| 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 (pqac-00000000) |
| 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 (pqac-00000007, pqac-00000024, pqac-00000008) |
| 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 (pqac-00000027, pqac-00000017) |
| 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 (pqac-00000010, pqac-00000009) |
| 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 (pqac-00000001, pqac-00000007, pqac-00000009) |
| 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 (pqac-00000001, pqac-00000007, pqac-00000009) |
| 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 (pqac-00000006, pqac-00000007, pqac-00000002) |
| 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 (pqac-00000010) |
| 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 (pqac-00000010, pqac-00000005) |
| 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 (pqac-00000005, pqac-00000006, pqac-00000032) |
| 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 (pqac-00000014, pqac-00000027) |
| 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 (pqac-00000012, pqac-00000029, pqac-00000030) |
| 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 (pqac-00000015) |
| 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 (pqac-00000007, pqac-00000022) |
| 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 (pqac-00000024) |
| 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 (pqac-00000016, pqac-00000013) |
| 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 (pqac-00000024, pqac-00000027, pqac-00000022) |


*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.*