| Field | Key fact | Evidence / uncertainty |
|---|---|---|
| Disease identity | Spondyloepiphyseal dysplasia, Nishimura type; also **SED, MIR140 type Nishimura** or **MIR140-related skeletal dysplasia** | Ultra-rare, monoallelic Mendelian skeletal dysplasia first delineated in 2019. (pqac-00000002, pqac-00000003) |
| Identifiers | **OMIM 618618**; **Orphanet 163649**; **MONDO:0032835** | Orphanet identifier is supported by Open Targets; OMIM and MONDO identifiers were user-supplied and were not independently verified with the available tools. (pqac-00000007) |
| Causal gene / variant | **MIR140** (microRNA 140; Ensembl **ENSG00000208017**); heterozygous **NR_029681.1:n.24A>G**, equivalent to **chr16:g.69967007A>G (hg19)** | The substitution affects the miR-140-5p seed region. Only this recurrent disease-causing variant was established in the retrieved human literature. (pqac-00000004, pqac-00000007) |
| Inheritance | Autosomal dominant / monoallelic; de novo in two probands and transmitted from an affected mother to her son | Germline variant with vertical segregation in one family; recurrence risk is 50% for an affected heterozygote, while parental germline mosaicism after an apparently de novo event remains theoretically possible but unquantified. (pqac-00000001, pqac-00000006) |
| Known human evidence | **3 affected individuals from 2 unrelated families** in the foundational report; **PMID 30804514** | No substantive additional human cohort was identified through the 2023–2024 literature search, so frequencies and penetrance estimates remain highly uncertain. (pqac-00000001, pqac-00000007) |
| Core phenotype | Disproportionate short stature, short limbs, small hands and feet, severe brachydactyly with cone-shaped phalangeal epiphyses, midface hypoplasia/small nose, delayed hip and knee epiphyseal ossification, small epiphyses, mild platyspondyly/spondylar dysplasia, and scaphocephaly | Adult findings included premature spondylosis and degenerative joint disease; respiratory infections, prolonged cough, stridor, and suspected laryngeal-cartilage laxity/narrowing occurred in two related patients. Intelligence, hearing, vision, dentition, routine blood tests, and age-adjusted bone density were reported as normal where assessed. (pqac-00000001, pqac-00000003, pqac-00000004) |
| Mechanism | Neomorphic miRNA seed mutation causes **loss of normal targeting plus gain of novel targeting**: wild-type miR-140-5p targets are derepressed, mutant-seed targets are repressed, and mutant miR-140-5p competes with **YBX1** at overlapping RNA sites | Demonstrated in chondrocytes and a corresponding knock-in mouse. A newer preclinical model proposes a downstream **HIF1A↓ → glycolysis↓ → citrate/acetyl-CoA↓ → histone acetylation↓ → FGFR3↑** branch, but direct MIR140-to-FGFR3 epigenetic causality remains inferred. (pqac-00000002, pqac-00000009, pqac-00000010) |
| Diagnosis | Recognition of the characteristic spondyloepiphyseal/brachydactyly pattern followed by sequencing that adequately covers **noncoding MIR140**; confirm the variant by an orthogonal method and test parents | WES may miss or inadequately prioritize a microRNA locus; WGS enabled discovery after coding-exome analysis was unrevealing. Differentiate from acrodysostosis, which commonly has advanced carpal ossification, endocrine abnormalities, and **PDE4D** or **PRKAR1A** variants. No standardized disease-specific criteria or validated biochemical biomarker exists. (pqac-00000003, pqac-00000006) |
| Management / trials | No disease-modifying drug, gene/RNA therapy, approved targeted treatment, or disease-specific interventional trial was identified | Care is supportive and individualized: orthopedic and spine surveillance, joint/pain management, physical and occupational therapy, airway/ENT evaluation when symptomatic, and genetic counseling. These measures are extrapolated from skeletal-dysplasia practice rather than tested specifically in MIR140 disease. |
| Epidemiology | Prevalence, incidence, carrier frequency, sex ratio, ethnic enrichment, and geographic distribution are unknown | Only three molecularly confirmed individuals in two families were documented in the retrieved primary human evidence; no founder effect is known. (pqac-00000001, pqac-00000012) |
| Models | CRISPR **Mir140 seed knock-in mouse**, **Mir140-null mouse**, primary mouse chondrocytes, reporter/transcriptomic systems, and zebrafish functional assays | Seed knock-in mice reproduce delayed ossification, reduced **Col10a1**, widened growth plates, expanded resting zones, reduced epiphyseal mineralization, and mildly flat vertebrae; null mice show distinct loss-of-function biology involving **DNPEP/BMP** and **PTHrP–HDAC4–MEF2C/p38** pathways. No naturally occurring veterinary counterpart was identified. (pqac-00000004, pqac-00000013, pqac-00000017, pqac-00000018) |


*Table: Compact evidence summary of the disease identity, defining MIR140 variant, clinical spectrum, mechanism, diagnosis, management, epidemiology, and experimental models. It highlights where conclusions rest on only three reported human cases or on preclinical evidence.*