| Domain | High-confidence finding | Suggested ontology identifiers/terms | Evidence type/strength |
|---|---|---|---|
| Identifiers | Short-rib thoracic dysplasia 9 with or without polydactyly (SRTD9) is an IFT140-related skeletal ciliopathy overlapping Mainzer–Saldino syndrome, Jeune/asphyxiating thoracic dystrophy, and occasionally cranioectodermal dysplasia. (pqac-00000000, pqac-00000001, pqac-00000008) | MONDO:0009964; OMIM:266920; Mainzer–Saldino syndrome; conorenal syndrome | Curated resources and human molecular studies; **high** |
| Gene and inheritance | SRTD9 is caused by biallelic germline pathogenic variants in **IFT140** and is autosomal recessive. Homozygous and compound-heterozygous cases are established. (pqac-00000002, pqac-00000003, pqac-00000004) | IFT140; HGNC:29077; ENSG00000187535; HP:0000007 Autosomal recessive inheritance | Human segregation and functional evidence; **high** |
| Allelic distinction | Monoallelic IFT140 loss-of-function variants cause a distinct autosomal-dominant polycystic-kidney-disease spectrum, not SRTD9. IFT172 may cause an overlapping Mainzer–Saldino phenotype but is not the defining gene for IFT140-related SRTD9. (pqac-00000000, pqac-00000007, pqac-00000011) | MONDO:0100509 IFT140-related recessive ciliopathy; IFT172; HP:0000006 Autosomal dominant inheritance | Human cohorts and curated associations; **high** |
| Variant spectrum | Disease alleles include missense, nonsense, frameshift, splice-altering variants, and multiexon tandem duplications. A recurrent exons 27–30 duplication may be missed by routine exome analysis. Viable patients commonly retain at least one hypomorphic/nontruncating allele, suggesting complete biallelic loss may be embryonically lethal. (pqac-00000002, pqac-00000005, pqac-00000008, pqac-00000014) | SO:0001583 missense; SO:0001587 stop-gained; SO:0001589 frameshift; SO:0001574 splice acceptor; SO:0001742 copy-number gain | Human molecular evidence; lethality inference **moderate–high** |
| Skeletal phenotype | Congenital findings include shortened limbs or short stature, short ribs, narrow thorax, brachydactyly, and characteristic cone-shaped phalangeal epiphyses. Polydactyly is variable and not required. (pqac-00000001, pqac-00000002, pqac-00000005, pqac-00000011) | HP:0000774 Narrow chest; HP:0000894 Short ribs; HP:0004322 Short stature; HP:0001156 Brachydactyly; HP:0010579 Cone-shaped epiphysis; HP:0010442 Polydactyly | Repeated human observations; **high**, percentages unavailable |
| Respiratory phenotype | Thoracic restriction ranges from mild narrowing to pulmonary hypoplasia or restrictive respiratory insufficiency. Recurrent respiratory infections and pneumonia occur in some patients. (pqac-00000001, pqac-00000002) | HP:0002091 Restrictive respiratory insufficiency; HP:0002089 Pulmonary hypoplasia; HP:0002205 Recurrent respiratory infections | Human cases and reviews; **moderate** |
| Renal phenotype | Progressive nephronophthisis-like tubulointerstitial or cystic kidney disease is a core manifestation and can cause childhood chronic kidney disease and end-stage kidney disease requiring dialysis or transplantation. (pqac-00000001, pqac-00000004, pqac-00000005, pqac-00000012) | HP:0000090 Nephronophthisis; HP:0012622 Chronic kidney disease; HP:0003774 End-stage renal disease; HP:0000107 Renal cyst; UBERON:0002113 kidney | Multiple human reports; **high** |
| Ocular phenotype | Early retinal dystrophy, commonly rod–cone degeneration or retinitis pigmentosa, may cause nystagmus, nyctalopia, refractive error, abnormal electroretinography, and progressive visual impairment. Rare renal-skeletal cases lack retinopathy, showing variable expressivity. (pqac-00000001, pqac-00000004, pqac-00000005) | HP:0000556 Retinal dystrophy; HP:0000510 Rod-cone dystrophy; HP:0000662 Nyctalopia; HP:0000639 Nystagmus; UBERON:0000966 retina; CL:0000210 photoreceptor cell | Human ophthalmic phenotyping; **high**, penetrance unquantified |
| Other phenotypes | Craniosynostosis, craniofacial dysmorphism, ectodermal abnormalities, liver disease, congenital heart defects, scoliosis, and possible hearing impairment occur variably across the IFT140 ciliopathy spectrum; none is obligatory. (pqac-00000001, pqac-00000002, pqac-00000008) | HP:0001363 Craniosynostosis; HP:0002650 Scoliosis; HP:0000365 Hearing impairment; HP:0001392 Abnormal liver morphology; HP:0001627 Abnormal heart morphology | Small series and cases; **low–moderate** |
| Mechanism | IFT140 is a core IFT-A component required for retrograde transport from the ciliary tip to base and for ciliary membrane-cargo handling. Pathogenic variants cause absent, shortened, or bulbous cilia and abnormal accumulation or localization of IFT proteins. (pqac-00000002, pqac-00000003, pqac-00000007, pqac-00000014) | GO:0035721 Intraciliary retrograde transport; GO:0060271 Cilium assembly; GO:0005929 Cilium; GO:0036064 Ciliary basal body | Patient cells and experimental models; **high** |
| Tissue pathophysiology | Defective ciliary transport perturbs developmental signaling, especially Hedgehog and possibly Wnt, in chondrocytes, renal tubular epithelia, and photoreceptors. This is inferred to produce abnormal endochondral ossification, tubulointerstitial/cystic renal injury, and defective photoreceptor transport followed by degeneration. (pqac-00000003, pqac-00000011) | GO:0007224 Smoothened signaling; GO:0060070 Canonical Wnt signaling; GO:0001503 Ossification; GO:0072080 Nephron tubule development; CL:0000138 Chondrocyte | Human cellular and animal evidence; downstream human chain partly inferred; **moderate–high** |
| Functional evidence | Patient fibroblasts show reduced ciliation and abnormal IFT localization. Urine-derived renal epithelial cells showed IFT88 accumulation at ciliary tips in **41%** of cells; engineered rescue assays reproduced impaired retrograde transport. (pqac-00000003) | GO:0035721 Intraciliary retrograde transport; GO:0005929 Cilium; renal epithelial cell | Direct patient-cell and engineered-cell experiments; **high** |
| Diagnosis | Diagnosis combines prenatal or postnatal skeletal imaging, renal assessment, retinal examination, and identification of two pathogenic or likely pathogenic IFT140 alleles in trans. Useful studies include skeletal survey, renal ultrasonography, serum creatinine/eGFR, urinalysis, retinal imaging, and electroretinography. | HPO-based phenotyping; LOINC creatinine, eGFR, urinalysis, and electroretinography concepts | Multidisciplinary clinical practice supported by human reports; **moderate–high** |
| Genetic testing | Use a skeletal-ciliopathy or renal-retinal ciliopathy panel with deletion/duplication analysis, or trio exome sequencing. If only one allele is found, use genome sequencing, CNV/read-depth analysis, breakpoint PCR, and possibly RNA studies to detect tandem duplications or cryptic splice variants. (pqac-00000001, pqac-00000005, pqac-00000006) | NCIT:C101296 Next-Generation Sequencing; NCIT:C101295 Whole Exome Sequencing; NCIT:C101294 Whole Genome Sequencing; NCIT:C116160 Copy Number Variation Analysis | Human diagnostic evidence; **high** |
| Differential diagnosis | Major alternatives include other short-rib thoracic dysplasias involving DYNC2H1, WDR19, WDR35, IFT122, IFT172, and IFT80; cranioectodermal dysplasia; Senior–Løken syndrome; isolated IFT140 retinal dystrophy; and monoallelic IFT140-associated ADPKD. (pqac-00000000, pqac-00000001, pqac-00000007, pqac-00000008) | MONDO skeletal ciliopathy; HP:0000894 Short ribs; HP:0000090 Nephronophthisis; HP:0000556 Retinal dystrophy | Genetic and phenotypic-overlap evidence; **high** |
| Epidemiology | SRTD9 is ultra-rare. Reliable prevalence, incidence, carrier-frequency, sex-ratio, and geographic-distribution estimates are **unavailable**. The foundational study identified IFT140 variants in 7 of 16 selected Mainzer–Saldino families, which is not a population prevalence estimate. (pqac-00000003) | MONDO:0009964; rare disease | Small, ascertainment-biased family series; **insufficient for population frequency** |
| Prognosis | Prognosis is highly variable and is driven principally by thoracic insufficiency and renal decline. Survivors may develop progressive visual disability and lifelong skeletal morbidity. Childhood kidney failure occurs, but transplantation is feasible. Disease-specific survival and life-expectancy estimates are **unavailable**. (pqac-00000001, pqac-00000005, pqac-00000012) | HP:0002091 Restrictive respiratory insufficiency; HP:0003774 End-stage renal disease; HP:0000556 Retinal dystrophy | Human cases and small series; **moderate**, quantitative survival data absent |
| Management | Management is multidisciplinary and organ-directed: respiratory support and infection treatment; renal-function, blood-pressure, and imaging surveillance; standard CKD care, dialysis, and transplantation; retinal surveillance and low-vision services; orthopedic, audiologic, nutritional, rehabilitation, and developmental support. | NCIT:C15329 Supportive Care; NCIT:C15231 Dialysis; NCIT:C15263 Kidney Transplantation; NCIT:C16268 Physical Therapy; NCIT:C16882 Genetic Counseling | Expert-practice extrapolation and reported transplantation; **moderate** |
| Disease-modifying therapy | **No approved SRTD9 disease-modifying drug, gene therapy, RNA therapy, or cell therapy exists, and no disease-specific interventional trial was identified.** Pathway-directed treatments studied in other renal-ciliopathy models remain experimental. | NCIT:C1908 Gene Therapy; NCIT:C15747 Investigational New Drug | Trial search and literature review; **high confidence for current absence** |
| Prevention and counseling | Lifestyle or environmental modification cannot prevent the congenital disorder. Familial-variant testing enables carrier and cascade testing, prenatal diagnosis, and preimplantation genetic testing. For two carrier parents, each pregnancy has 25% affected, 50% carrier, and 25% unaffected/non-carrier probabilities. | HP:0000007 Autosomal recessive inheritance; NCIT:C16882 Genetic Counseling; prenatal and preimplantation genetic testing | Mendelian genetics and established reproductive practice; **high** |
| Model organisms | ENU/hypomorphic and conditional **Ift140** mouse models reproduce ciliary, skeletal, renal, craniofacial, cardiac, pulmonary, and polydactyly phenotypes; renal collecting-duct deletion causes cysts, fibrosis, and short cilia. Zebrafish complementation supports loss of function, and C. elegans variant models reproduce short cilia, IFT accumulation, and cargo mislocalization. (pqac-00000004, pqac-00000011) | NCBI Taxon:10090 Mus musculus; NCBI Taxon:7955 Danio rerio; NCBI Taxon:6239 Caenorhabditis elegans; MGI Ift140 | Multiple induced genetic models; **high mechanistic value**, incomplete human phenocopy |
| Natural disease in animals | No well-established naturally occurring veterinary SRTD9 caused by orthologous biallelic IFT140 variants was identified. Reported animal systems are predominantly experimentally induced models. | NCBI Taxonomy; OMIA—no confirmed entry identified | Database/literature gap; **unavailable** |


*Table: Compact ontology-ready summary of the genetic basis, phenotypes, mechanism, diagnosis, management, prognosis, epidemiologic gaps, and experimental models for SRTD9. Evidence strength distinguishes established human findings from mechanistic inference and unavailable data.*