| domain | established finding | ontology/identifier suggestions | evidence type/source |
|---|---|---|---|
| Disease identity | Neurodevelopmental disorder with hearing loss and spasticity is the exact disease entity linked to **AFG2B** (alias **SPATA5L1**). Open Targets maps the disease to **MONDO:0859206** and the causal target to **AFG2B**. | **MONDO suggestion:** MONDO:0859206; **gene suggestion:** AFG2B/SPATA5L1; **disease label suggestion:** AFG2B-related neurodevelopmental disorder with hearing loss and spasticity | Curated disease-target resource plus cited literature linkage (pqac-00000000) |
| Key identifiers | The disorder is described as **OMIM phenotype 619616** in a recent case report discussing SPATA5L1-related disease. | **OMIM suggestion:** 619616 | Human clinical case report / literature synthesis (pqac-00000011) |
| Synonymy / nomenclature | Recent literature uses **SPATA5L1-related neurodevelopmental disorder**, **AFG2B-related disorder**, and the descriptive disease name with hearing loss and spasticity. | **Synonym suggestions:** SPATA5L1-related NDD; AFG2B-related NEDHLS | Human clinical case report and review-style discussion (pqac-00000001, pqac-00000012) |
| Genetic etiology | Cause is **biallelic germline variants in SPATA5L1/AFG2B**; inheritance is **autosomal recessive**. | **Inheritance suggestion:** HP:0000007 Autosomal recessive inheritance | Open Targets/literature association and human clinical genetics report (pqac-00000000, pqac-00000011) |
| Example pathogenic variants | A recent patient had compound heterozygous **c.1918C>T (p.Arg640Ter)** and **c.2066G>T (p.Gly689Val)**, inherited **in trans** from carrier parents. | **Variant annotation suggestion:** HGVS c./p. notation; ACMG/AMP classification in case report: p.Arg640Ter uncertain significance, p.Gly689Val likely/pathogenic in cited resources | Human trio-WES case report (pqac-00000011) |
| Core neurodevelopmental phenotype | Established clinical spectrum includes **global psychomotor/developmental delay**, **intellectual disability/developmental impairment**, and abnormal motor development. | **HPO suggestions:** HP:0001263 Global developmental delay; HP:0001249 Intellectual disability; HP:0011344 Severe global developmental delay (severity if documented per case) | Foundational human cohort summarized by later case report; direct recent case findings (pqac-00000002, pqac-00000012, pqac-00000014) |
| Hearing phenotype | **Bilateral sensorineural hearing loss** is a core feature; in the 2025 case it was detected in infancy and measured at **60 dBnHL** with hearing aids fitted. | **HPO suggestions:** HP:0000407 Sensorineural hearing impairment; HP:0008619 Bilateral hearing impairment | Human clinical case report (pqac-00000012, pqac-00000014) |
| Motor phenotype | Published cases commonly show **spasticity and/or dystonia**; the recent infant case showed early **central hypotonia** with concern for later evolution toward a spastic-dystonic pattern. | **HPO suggestions:** HP:0001257 Spasticity; HP:0001332 Dystonia; HP:0001252 Hypotonia; **disease-overlap suggestion:** cerebral palsy spectrum phenotype | Human cohort summary and detailed case follow-up (pqac-00000002, pqac-00000012, pqac-00000013) |
| Epilepsy / EEG | **Epilepsy** is part of the reported disease spectrum, but not universal. In the 2025 case, early EEG was negative; later EEG showed **bilateral sharp waves, incomplete FO-FW complexes, and theta activity** without clinically confirmed seizures to date. | **HPO suggestions:** HP:0001250 Seizure; HP:0010848 Abnormal EEG | Human clinical case report (pqac-00000012, pqac-00000013) |
| Craniofacial / ocular findings | Variable **craniofacial dysmorphism** is reported; the recent case had **bitemporal narrowing, wide mouth, epicanthal folds**, plus **intermittent strabismus**, hypermetropia, and astigmatism. | **HPO suggestions:** HP:0001999 Bitemporal narrowing; HP:0000286 Epicanthus; HP:0000341 Broad mouth / wide mouth; HP:0000486 Strabismus | Human clinical case report (pqac-00000012, pqac-00000014) |
| Brain imaging phenotype | MRI abnormalities can include **cortical/white matter atrophy or volume loss**, **delayed myelination**, **thin/hypoplastic corpus callosum**, and white matter T2 hyperintensities. | **HPO suggestions:** HP:0007058 Delayed CNS myelination; HP:0002079 White matter abnormality; HP:0002078 Cerebral atrophy; HP:0001273 Agenesis/hypoplasia of corpus callosum (use hypoplasia when appropriate) | Human clinical case report; consistent with earlier cohort per author summary (pqac-00000012, pqac-00000013) |
| Molecular complex | SPATA5L1/AFG2B functions in the **SPATA5-SPATA5L1-C1orf109-CINP** complex, termed **55LCC**. The complex is a DNA-binding AAA+ ATPase assembly with unusual **4:2:2:2 stoichiometry** for SPATA5:SPATA5L1:C1orf109:CINP. | **GO suggestions:** GO:0140657 ATP-dependent activity, acting on DNA (suggestion); GO:0006260 DNA replication; **complex label suggestion:** 55LCC complex | Structural/biochemical/cell-biology study in Cell 2024 (pqac-00000006, pqac-00000009, pqac-00000010) |
| Mechanistic disease model | 55LCC binds DNA, shows ATPase activity enhanced specifically by **replication fork DNA**, and promotes **ubiquitin-independent replisome proteostasis**. Loss of the complex causes **replication stress**, reduced fork progression/restart, and downstream chromosome instability. | **GO suggestions:** GO:0006281 DNA repair; GO:0045005 DNA replication restart; GO:0031573 mitotic cell cycle checkpoint; GO:0031267 small GTPase-independent? not established, avoid; **use suggested terms only where broadly matching:** DNA replication, response to replication stress, protein unfolding/proteostasis | Mechanistic cell/biochemistry study (pqac-00000007, pqac-00000008, pqac-00000009, pqac-00000010) |
| Replisome substrates / downstream biology | Replisome-associated factors reported as processed by 55LCC include **POLD3, RFC1, POLA1, POLD1**; additional processed factors include **ATR, ATRIP, RAD21** under replication stress conditions. | **GO suggestions:** GO:0005657 replication fork; **protein/pathway suggestions:** DNA polymerase delta complex, RFC complex, ATR signaling | Mechanistic cell/biochemistry study (pqac-00000008, pqac-00000010) |
| Cell compartments / localization | The complex associates with **chromatin**, including **replicating chromatin**, and chromatin association varies across the cell cycle. | **GO Cellular Component suggestions:** GO:0000785 chromatin; GO:0005657 replication fork; GO:0005634 nucleus | Cell-based chromatin assays (pqac-00000007, pqac-00000010) |
| Affected anatomy and cell types | Clinical and mechanistic evidence implicate the **central nervous system** and **auditory system**; recent literature also notes SPATA5L1 enrichment in **neurons**, **glial nuclei**, and **neurosensory hair cells**. | **UBERON suggestions:** brain, cerebral white matter, corpus callosum, inner ear/cochlea; **CL suggestions:** neuron, glial cell, hair cell | Human case synthesis and mechanistic discussion (pqac-00000001, pqac-00000012) |
| Diagnostic strategy | Current practice is genomic diagnosis via **trio whole-exome sequencing** or broader sequencing with segregation analysis; CNV and uniparental disomy analysis may be performed to exclude alternative causes. Clinical workup includes **audiology**, **EEG**, **brain MRI**, and neurologic/developmental assessment. | **Testing suggestions:** WES/WGS; segregation testing; MRI brain; audiology/BAEP; EEG; **HPO-driven phenotyping suggested** | Human case report demonstrating real-world diagnostic workflow (pqac-00000011, pqac-00000013, pqac-00000014) |
| Management / real-world care | No disease-specific therapy was identified. Current care is **supportive and rehabilitative**, including **hearing aids**, early **physical/neurodevelopmental rehabilitation** (including Vojta-based therapy in one report), and monitoring for seizures and motor evolution. | **NCIT intervention suggestions:** hearing aid device; physical therapy; occupational therapy; speech/hearing rehabilitation; antiseizure therapy if clinically indicated | Human case management and trial-gap search (pqac-00000011, pqac-00000012, pqac-00000014, pqac-00000000) |
| Prognosis / disease course | Disease appears **chronic** with early-childhood onset and persistent neurodevelopmental disability; expression is **variable**, especially for seizures and the timing of spastic-dystonic features. Robust survival or life-expectancy data were not identified. | **Course suggestions:** congenital/infantile onset neurodevelopmental disorder; variable expressivity | Human clinical reports with explicit knowledge gaps (pqac-00000012, pqac-00000013) |
| Epidemiology | Ultra-rare Mendelian disorder; recent literature notes **fewer than 30 affected individuals** reported to date, and one recent paper cites a **cohort of 25 patients** from Richard et al. | **Epidemiology suggestion:** prevalence/incidence unknown | Recent clinical case report summarizing prior literature (pqac-00000001, pqac-00000013) |
| Population / consanguinity | Both **consanguineous and non-consanguineous** family structures are represented in the literature summary; the 2025 case arose in a **non-consanguineous** family. Population-specific founder frequency was not established here. | **Counseling suggestion:** carrier testing and reproductive counseling for at-risk relatives | Human clinical case report / literature synthesis (pqac-00000013, pqac-00000014) |
| Modifier / environmental factors | No established environmental risk factors, protective factors, or gene-environment interactions were identified in the available evidence. | **Knowledge-gap suggestion:** none established | Negative/insufficient evidence from available sources (pqac-00000000, pqac-00000012) |
| Experimental therapeutics / trials | No relevant disease-specific interventional clinical trial was found in the trial search. Translational work is mechanistic/preclinical rather than therapeutic at present. | **Trial status suggestion:** no disease-specific registered interventional study identified | Clinical trial search and disease-target resource (pqac-00000000) |


*Table: This table summarizes high-confidence disease facts for AFG2B/SPATA5L1-related neurodevelopmental disorder with hearing loss and spasticity, including identifiers, phenotypes, mechanism, diagnostics, and current care gaps. It is designed as a compact knowledge-base artifact with suggested ontology mappings clearly labeled as suggestions.*