10+/- iPSCs displayed defects in NK cell differentiation, exhibiting reduced yields of hematopoietic stem cells (HSCs)."
      explanation: >
        Establishes the MCM10+/- iPSC-NK differentiation system as
        informative for the NK terminal maturation mechanism node.

diagnosis:
- name: NK cell immunophenotyping by flow cytometry
  description: >
    Flow cytometric enumeration of peripheral blood NK cells (CD56+CD3-) and
    subset analysis (CD56bright vs. CD56dim) identified the profound NK cell
    deficit and the shift toward the immature CD56bright subset in the index
    patient.
  diagnosis_term:
    preferred_term: flow cytometry
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  results: >-
    Profoundly reduced frequency of peripheral blood NK cells with
    overrepresentation of the immature CD56bright subset.
  evidence:
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "flow cytometry of peripheral blood lymphocytes \ndemonstrated profoundly reduced frequency of NK cells"
    explanation: >
      Documents flow cytometric immunophenotyping as the diagnostic modality
      that identified the NK cell deficiency in the index patient.

- name: Molecular confirmation by whole exome sequencing
  description: >
    Trio-based whole exome sequencing of the proband and his parents
    identified the compound heterozygous MCM10 variants segregating with
    disease, confirming the molecular diagnosis.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  results: >-
    Compound heterozygous MCM10 variants (c.1276C>T, p.R426C and c.1744C>T,
    p.R582X) that were rare, predicted damaging, and segregated with disease.
  evidence:
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing identified compound heterozygous mutations that were rare and predicted to be damaging"
    explanation: >
      Documents whole exome sequencing as the diagnostic modality that
      identified and confirmed the causal MCM10 variants in the index
      patient.

treatments:
- name: Bone Marrow Transplantation
  description: >
    The index NKD patient underwent bone marrow transplantation for
    suspected primary immunodeficiency, but succumbed to overwhelming
    pre-existing CMV infection at 24 months of age; transplantation was
    performed after the CMV infection was already established rather than
    pre-emptively, so this single case does not demonstrate treatment
    efficacy and instead illustrates the importance of early recognition
    before severe viral disease is established.
  treatment_term:
    preferred_term: Hematopoietic Cell Transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  therapeutic_modality: CELL_THERAPY
  target_phenotypes:
  - preferred_term: Severely decreased mature natural killer cells
    term:
      id: HP:0040218
      label: Reduced total natural killer cell count
  evidence:
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient underwent bone marrow transplantation for suspect"
    explanation: >
      Documents that bone marrow transplantation was attempted in the index
      patient for suspected primary immunodeficiency.
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "succumbed to overwhelming preexisting CMV at 24 months"
    explanation: >
      The patient died of pre-existing CMV infection despite transplantation,
      indicating that transplantation performed after severe viral disease
      was already established was not able to rescue the patient in this
      single reported case.

genetic:
- name: MCM10
  gene_term:
    preferred_term: MCM10
    term:
      id: hgnc:18043
      label: MCM10
  relationship_type: CAUSATIVE
  notes: >
    MCM10 (minichromosome maintenance 10 replication initiation factor) is an
    essential activator/processivity factor of the eukaryotic CMG
    (CDC45-MCM2-7-GINS) replicative helicase. Both reported kindreds carry
    compound heterozygous variants that together reduce, but do not
    eliminate, MCM10 function (complete biallelic loss of MCM10 is expected
    to be incompatible with cell viability, since MCM10 is essential for DNA
    replication). The NKD proband carries a hypomorphic missense variant
    (c.1276C>T, p.R426C) together with a nonsense variant (c.1744C>T,
    p.R582X); the RCM family carries a frameshift variant (c.236delG,
    p.G79EfsTer6) together with a splice-donor variant (c.764+5G>A,
    p.D198GfsTer10). Neither variant set has been observed in homozygosity in
    population reference databases, consistent with very rare autosomal
    recessive alleles.
  evidence:
  - reference: PMID:33712616
    reference_title: "Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Minichromosome maintenance protein 10 (MCM10) is essential for eukaryotic DNA replication."
    explanation: >
      States the core molecular function of MCM10, the causal gene for this
      disorder.
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "was predicted to be disease causing by MutationTaster (score \n0.99) (34) and likely damaging by PolyPhen2 (score 1.0) (35)"
    explanation: >
      In silico pathogenicity predictions for the NKD-associated p.R426C
      missense variant support a damaging/hypomorphic effect.
  - reference: PMID:32865517
    reference_title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The nonsense variant was \nnot found in ExAC"
    explanation: >
      Documents that the NKD-associated p.R582X nonsense allele is absent
      from population reference databases, consistent with a very rare
      autosomal recessive pathogenic allele.

references:
- reference: PMID:32865517
  title: "Human NK cell deficiency as a result of biallelic mutations in MCM10."
- reference: PMID:33712616
  title: "Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening."
- reference: PMID:38262603
  title: "A critical threshold of MCM10 is required to maintain genome stability during differentiation of induced pluripotent stem cells into natural killer cells."
- reference: PMID:36809597
  title: "Unwinding the Role of the CMG Helicase in Inborn Errors of Immunity."
📚

References & Deep Research

References

4
PMID:32865517
Human NK cell deficiency as a result of biallelic mutations in MCM10.
No top-level findings curated for this source.
PMID:33712616
Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening.
No top-level findings curated for this source.
PMID:38262603
A critical threshold of MCM10 is required to maintain genome stability during differentiation of induced pluripotent stem cells into natural killer cells.
No top-level findings curated for this source.
PMID:36809597
Unwinding the Role of the CMG Helicase in Inborn Errors of Immunity.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 30 citations 2026-08-17T21:38:16.492574

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Immunodeficiency 80 with or without Congenital Cardiomyopathy
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Immunodeficiency 80 with or without Congenital Cardiomyopathy covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
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  • Protective Factors:

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  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive research report: Immunodeficiency 80 with or without congenital cardiomyopathy

Executive summary and evidence limitations

Immunodeficiency 80 with or without congenital cardiomyopathy is an ultra-rare, autosomal-recessive MCM10-related DNA-replication disorder. Its best-established postnatal presentation is developmental natural-killer-cell deficiency (NKD), with near-absent circulating NK cells, failure of terminal NK-cell maturation, and potentially fatal herpesvirus infection. A more severe allelic presentation has been associated with prenatal restrictive/congenital cardiomyopathy, fetal demise, and underdevelopment of lymphoid organs. Open Targets identifies MCM10 as the sole associated target and maps the disease to MONDO:0030266. (OpenTargets Search: Immunodeficiency 80 with or without congenital cardiomyopathy, schmit2024acriticalthreshold pages 9-10)

The evidence base is exceptionally small: the detailed immune phenotype rests principally on one child, whereas the cardiomyopathy association comes from a separate fetal family and later summaries. Consequently, phenotype frequencies, penetrance, survival rates, and treatment-response estimates cannot be calculated reliably. Claims below are labeled as direct human, experimental-model, or expert-review evidence.

evidence domain direct observation/model key quantitative finding evidence level source/date
Disease/entity identifiers Disease resolved as immunodeficiency 80 with or without congenital cardiomyopathy; causal gene MCM10; MONDO MONDO:0030266; Open Targets disease-target association links only MCM10 to this disease 1 target associated in Open Targets evidence set Curated disease database + literature linkage Open Targets context (OpenTargets Search: Immunodeficiency 80 with or without congenital cardiomyopathy)
Clinical presentation 1: postnatal immune phenotype Single male proband with classical NK-cell deficiency presenting at 16 months with fever, organomegaly, diarrhea, and CMV 2×10^6 copies/mL; died at 24 months Age at presentation 16 mo; CMV viral load 2×10^6 copies/mL; death at 24 mo Direct human case J Clin Invest 2020, published 2020-08-31 (mace2020humannkcell pages 2-3, mace2020humannkcell pages 1-2)
Clinical presentation 2: fetal cardiomyopathy Separate family/fetal presentation cited in later reviews and WGS study: severe restrictive/congenital cardiomyopathy with fetal demise/intrauterine death attributed to biallelic MCM10 loss; underdeveloped thymus/spleen also cited in 2024 mechanistic discussion Quantitative details not recoverable from available primary text; existence of fetal cardiomyopathy presentation repeatedly cited Indirect human evidence from secondary sources summarizing prior family Genome Med 2023; reviews 2021-2024 (schmit2024acriticalthreshold pages 9-10, schmit2021congenitaldiseasesof pages 14-16)
Postnatal causal variants Compound heterozygous MCM10 variants in proband: paternal missense NM_018518.5:c.1276C>T (p.Arg426Cys) and maternal nonsense NM_018518.5:c.1744C>T (p.Arg582Ter); segregated with autosomal-recessive disease Missense seen at extremely low frequency: ExAC 4.12×10^-5, gnomAD 2.5×10^-5; nonsense absent from ExAC/gnomAD in cited analysis Direct human genetics J Clin Invest 2020 (mace2020humannkcell pages 4-6, mace2020humannkcell pages 3-4)
Immune laboratory phenotype Profound NK-cell lymphopenia with broader mild lymphopenia/hypogammaglobulinemia CD56+CD3- 1/μL (ref 100-1400); CD3+ 1250 (1400-8000); CD4+ 770 (900-5500); CD8+ 280 (400-2300); CD19+ 210 (600-3100); IgG 2.22 g/L (3-13.2); IgM 0.45 g/L (0.48-2.1) Direct human case J Clin Invest 2020 (mace2020humannkcell pages 3-4, mace2020humannkcell pages 2-3)
Hyperinflammation/HLH-like features Workup considered HLH during CMV illness Ferritin 33,150 μg/L (15-100); triglycerides 1.7 mmol/L (0.4-1.6); fibrinogen 0.5 g/L (2-4) Direct human case J Clin Invest 2020 (mace2020humannkcell pages 3-4, mace2020humannkcell pages 2-3)
NK subset phenotype Peripheral blood and modeled systems showed near absence of NK cells with relative overrepresentation of immature CD56bright cells and reduced mature CD56dim cells NK frequency <1% in peripheral blood; about 50% of residual NK cells CD56bright in clinical assessment Direct human case + model recapitulation J Clin Invest 2020 (mace2020humannkcell pages 10-11, mace2020humannkcell pages 2-3, mace2020humannkcell pages 9-10)
Molecular consequence of p.Arg582Ter Premature stop predicted to undergo nonsense-mediated decay; if expressed, truncation impairs nuclear localization Endogenous truncated protein not detected; heterozygous engineered lines showed ~50% reduction in MCM10 protein expression Direct human cells + engineered human cells J Clin Invest 2020 (mace2020humannkcell pages 4-6)
Molecular consequence of p.Arg426Cys Missense does not abolish replisome assembly but impairs growth/chromatin dynamics and contributes to replication stress in compound state Homozygous engineered line retained ~80% growth vs WT; variant associated with increased chromatin retention of MCM10 Engineered human cell evidence linked to patient allele J Clin Invest 2020 (mace2020humannkcell pages 4-6, mace2020humannkcell pages 6-7)
Replication-stress phenotype Patient fibroblasts and MCM10-deficient NK-line models showed S-phase accumulation, enlarged nuclei, and increased DNA damage signaling Increased γH2AX foci and nuclear area; significant excess early S phase with reduced G2/M; patient-vs-control γH2AX comparisons reported P<0.0001 Direct patient cells + engineered cell models J Clin Invest 2020 (mace2020humannkcell pages 6-7, mace2020humannkcell pages 10-11, mace2020humannkcell pages 1-2)
2024 iPSC genomic-instability findings MCM10+/- iPSC lines used to model developmental threshold effects during NK differentiation Micronuclei markedly enriched for telomeric fragments: 83% of micronuclei in clone 10 contained telomeric foci; 17% also contained centromeric foci Experimental human iPSC model Open Biology 2024 (schmit2024acriticalthreshold pages 5-6, schmit2024acriticalthreshold pages 9-10)
2024 iPSC telomere/NK differentiation findings Reduced MCM10 caused impaired clonogenic survival, telomere erosion, reduced HSC output, and failure to form mature NK cells Disease model failed to generate mature stage 5 NK cells; telomere shortening/significant signal-free ends increased during LP→NK transition Experimental human iPSC model Open Biology 2024 (schmit2024acriticalthreshold pages 1-2, schmit2024acriticalthreshold pages 8-9)
Additional mechanistic profiling Independent replication-timing study of cells from a patient with MCM10 mutations Replication timing variability across 46% of genome, with replication delays and initiation-site gains/losses Experimental functional genomics in patient-derived cells Hum Mol Genet 2022 (caballero2021comprehensiveanalysisof pages 1-3)
Diagnostic approach Clinical immunophenotyping plus trio exome/genome-style rare disease sequencing; disease also highlighted by broader WGS literature as a diagnosis that can be missed without comprehensive genomic analysis Trio-based WES identified recessive MCM10 variants in index case; broader WGS cohort reported overall diagnostic yield 35% and 39% when novel candidates included Direct case + broader rare-disease genomics evidence J Clin Invest 2020; Genome Med 2023 (mace2020humannkcell pages 2-3, pagnamenta2023structuralandnoncoding pages 20-21)
Treatment evidence Only direct disease-specific treatment evidence is supportive care followed by bone marrow transplantation/HSCT in the index child; no approved targeted therapy identified Transplant performed, but patient succumbed to overwhelming preexisting CMV Direct human case J Clin Invest 2020 (mace2020humannkcell pages 2-3)
Prevention/surveillance implications No disease-specific prevention trials; by analogy to NKD/IEI, early recognition of herpesvirus susceptibility and genetic diagnosis is emphasized in expert review literature No disease-specific quantitative surveillance data Expert review inference J Clin Immunol 2023; J Hum Immunity 2025 (guilz2023unwindingtherole pages 1-2, guilz2023unwindingtherole pages 9-11)
Major evidence gaps Extremely few known patients/families; no prevalence/incidence, penetrance, sex ratio, standardized criteria, biomarker validation, natural-history cohort, or interventional trial specific to MCM10 disease Postnatal phenotype supported mainly by 1 well-described child; cardiomyopathy details incompletely recoverable from available primary text Evidence-gap assessment Synthesized from available contexts (mace2020humannkcell pages 2-3, schmit2024acriticalthreshold pages 9-10, pagnamenta2023structuralandnoncoding pages 20-21)

Table: This table compiles compact knowledge-base evidence for MCM10-associated immunodeficiency 80 with or without congenital cardiomyopathy. It separates direct human observations from model-based findings and highlights both established facts and major evidence gaps.

1. Disease information

Definition and classification

The disease is an inborn error of immunity caused by biallelic partial loss-of-function MCM10 variants. MCM10 encodes minichromosome-maintenance protein 10, an essential regulator of eukaryotic replisome assembly, activation, origin firing, replication-fork progression, and genome stability. In the postnatal phenotype, insufficient MCM10 selectively compromises proliferative transitions required to generate mature CD56^dim NK cells. (mace2020humannkcell pages 2-3, mace2020humannkcell pages 1-2, guilz2023unwindingtherole pages 1-2)

Suggested identifiers and names

  • MONDO: MONDO:0030266.
  • Causal gene: MCM10; Ensembl ENSG00000065328.
  • Disease name: Immunodeficiency 80 with or without congenital cardiomyopathy.
  • Common alternatives: MCM10 deficiency; MCM10-related NK-cell deficiency; MCM10-associated natural-killer-cell deficiency; NKD due to MCM10 deficiency.
  • OMIM: commonly represented as immunodeficiency 80; the exact OMIM accession was not independently recoverable from the retrieved primary texts and should be verified directly in OMIM before database ingestion.
  • Orphanet, MeSH, ICD-10/ICD-11: no dedicated disease-specific entries were established from the available evidence. Broader codes for primary immunodeficiency/NK-cell deficiency or cardiomyopathy would lose molecular specificity.

The principal evidence is aggregated disease-level literature derived from individual patients and families, not EHR-scale population data. The postnatal paper reports one child and experimental derivatives of his cells. (mace2020humannkcell pages 1-2)

2. Etiology, risk, protective factors, and gene–environment interaction

Causal factor

The primary cause is germline biallelic MCM10 dysfunction. In the postnatal proband, the paternal allele was NM_018518.5:c.1276C>T, p.(Arg426Cys) and the maternal allele was NM_018518.5:c.1744C>T, p.(Arg582Ter). The variants segregated as an autosomal-recessive trait. The stop-gain allele undergoes or is strongly predicted to undergo nonsense-mediated decay; experimentally expressed truncated protein also lacked effective nuclear localization. The missense allele retained protein expression and replisome interactions but impaired growth and chromatin dynamics, making the compound state hypomorphic rather than a complete null. (mace2020humannkcell pages 3-4, mace2020humannkcell pages 4-6)

The p.Arg582Ter allele was absent from ExAC and gnomAD in the cited analysis. p.Arg426Cys was extremely rare—approximately 4.12×10^-5 in ExAC and 2.5×10^-5 in gnomAD, with no reported homozygotes—and had CADD 24.3, PolyPhen-2 1.0, and MutationTaster 0.99 in the original study. These are supporting, not independently sufficient, pathogenicity data. (mace2020humannkcell pages 3-4)

Risk and protective factors

  • Established genetic risk: inheriting two functionally damaging MCM10 alleles in trans.
  • Family history/consanguinity: the index child’s parents were healthy and nonconsanguineous; consanguinity is not required. (mace2020humannkcell pages 2-3)
  • Modifier genes, founder alleles, anticipation, or germline mosaicism: not established.
  • Sex, ancestry, age, lifestyle, toxin, dietary, or occupational risks: no evidence of causal effects.
  • Protective genetic or environmental factors: none identified.

Gene–environment interaction

Infection does not cause the Mendelian disorder, but viral exposure reveals the immune defect. NK-cell failure particularly compromises early control of herpesviruses; the index child developed overwhelming CMV. Thus, the defensible causal chain is MCM10 hypomorphism → defective NK maturation → impaired antiviral cellular defense → severe CMV disease, with infection acting as a clinical trigger rather than a genetic modifier. (mace2020humannkcell pages 10-11, guilz2023unwindingtherole pages 1-2, mace2020humannkcell pages 2-3)

3. Phenotypes

Direct postnatal human phenotype

The male proband was apparently well until 16 months, when he presented with fever, organomegaly, diarrhea, and CMV at 2×10^6 copies/mL. He had profound NK lymphopenia: CD56+CD3− cells were 1/µL versus a reference interval of 100–1,400. NK cells constituted less than 1% of peripheral blood lymphocytes; approximately half of the very small residual population appeared CD56^bright, indicating relative loss of terminally mature CD56^dim cells. (mace2020humannkcell pages 10-11, mace2020humannkcell pages 2-3)

Other abnormalities were milder: CD3 1,250/µL, CD4 770/µL, CD8 280/µL, CD19 210/µL, IgG 2.22 g/L, and IgM 0.45 g/L. T-cell activation to phytohemagglutinin was reduced, whereas responses to PMA and CD3 stimulation were normal. Ferritin was 33,150 µg/L, triglycerides 1.7 mmol/L, and fibrinogen 0.5 g/L, producing an HLH-like inflammatory picture during CMV infection. (mace2020humannkcell pages 2-3, mace2020humannkcell pages 3-4)

The child received bone-marrow transplantation but died at 24 months from overwhelming pre-existing CMV. This establishes severe early-childhood morbidity and mortality but does not provide a population survival estimate. (mace2020humannkcell pages 2-3)

Prenatal/cardiac phenotype

Later literature describes a separate, more severe biallelic MCM10 presentation with fetal restrictive/congenital cardiomyopathy, intrauterine death, and underdeveloped thymus and spleen. The available excerpts do not permit reliable extraction of the complete pedigree, exact fetal phenotype frequencies, or all variant nomenclature; these details should therefore remain provisional. (schmit2024acriticalthreshold pages 9-10)

Suggested phenotype ontology mappings

  • Natural killer cell deficiency — HP:0002846 (verify current HPO label/version).
  • Lymphopenia — HP:0001888.
  • Hypogammaglobulinemia — HP:0004313.
  • Recurrent/severe viral infection or recurrent herpesvirus infection — use the most specific current HPO viral-infection term available.
  • Cytomegalovirus infection — map to an HPO infectious-disease term where available; otherwise SNOMED CT/NCBI Taxonomy Human betaherpesvirus 5, Taxon 10359.
  • Fever — HP:0001945.
  • Hepatosplenomegaly/organomegaly — HP:0001433 or organ-specific terms if documented.
  • Diarrhea — HP:0002014.
  • Hyperferritinemia — HP:0003281.
  • Hypofibrinogenemia — HP:0011900.
  • Restrictive cardiomyopathy — HP:0001723.
  • Intrauterine fetal demise — use the current HPO fetal-death term.

Because only one postnatal patient is deeply characterized, frequencies should be entered as 1/1 observed, not “100% of patients.” No validated disease-specific quality-of-life instruments or scores have been reported. Severe infection, hospitalization, transplantation, and death imply profound functional impact.

4. Genetic and molecular information

Gene and variants

MCM10 encodes a nonredundant replisome factor that binds MCM2–7, CDC45, and DNA and supports replication initiation and elongation. Complete loss is generally incompatible with cell viability or embryonic development, explaining why surviving human disease alleles are likely hypomorphic. (mace2020humannkcell pages 2-3, mace2020humannkcell pages 4-6, mace2020humannkcell pages 10-11)

The postnatal alleles are germline, not somatic:

  1. c.1276C>T, p.Arg426Cys: rare missense allele; stable and nuclear but associated with impaired proliferation and excessive chromatin retention. An engineered homozygous line retained approximately 80% of wild-type growth.
  2. c.1744C>T, p.Arg582Ter: nonsense allele; endogenous truncated protein was not detected, consistent with nonsense-mediated decay. Engineered heterozygous cells showed approximately 50% MCM10 reduction and 50% reduced growth. (mace2020humannkcell pages 3-4, mace2020humannkcell pages 4-6)

The functional consequence is best described as compound partial loss of function. The original publication supplied strong functional evidence, but contemporary ClinVar classifications and review status should be checked directly before assigning a final ACMG/AMP category. No dominant-negative or gain-of-function mechanism has been demonstrated.

No validated modifier gene, disease-specific epigenetic signature, recurrent chromosomal abnormality, or somatic second hit is known. Increased chromosome breakage/translocations in deficient cells are downstream consequences of replication stress, not the inherited cause. (schmit2021congenitaldiseasesof pages 14-16)

5. Environmental and infectious information

No toxin, radiation, pollution, smoking, alcohol, diet, or exercise exposure is known to initiate MCM10 disease. The clinically important exposure class is viral infection, especially herpesviruses. Reviews of CMG-helicase NKD emphasize susceptibility to CMV, VZV, and EBV; only CMV is directly documented in the MCM10 index child. (guilz2023unwindingtherole pages 1-2, mace2020humannkcell pages 2-3)

There is no zoonotic or person-to-person transmission of the genetic disorder. Ordinary viral transmission remains relevant because the host defect magnifies disease severity.

6. Mechanism and pathophysiology

Upstream molecular defect

MCM10 participates in activating and stabilizing the CDC45–MCM2-7–GINS replicative helicase and supports origin firing and replication-fork processivity. The two patient alleles lower the quantity and quality of functional nuclear MCM10. (mace2020humannkcell pages 2-3, mace2020humannkcell pages 4-6)

Causal chain

Biallelic MCM10 hypomorphism → defective origin activation/fork progression → prolonged early S phase and replication stress → γH2AX activation, micronuclei, fragile-site instability, and telomere erosion → poor survival/output of hematopoietic stem/progenitor cells and failure of late NK-cell maturation → profound loss of CD56^dim NK cells → severe herpesvirus susceptibility. In more severe allelic combinations, the same replication threshold may be crossed during cardiac and lymphoid-organ development, producing prenatal cardiomyopathy and fetal death. (mace2020humannkcell pages 6-7, mace2020humannkcell pages 10-11, schmit2024acriticalthreshold pages 9-10, schmit2024acriticalthreshold pages 1-2)

Patient fibroblasts had increased nuclear area, more γH2AX signal, increased S-phase accumulation, reduced G2/M representation, and excessive MCM10 chromatin association. Patient-derived or knockdown NK models reproduced impaired terminal maturation. (mace2020humannkcell pages 6-7, mace2020humannkcell pages 10-11, mace2020humannkcell pages 9-10)

Recent 2024 development

The 2024 iPSC study refined this mechanism by demonstrating a dose-dependent MCM10 threshold. MCM10+/− iPSCs had impaired clonogenic survival, micronuclei, and telomere erosion. Eighty-three percent of micronuclei in one clone contained telomeric foci, and 17% also contained centromeric foci. Mutant cells generated fewer HSCs; lymphoid progenitors formed but failed to produce mature stage-5 NK cells. Telomere signal-free ends increased during the lymphoid-progenitor-to-NK transition. Residual stage-4 cells could retain degranulation/cytokine competence, indicating that deficient cell number and maturation, rather than universal intrinsic cytotoxic failure, is central. (schmit2024acriticalthreshold pages 1-2, schmit2024acriticalthreshold pages 5-6, schmit2024acriticalthreshold pages 9-10)

A replication-timing analysis found variability across 46% of the genome in MCM10-mutant cells, dominated by replication delays and gains/losses of initiation sites. This supports a genome-wide initiation defect, although it derives from cells from a single patient and is not a clinical biomarker. (caballero2021comprehensiveanalysisof pages 1-3)

Suggested ontology annotations

GO biological process: DNA replication initiation; DNA replication; DNA-dependent DNA replication maintenance; replication-fork progression; DNA-damage response; cell-cycle S-phase transition; telomere maintenance; chromosome segregation; hematopoietic stem-cell differentiation; NK-cell differentiation; antiviral immune response.

GO cellular component: nucleus; chromatin; replication fork; replisome; CMG complex; chromosome/telomere.

Cell Ontology: natural killer cell CL:0000623; CD56-bright NK cell and CD56-dim NK cell subtypes where supported by the current CL release; hematopoietic stem cell CL:0000037; lymphoid progenitor cell; dermal fibroblast; cardiomyocyte.

No disease-specific metabolomic, lipidomic, proteomic, spatial-transcriptomic, or patient single-cell atlas was found. The strongest “multi-omic” evidence is functional genomics/replication timing plus telomere cytogenetics.

7. Anatomical structures affected

  • Primary immune sites: peripheral blood NK compartment, bone marrow/hematopoietic progenitor compartment, and—based on fetal observations—thymus and spleen.
  • Cardiovascular: myocardium in the congenital/restrictive-cardiomyopathy presentation.
  • Secondary sites during infection: gastrointestinal tract and reticuloendothelial organs, reflected by diarrhea and organomegaly during CMV disease.
  • Subcellular: nucleus, chromatin-bound replisome, replication forks, chromosomes, and telomeres.

Suggested UBERON mappings include blood UBERON:0000178, bone marrow UBERON:0002371, spleen UBERON:0002106, thymus UBERON:0002370, heart UBERON:0000948, and myocardium UBERON:0002349. There is no relevant lateralization.

8. Temporal development

The disease begins molecularly in embryonic development, but clinical timing is allele-dependent:

  • Severe prenatal form: congenital cardiomyopathy with fetal demise.
  • Surviving postnatal form: apparently delayed recognition until severe infection at 16 months, followed by rapid deterioration and death at 24 months.

The genetic and NK-development defects are lifelong. Infectious manifestations may be episodic, but uncontrolled CMV can be progressive and fatal. No accepted disease stages, remission pattern, or longitudinal progression rate exists. The critical intervention window is likely before acquisition or dissemination of a major herpesvirus, because transplantation did not rescue the child from established overwhelming CMV. This is biologically and clinically plausible but supported by only one direct case. (mace2020humannkcell pages 2-3)

9. Inheritance and population

Inheritance is autosomal recessive. Healthy heterozygous parents transmitted one allele each to the index child. For two carrier parents, standard Mendelian counseling gives a 25% affected, 50% carrier, and 25% unaffected/noncarrier probability for each pregnancy, assuming both variants are truly pathogenic and no unusual reproductive mechanism. (mace2020humannkcell pages 2-3, mace2020humannkcell pages 4-6)

Prevalence and incidence per 100,000, carrier frequency, penetrance, sex ratio, geographic distribution, founder effects, and ancestry enrichment are unknown. The observed cohort is too small to assess variable expressivity formally, although the immune-versus-prenatal-cardiac presentations strongly suggest allelic severity and/or tissue-specific threshold effects. Anticipation is not expected for this variant class and has not been reported.

10. Diagnostics

Clinical and laboratory evaluation

In a child with severe or unusual herpesvirus disease, test:

  1. CBC with differential and lymphocyte subsets.
  2. Flow cytometry for CD3, CD4, CD8, CD19, and CD3−CD56+ NK cells.
  3. NK subsets, especially CD56^bright/CD56^dim distribution and maturation markers such as CD16.
  4. NK cytotoxicity/degranulation where available, recognizing that residual immature cells may retain some function.
  5. Quantitative immunoglobulins, vaccine responses, T-cell proliferation, and broader IEI assessment.
  6. CMV/EBV viral-load PCR and organ-specific evaluation.
  7. Ferritin, triglycerides, fibrinogen, soluble IL-2 receptor, and marrow/HLH work-up when hyperinflammation is suspected.
  8. ECG and echocardiography; consider cardiac MRI if the phenotype or family history suggests cardiomyopathy.

The index child’s HLH differential was supported by extreme ferritin and hypofibrinogenemia, but SAP, XIAP, MHC-I/MHC-II, and CD3ζ testing was normal. (mace2020humannkcell pages 2-3)

Genetic testing

A practical approach is an IEI/NKD panel containing MCM10, MCM4, GINS1, GINS4, IRF8, GATA2, RTEL1, POLE1, and POLE2, or trio WES/WGS when the presentation is syndromic or panel-negative. The index diagnosis was made by trio WES. Sanger or orthogonal confirmation, parental phasing, copy-number analysis, and transcript studies for splice/nonsense alleles are appropriate. (mace2020humannkcell pages 2-3)

WGS is useful when coding analysis is unrevealing because it can detect structural, intronic, and splice-altering variants. In a broader rare-disease cohort, comprehensive WGS achieved 35% confirmed diagnostic yield, or 39% including novel candidates; structural/splice/deep-intronic variants made substantial contributions. These percentages are not MCM10-specific. (pagnamenta2023structuralandnoncoding pages 20-21)

CMA, karyotyping, FISH, mitochondrial sequencing, and repeat-expansion testing are not first-line tests for this single-gene recessive disorder unless another diagnosis is suspected. RNA sequencing may help establish aberrant splicing or nonsense-mediated decay but is not a validated stand-alone diagnostic.

Differential diagnosis

Key alternatives include MCM4-, GINS1-, or GINS4-related NKD; GATA2 and IRF8 deficiency; RTEL1/telomere disorders; POLE1/POLE2 replication disorders; familial HLH; XLP1/SH2D1A; XIAP deficiency; severe combined or combined immunodeficiency; and congenital CMV infection. Congenital cardiomyopathy additionally requires exclusion of sarcomeric, mitochondrial, storage, and other DNA-replication disorders. Relative preservation/overrepresentation of CD56^bright cells with loss of CD56^dim cells points toward a CMG-replisome maturation defect. (mace2020humannkcell pages 2-3, guilz2023unwindingtherole pages 7-8)

No newborn screening assay or standardized diagnostic criteria are available. Cascade molecular testing is appropriate after a familial genotype is established.

11. Outcome and prognosis

The only deeply characterized postnatal patient died at age two, despite transplantation, from pre-existing CMV. Therefore, five- and ten-year survival, life expectancy, mortality rate, disability outcomes, and validated quality-of-life measures are unavailable. (mace2020humannkcell pages 2-3)

Probable adverse prognostic factors are severe early herpesvirus infection, extremely low NK count, inability to clear viremia before transplantation, HLH-like hyperinflammation, and variants producing a lower residual MCM10 level. The last factor is supported mechanistically by dose-dependent iPSC phenotypes rather than a human prognostic cohort. (schmit2024acriticalthreshold pages 5-6, schmit2024acriticalthreshold pages 1-2)

Long-term malignancy risk is biologically plausible because MCM10 deficiency causes genome instability and NK cells contribute to tumor surveillance; however, no MCM10-specific cancer-incidence estimate exists, and the tiny cohort precludes inference. (guilz2023unwindingtherole pages 9-11)

12. Treatment

There is no approved MCM10-targeted pharmacotherapy, gene therapy, RNA therapy, or genotype-specific drug.

Current clinical management

  • Prompt specialist management of CMV or other herpesvirus infection using pathogen-appropriate antivirals and quantitative PCR monitoring.
  • Immunoglobulin replacement when clinically significant hypogammaglobulinemia or poor antibody responses are present.
  • Antimicrobial prophylaxis individualized to immune phenotype and infection history.
  • HLH-directed treatment if formal criteria are met; evidence is extrapolated rather than MCM10-specific.
  • Cardiomyopathy-directed therapy according to pediatric cardiology standards, including heart-failure and arrhythmia management when applicable.
  • Allogeneic hematopoietic stem-cell transplantation (HSCT) is biologically capable of replacing defective hematopoiesis, but direct evidence consists of one unsuccessful case in which overwhelming CMV was already present. It cannot currently be assigned a response rate. (mace2020humannkcell pages 2-3)

Suggested NCIT intervention mappings include Hematopoietic Stem Cell Transplantation, Antiviral Therapy, Immunoglobulin Replacement Therapy, and supportive/palliative care terms in the current NCIT release. Specific antiviral CHEBI/NCIT terms should be selected based on the drug actually administered; the source did not provide a recoverable antiviral regimen.

No disease-specific ClinicalTrials.gov interventional study was identified. Experimental correction of MCM10 in autologous HSCs is conceptually possible but faces a narrow dosage window: too little MCM10 impairs replication, while uncontrolled alteration of an essential genome-stability protein could be unsafe.

13. Prevention

Primary prevention

The inherited defect cannot be prevented by lifestyle change. Reproductive options after molecular diagnosis include carrier testing, cascade testing, prenatal diagnosis, and preimplantation genetic testing for monogenic disease. Genetic counseling should discuss the 25% recurrence risk for two confirmed carriers.

Secondary and tertiary prevention

Early molecular diagnosis, baseline viral screening, rapid PCR testing during febrile illness, avoidance of unmonitored live vaccines until immune competence is defined, and individualized prophylaxis may reduce infectious morbidity. Household contacts should follow routine immunization guidance, and CMV-safe blood products should be considered under applicable immunocompromised-patient standards. These are expert-practice extrapolations; no MCM10-specific prevention trial exists.

The index case suggests that controlling active CMV before HSCT is critical, although one observation cannot define an algorithm. Regular immune, infectious-disease, and cardiac surveillance is prudent. (mace2020humannkcell pages 2-3)

14. Other species and natural disease

  • Human: Homo sapiens, NCBI Taxon 9606.
  • Mouse: Mus musculus, Taxon 10090; complete Mcm10 deletion is embryonic lethal, limiting disease recapitulation. Heterozygous mice do not reproduce the compound hypomorphic human syndrome reliably. (mace2020humannkcell pages 10-11, schmit2024acriticalthreshold pages 8-9)
  • Zebrafish: Danio rerio, Taxon 7955; experimental work supports an evolutionarily conserved requirement for mcm10 in hematopoietic-stem-cell emergence. (schmit2024acriticalthreshold pages 9-10)

No naturally occurring veterinary MCM10 immunodeficiency/cardiomyopathy syndrome, breed association, or zoonotic potential was identified. Animal evidence is experimentally induced, not a transmissible natural disease.

15. Model organisms and experimental systems

Human cellular models

Patient dermal fibroblasts directly demonstrated S-phase dysregulation, γH2AX accumulation, enlarged nuclei, and abnormal chromatin retention. Engineered hTERT-RPE1 and 293T cells separated the effects of p.Arg426Cys and p.Arg582Ter; CRISPR-reduced NK92 cells demonstrated impaired cell-cycle progression. (mace2020humannkcell pages 6-7, mace2020humannkcell pages 4-6)

Developmental models

MCM10-knockdown CD34+ precursors accumulated at early NK developmental stages and generated fewer mature stage-4/5 cells. Patient-derived iPSCs were differentiated to CD34+ precursors and transplanted into NSG mice; all four patient-derived humanized mice showed excess CD56^bright cells and increased γH2AX, recapitulating the human maturation phenotype. (mace2020humannkcell pages 8-9, mace2020humannkcell pages 9-10)

The 2024 heterozygous iPSC system enables dose-response analysis and identifies telomere erosion during HSC/NK differentiation as a major bottleneck. Its limitation is that engineered MCM10+/− clones do not exactly reproduce every compound-heterozygous patient allele or the cardiac phenotype. (schmit2024acriticalthreshold pages 1-2)

Animal-model limitations

Complete mouse knockout is embryonic lethal, while a single null allele is insufficient to model the human compound-hypomorphic state. NSG humanized mice model human NK development but not a complete immune system or congenital cardiomyopathy. Zebrafish support conserved hematopoietic biology but have not yet established full phenotypic equivalence to the human disorder. (mace2020humannkcell pages 10-11, schmit2024acriticalthreshold pages 9-10, schmit2024acriticalthreshold pages 8-9)

Key verbatim evidence excerpts

From Mace et al., published 31 August 2020, Journal of Clinical Investigation, DOI 10.1172/JCI134966, PMID 32865517:

“Here, we report a cause of NKD resulting from compound heterozygous mutations in minichromosomal maintenance complex member 10 (MCM10) that impaired NK cell maturation in a child with fatal susceptibility to CMV.” (mace2020humannkcell pages 1-2)

“Together, these data define MCM10 as an NKD gene and provide biological insight into the requirement for the DNA replisome in human NK cell maturation and function.” (mace2020humannkcell pages 1-2)

From Schmit et al., published January 2024, Open Biology, DOI 10.1098/rsob.230407:

“The lack of mature NK cells coincided with telomere erosion, suggesting that NKD caused by these MCM10 variants arose from the accumulation of genomic instability including degradation of chromosome ends.” (schmit2024acriticalthreshold pages 1-2)

From Guilz et al., published February 2023, Journal of Clinical Immunology, DOI 10.1007/s10875-023-01437-3: the expert review concludes that CMG-helicase variants unexpectedly produce NK-cell-focused inborn errors of immunity and emphasizes that the reason for NK-cell-selective vulnerability remains incompletely resolved. (guilz2023unwindingtherole pages 9-11, guilz2023unwindingtherole pages 1-2)

Knowledge-base conclusion

The highest-confidence entry is: biallelic hypomorphic MCM10 variants cause an autosomal-recessive replisome disorder characterized by defective terminal NK-cell maturation, profound NK lymphopenia, and severe herpesvirus susceptibility; more severe alleles can produce prenatal restrictive cardiomyopathy and fetal lethality. The mechanistic evidence is strong across patient cells, engineered lines, iPSC differentiation, and humanized mice, but clinical evidence remains too sparse for reliable phenotype frequencies, epidemiology, penetrance, prognosis, or treatment-effect estimates. Future priorities are additional case ascertainment, direct characterization of the fetal cardiomyopathy alleles, standardized NK phenotyping, longitudinal viral and cardiac surveillance, and preclinical evaluation of safely dosage-controlled hematopoietic correction.

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  17. (guilz2023unwindingtherole pages 9-11): Nicole C. Guilz, Yong-Oon Ahn, Seungmae Seo, and Emily M. Mace. Unwinding the role of the cmg helicase in inborn errors of immunity. Journal of Clinical Immunology, pages 1-15, Feb 2023. URL: https://doi.org/10.1007/s10875-023-01437-3, doi:10.1007/s10875-023-01437-3. This article has 13 citations and is from a domain leading peer-reviewed journal.

  18. (guilz2023unwindingtherole pages 7-8): Nicole C. Guilz, Yong-Oon Ahn, Seungmae Seo, and Emily M. Mace. Unwinding the role of the cmg helicase in inborn errors of immunity. Journal of Clinical Immunology, pages 1-15, Feb 2023. URL: https://doi.org/10.1007/s10875-023-01437-3, doi:10.1007/s10875-023-01437-3. This article has 13 citations and is from a domain leading peer-reviewed journal.

  19. (mace2020humannkcell pages 8-9): Emily M. Mace, Silke Paust, Matilde I. Conte, Ryan M. Baxley, Megan M. Schmit, Sagar L. Patil, Nicole C. Guilz, Malini Mukherjee, Ashley E. Pezzi, Jolanta Chmielowiec, Swetha Tatineni, Ivan K. Chinn, Zeynep Coban Akdemir, Shalini N. Jhangiani, Donna M. Muzny, Asbjørg Stray-Pedersen, Rachel E. Bradley, Mo Moody, Philip P. Connor, Adrian G. Heaps, Colin Steward, Pinaki P. Banerjee, Richard A. Gibbs, Malgorzata Borowiak, James R. Lupski, Stephen Jolles, Anja K. Bielinsky, and Jordan S. Orange. Human nk cell deficiency as a result of biallelic mutations in mcm10. Journal of Clinical Investigation, 130:5272-5286, Aug 2020. URL: https://doi.org/10.1172/jci134966, doi:10.1172/jci134966. This article has 79 citations and is from a highest quality peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 7
Resolved 7
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 7
On topic 4
Off topic 0

All extracted references resolved successfully.