🏷

Classifications

Harrison's Part

👪

Inheritance

1

Autosomal recessive HP:0000007

Biallelic (homozygous or, more commonly, compound heterozygous) AFG2B variants are required. Heterozygous carrier parents are unaffected, and segregation in trans has been confirmed in the reported families.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:34626583 SUPPORT Human Clinical

"Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype."

The founding cohort establishes that the disorder requires biallelic variants.

PMID:37902276 SUPPORT Human Clinical

"Bi-allelic variants in AFG2B (previously known as SPATA5L1) have recently been associated with a neurodevelopmental disorder with hearing loss and spasticity, as well as isolated hearing loss."

Independent restatement of the biallelic requirement, and the only report to use the current gene symbol in its title.

◆

Subtypes

1

Isolated sensorineural hearing loss (DFNB119, OMIM:619615) MONDO:0030480

22/47 (47%) of individuals in the founding cohort AFG2B hgnc:28762

DFNB119 is the presentation in which biallelic AFG2B variants produce sensorineural hearing loss and nothing else - no microcephaly, no developmental delay or impaired intellectual development, no spastic-dystonic motor phenotype and no epilepsy. OMIM gives it a separate phenotype number (OMIM:619615) from the syndromic presentation this entry is named for (NEDHLS, OMIM:619616), but both numbers were assigned from the same founding cohort and the same gene, and the separation is a description of how far the phenotype extends in a given individual rather than of a different lesion. It is modelled here as a subtype for three reasons, each of which is evidenced below. The founding report frames the disorder as a single entity with a variable extension ("with or without a nonprogressive mixed neurodevelopmental phenotype"). The same allele recurs on both sides of the split - c.527G>T, p.(Gly176Val) is reported in individuals with the full neurodevelopmental phenotype and repeatedly in individuals with isolated hearing loss - so no genotype partitions the two. And the hearing-loss mechanism curated in this entry's pathophysiology is the mechanism of DFNB119: the divergence between the two presentations lies in whether the neural branch is also manifest, not in how the cochlear lesion arises.

Show evidence (4 references)

PMID:37902276 SUPPORT BACKGROUND Human Clinical

"bi‐allelic variants in AFG2B have been associated with neurodevelopmental disorder with hearing loss and spasticity (OMIM #619616), as well as with isolated hearing loss (OMIM #619615)"

Names both OMIM phenotype numbers, attributes both to biallelic variants in the one gene, and cites the one founding report for both. This is the sentence that establishes DFNB119 as the isolated-hearing-loss end of this entry's disorder rather than a separate gene-disease relationship. Quoted from the paper's introduction, where it restates the founding report, so the finding is not this paper's own.

PMID:34626583 SUPPORT Human Clinical

"In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy."

Hearing loss was present in all 47 individuals of the founding cohort and the neurodevelopmental burden in 25 of them, so 22 of 47 (47%) had hearing loss without any of the neurodevelopmental features. That complement is the subtype frequency recorded here. It is the cohort's own split and is not a redistribution across individual features, which the founding abstract does not support.

PMID:34626583 SUPPORT Human Clinical

"Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype."

The founding report's own summary treats the isolated and syndromic presentations as one disease with a variable extension, which is the claim a subtype models and a separate disease entry would contradict.

+ 1 more reference

?

Discussions and Knowledge Gaps

7

What actually happens in the AFG2B-deficient cochlea downstream of the expression of AFG2B in hair cells and supporting cells?

KNOWLEDGE GAP OPEN afg2b_cochlear_mechanism_gap

Attached to

pathophysiology#Cochlear Sensory Epithelium Involvement

Sensorineural hearing loss is the defining feature of this disorder, yet the only cochlear data in existence are rodent expression studies showing Spata5l1 in neurosensory hair cells, supporting cells and the pillar cells of the organ of Corti. Nobody has published hair cell counts, cochlear histology, endocochlear potential measurements, distortion-product otoacoustic emissions or spiral ganglion studies in an AFG2B-deficient animal or human temporal bone. Consequently the entry conforms to the `sensorineural_hair_cell_loss` module at its trigger node only and cannot claim the module's hair-cell-death, ionic-homeostasis or spiral-ganglion nodes. Whether hair cells die (as in most hereditary sensorineural loss) or merely function abnormally, and whether the loss is cochlear or retrocochlear, is completely open. The only indirect human hint is the founding report's observation, in the body of PMID:34626583 rather than in its abstract, of apparent benefit from cochlear implantation in the individuals who received it, which is weakly consistent with a preserved auditory nerve but is uncontrolled and unquantified.

Proposed experiments

Afg2b knockout cochlear phenotyping

afg2b_cochlear_knockout_phenotyping

Generate a cochlea-conditional or constitutive Afg2b knockout mouse and perform ABR and DPOAE phenotyping alongside serial cochlear histology with inner and outer hair cell counts, to establish whether hair cells are lost or merely dysfunctional.

Endocochlear potential measurement

afg2b_endocochlear_potential

Measure the endocochlear potential in the same model to test whether the module's cochlear ionic homeostasis arm is engaged, which would distinguish a strial mechanism from a primary hair-cell mechanism.

Spiral ganglion neuron density quantification

afg2b_spiral_ganglion_density

Quantify spiral ganglion neuron density to test the module's retrocochlear node and to predict whether cochlear implantation would be expected to work in affected individuals.

Cochlear implant outcome collation

afg2b_cochlear_implant_outcomes

Collate audiological and cochlear implant outcomes across the reported human cohort, which would provide indirect human evidence about spiral ganglion integrity without requiring temporal bone histology.

Does loss of Afg2b in an animal model recapitulate the human hearing-loss-plus-spasticity phenotype?

KNOWLEDGE GAP OPEN afg2b_no_animal_model

Attached to

pathophysiology#Biallelic AFG2B Loss of Function

No animal model of AFG2B deficiency has been published, which is why this entry carries no `animal_models` block. The only in vivo AFG2B data located are rodent expression studies (PMID:34626583); a PubMed search for SPATA5L1 combined with zebrafish returned no records, and the Falcon deep-research run likewise found no stable Afg2b-knockout mouse, rat, zebrafish, Drosophila, iPSC neuron, cochlear organoid or cerebral organoid model. Every functional claim in this entry therefore rests either on human observational data, on patient fibroblast transcriptomics, or on cell-based work performed on other subunits of the 55LCC complex. Without a model the causal direction from ribosome biogenesis failure or replication stress to the neurological and auditory phenotype remains inferred rather than demonstrated.

Proposed experiments

Afg2b null mouse neurodevelopmental phenotyping

afg2b_mouse_null_phenotyping

Characterise any existing IMPC allele, or generate an Afg2b null mouse, and phenotype brain volume, myelination, motor tone and hearing to test whether the human phenotype is reproduced.

Zebrafish afg2b hair cell development assay

afg2b_zebrafish_hair_cell

Use a zebrafish afg2b knockdown or knockout to test hair cell development in the lateral line and inner ear, the standard rapid assay applied to other deafness genes.

Patient iPSC organoid translation assay

afg2b_ipsc_organoid_translation

Differentiate patient-derived iPSC into cortical and inner-ear organoids and assay 60S subunit levels and global translation, to test the proximal ribosome-biogenesis defect in human AFG2B-mutant cells.

Which arm of 55LCC dysfunction - impaired pre-60S ribosome maturation or replisome proteostasis failure - actually produces the neural and cochlear phenotype of AFG2B deficiency?

KNOWLEDGE GAP OPEN afg2b_replication_stress_to_neural_gap

Attached to

pathophysiology#Replisome Proteostasis Failure and Replication Stress pathophysiology#Reduced Global Protein Synthesis

The 55LCC complex has two experimentally established jobs, and PMID:38554706 reports that the replication and genome-instability phenotype is separable from the previously described ribosomal function. Both are therefore modelled here as parallel branches from complex dysfunction, and both carry an edge into the neural node - but neither edge has been demonstrated in a neural or cochlear context for AFG2B. The replication-stress work was done in HeLa and engineered degron cell lines, and the ribosome work was done on other subunits. Because all four 55LCC components are pan-essential in cultured cells, yet the human disease is tissue-restricted and survivable, something about the developing brain and cochlea must determine selectivity, and which branch drives that selectivity is unknown. This is the weakest link in the pathograph and the reason both intermediate nodes are marked PROVISIONAL.

Proposed experiments

Branch separation in a neural model

afg2b_branch_separation_neural

Introduce separation-of-function AFG2B alleles that impair replisome substrate processing without disturbing pre-60S maturation (and the converse) into a human neural progenitor or organoid model, and determine which allele class reproduces the growth and differentiation defect.

Replication-stress markers in patient cells

afg2b_replication_stress_markers_patient

Measure phosphorylated RPA, DNA-fiber fork progression, cohesion defects and micronucleus frequency in fibroblasts and iPSC-derived neural cells from individuals with biallelic AFG2B variants, to test whether the cell-line replication-stress phenotype is present at physiological patient-allele dosage.

Does the mTOR-activation rescue demonstrated for the AIRIM/C1orf109 subunit of the 55LCC complex generalise to AFG2B deficiency?

HUMAN MODEL MISMATCH OPEN afg2b_mtor_rescue_untested

Attached to

pathophysiology#Neuroepithelial Vulnerability During Differentiation

Enhancing mTOR activity suppresses the growth and developmental defects caused by AIRIM/C1orf109 variants in human cerebral organoids (PMID:40760247). AIRIM/C1orf109 is a subunit of the same 55LCC complex as AFG2B, and the proposed mechanism, restoring translational output when ribosome availability falls during neuroepithelial differentiation, would apply equally to AFG2B loss on paper. But the experiment has never been done for AFG2B, the organoid system models early cortical development rather than the cochlea where this disorder's defining phenotype lies, and mTOR activation is not a benign intervention. The mismatch between an encouraging organoid result on one subunit and the complete absence of data on the subunit that causes this disease is exactly why the finding is curated as a pathophysiology observation and a discussion rather than as a treatment.

Proposed experiments

mTOR rescue in AFG2B-variant cerebral organoids

afg2b_organoid_mtor_rescue

Generate AFG2B-variant human cerebral organoids and test whether mTOR activation rescues growth and cell-fate commitment as it does for AIRIM/C1orf109 organoids.

60S availability and translation in AFG2B-deficient neuroepithelia

afg2b_60s_translation_measurement

Measure 60S subunit availability and global translation in AFG2B-deficient neuroepithelia to confirm that the proximal defect assumed by the rescue rationale is actually present.

Inner-ear organoid rescue test

afg2b_inner_ear_organoid_rescue

Test whether any mTOR rescue extends to inner-ear organoids, since cortical rescue alone would not address the disorder's defining hearing loss.

Show evidence (1 reference)

PMID:40760247 SUPPORT In Vitro

"Enhancing mTOR activity suppresses the growth and developmental defects associated with AIRIM/C1orf109 variants."

The rescue result that motivates the question, obtained for a different subunit of the same complex in human cerebral organoids.

What is the natural history of AFG2B-related disease beyond childhood, and does the hearing loss progress?

KNOWLEDGE GAP OPEN afg2b_natural_history_gap

Attached to

pathophysiology#Bilateral Sensorineural Hearing Loss

The founding cohort described the neurodevelopmental phenotype as nonprogressive, but no longitudinal audiometric data have been published, so whether the hearing loss itself is stable or progressive is unknown. This matters directly for the module-conformance decision recorded in entry note (6), because the `sensorineural_hair_cell_loss` module terminates in a node named "Progressive Sensorineural Hearing Loss", which cannot be claimed here. No survival, life-expectancy, adult-outcome or quality-of-life data exist for this disorder either.

Proposed experiments

Serial audiometry across the reported cohort

afg2b_serial_audiometry

Perform serial audiometry across the reported cohort to establish whether hearing thresholds deteriorate with age, which would determine whether the module's progressive-hearing-loss endpoint can be claimed.

Prospective natural-history registry

afg2b_natural_history_registry

Establish a prospective natural-history registry capturing motor function, epilepsy course, communication outcome and survival into adulthood.

Longitudinal brain MRI

afg2b_longitudinal_mri

Acquire longitudinal MRI to determine whether the cerebral and white matter volume loss is static or progressive.

By what mechanism do biallelic AFG2B variants produce craniofacial dysmorphism and exotropia?

KNOWLEDGE GAP OPEN afg2b_dysmorphism_strabismus_mechanism_gap

Attached to

phenotypes#Craniofacial dysmorphism phenotypes#Strabismus phenotypes#Bitemporal narrowing phenotypes#Wide mouth phenotypes#Epicanthal folds

These facial and ocular phenotypes are left deliberately unconnected in the pathograph. Craniofacial dysmorphism (bitemporal narrowing, wide mouth, epicanthal folds, reported in roughly a third of individuals) has no described mechanism: no craniofacial expression, neural crest, or skeletal data exist for AFG2B, and ribosome-biogenesis disorders as a class produce craniofacial anomalies through several non-equivalent routes, so wiring the dysmorphism to any existing node would be guesswork. The single documented strabismus is intermittent divergent strabismus of the right eye with refractive error; strabismus is common in children with periventricular leukomalacia and cerebral visual involvement, and the same report notes sluggish pursuit and limited eye contact, but no source localises this patient's exotropia to a central versus refractive origin, so no edge from the white-matter node is asserted. Recording the gap keeps the connectivity honest rather than manufactured.

Proposed experiments

Systematic craniofacial phenotyping across the cohort

afg2b_craniofacial_phenotyping

Collect standardized dysmorphology assessments (ideally with facial photograph analysis) across reported individuals to establish whether a consistent gestalt exists and whether it tracks with the neurodevelopmental subgroup.

Structured ophthalmological and orthoptic assessment

afg2b_ophthalmic_workup

Perform structured ophthalmological, orthoptic and cerebral visual function assessment in affected individuals to distinguish refractive, strabismic and cerebral visual contributions, none of which have been systematically reported.

Which neural dysfunction produces EEG abnormalities in AFG2B disease, including in children without confirmed epilepsy?

KNOWLEDGE GAP OPEN afg2b_eeg_mechanism_gap

Attached to

phenotypes#EEG abnormality

PMID:41375745 documents emerging epileptiform and slow-wave abnormalities without clinically confirmed seizures. The clinical report does not establish a causal link from its MRI abnormalities or motor disability to the EEG finding. Linking this phenotype through Epilepsy would also imply an unsupported dependence on clinical seizures, so it remains unconnected.

⚙

Pathophysiology

11

Biallelic AFG2B Loss of Function

Mechanism confidence: Established

Biallelic pathogenic variants in AFG2B (SPATA5L1) are the initiating lesion. Twenty-eight distinct biallelic variants were reported in the founding cohort; most are private missense changes, with nonsense alleles also described. Protein modelling indicated that the missense variants act largely by destabilising folded domains of the protein rather than by a gain of function, and specific substitutions in the ATPase motor (for example p.Gly689Val) are predicted to disrupt ATP binding and hydrolysis. The gene was an orphan gene of unknown function when the disease association was first made.

AFG2B hgnc:28762

ATP hydrolysis activity GO:0016887 ↓ DECREASED

Downstream

55LCC ATPase Complex Dysfunction

Cochlear Sensory Epithelium Involvement

Show evidence (3 references)

PMID:34626583 SUPPORT Human Clinical

"We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families."

Establishes the biallelic genetic lesion as the root of the disorder.

PMID:34626583 SUPPORT Computational

"Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains."

In silico structural modelling supports a destabilising loss-of-function mechanism rather than a gain of function.

PMID:41375745 SUPPORT Computational

"Missense variants such as p.Gly689Val are predicted to disrupt ATP binding and hydrolysis, thereby impairing the catalytic function of the ATPase motor"

Links a recurrent missense allele specifically to loss of ATPase catalytic activity. Predicted, not measured, hence COMPUTATIONAL.

55LCC ATPase Complex Dysfunction

Mechanism confidence: Established

AFG2B does not act alone. It is an obligate subunit of the 55LCC complex, a 4:2:2:2 assembly of AFG2A (SPATA5), AFG2B (SPATA5L1), C1orf109 and CINP in which the N-terminal domains of the two AAA+ ATPases interact with the C1orf109-CINP heterodimer to form a funnel-like ring sitting above a cylindrical stacked-ring ATPase motor. The assembled complex hydrolyses ATP several-fold faster than AFG2A alone, so loss of AFG2B compromises a multi-subunit machine rather than a single enzyme. That shared machine is the structural reason why AFG2A- and AFG2B-related diseases overlap clinically.

ATP hydrolysis activity GO:0016887 ↓ DECREASED

Downstream

Impaired Cytoplasmic Pre-60S Ribosomal Maturation

Replisome Proteostasis Failure and Replication Stress

Show evidence (2 references)

PMID:40268917 SUPPORT In Vitro

"Here we reveal that SPATA5 forms a 4:2:2:2 complex with SPATA5L1, C1orf109, and CINP."

Cryo-EM defines the stoichiometry of the complex and places AFG2B (SPATA5L1) inside it as an obligate subunit.

PMID:38554706 SUPPORT In Vitro

"An integrative structural biology approach revealed a molecular architecture of SPATA5-SPATA5L1 N-terminal domains interacting with C1orf109-CINP to form a funnel-like structure above a cylindrically shaped ATPase motor."

Independent structural work describing the same architecture and naming the complex 55LCC.

Impaired Cytoplasmic Pre-60S Ribosomal Maturation

Mechanism confidence: Established

The 55LCC complex, of which AFG2B is a subunit, executes a late cytoplasmic maturation step of the pre-60S large ribosomal subunit. AFG2A is the human homolog of yeast Drg1, which releases the assembly factor Rlp24 from newly exported pre-60S particles; in humans the reaction requires the whole four-protein complex, and recognition of the pre-60S particle is mediated by the human-specific subunit CINP. Loss of AFG2B is therefore expected to stall the final step of large-subunit biogenesis.

ribosomal large subunit biogenesis GO:0042273 ↓ DECREASED ribosome biogenesis GO:0042254 ⚠ ABNORMAL

Downstream

Reduced Global Protein Synthesis

Show evidence (2 references)

PMID:35354024 SUPPORT In Vitro

"We provide evidence that these factors, together with CINP and SPATA5L1, control a late step of human pre-60S maturation in the cytoplasm."

Names SPATA5L1 (AFG2B) explicitly as one of the four factors controlling the late cytoplasmic pre-60S maturation step.

PMID:40268917 SUPPORT In Vitro

"We also obtained a cryo-EM structure of pre-60S-bound SPATA5 complex."

Direct structural demonstration that the AFG2A-AFG2B-containing complex engages the pre-60S particle.

Reduced Global Protein Synthesis

Mechanism confidence: Provisional

Failure of the late pre-60S maturation step reduces the supply of mature 60S subunits and lowers global translational capacity. This has been measured directly for the other 55LCC subunits (C1ORF109 and AFG2A/SPATA5), where loss impairs global protein synthesis; the equivalent measurement has not been made after loss of AFG2B itself, so the node is provisional for this disorder even though the complex-level logic is strong.

cytoplasmic translation GO:0002181 ↓ DECREASED

Downstream

Neuroepithelial Vulnerability During Differentiation

Show evidence (1 reference)

PMID:35354024 SUPPORT In Vitro

"Loss of either C1orf109 or SPATA5 impairs global protein synthesis."

Demonstrates the translational consequence for two of the four 55LCC subunits. PARTIAL because the experiment was not performed for AFG2B (SPATA5L1) itself; the extrapolation rests on shared complex membership.

Neuroepithelial Vulnerability During Differentiation

Mechanism confidence: Provisional

Ribosome levels fall physiologically as neuroepithelial cells differentiate during early human brain development, which makes precisely this window hypersensitive to any further reduction in ribosome biogenesis. Reduced ribosome availability preferentially impairs translation of specific transcripts and disrupts both survival and cell-fate commitment of transitioning neuroepithelia. This is the leading explanation for why a housekeeping defect in a ubiquitously required complex produces a predominantly neurodevelopmental disease.

neuroepithelial progenitor cell CL:0011020

cerebral cortex development GO:0021987 ⚠ ABNORMAL

Downstream

Impaired Neuronal and White Matter Development

Show evidence (1 reference)

PMID:40760247 SUPPORT In Vitro

"We find that ribosome levels decrease during neuroepithelial differentiation, making differentiating cells particularly vulnerable to perturbations in ribosome biogenesis during this time."

Explains the tissue specificity of 55LCC-complex disease. PARTIAL because the human cerebral organoid work was done for the AIRIM/C1orf109 subunit, not for AFG2B; the argument generalises across the complex but has not been tested for this gene.

Replisome Proteostasis Failure and Replication Stress

Mechanism confidence: Provisional

The second established function of the 55LCC complex is to direct turnover of replisome components, a proteostasis job distinct from the ubiquitin-dependent VCP/p97 unfolding of the CMG helicase that terminates DNA replication. The complex acts as an unfoldase on chromatin-bound replisome proteins, and its deficiency produces ubiquitin-independent proteotoxicity, replication stress, and severe chromosome instability. Consistent with this, transcriptomic profiling of fibroblasts from affected individuals with biallelic AFG2B variants implicated DNA replication and mitosis alongside cell-surface adhesion and focal adhesion pathways.

DNA replication GO:0006260 ⚠ ABNORMAL replication fork processing GO:0031297 ⚠ ABNORMAL

Downstream

Impaired Neuronal and White Matter Development

Show evidence (3 references)

PMID:38554706 SUPPORT In Vitro

"Here, we identify replisome factor interactions with a protein complex composed of AAA+ ATPases SPATA5-SPATA5L1 together with heterodimeric partners C1orf109-CINP (55LCC)."

Establishes that the AFG2B-containing complex physically engages replisome factors, the basis of the replisome-proteostasis role.

PMID:38554706 SUPPORT In Vitro

"Deficiency in the 55LCC complex elicited ubiquitin-independent proteotoxicity, replication stress, and severe chromosome instability."

Direct demonstration of the replication-stress consequence of losing the complex that contains AFG2B.

PMID:34626583 SUPPORT In Vitro

"Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis."

Patient-fibroblast transcriptomics independently points at DNA replication and mitosis, but this is a correlative expression signature rather than a functional replication assay, hence PARTIAL.

Impaired Neuronal and White Matter Development

Mechanism confidence: Established

AFG2B protein localises to neuronal and glial nuclei, with more prominent expression in neurons, so the brain is a directly affected tissue rather than a bystander. The structural consequence seen in affected individuals is a global reduction in cerebral volume with disproportionate white matter loss: quantitative volumetry showed significantly diminished white matter volumes, and imaging shows a thin corpus callosum, delayed myelination and periventricular leukomalacia.

neuron CL:0000540 glial cell CL:0000125

myelination GO:0042552 ↓ DECREASED nervous system development GO:0007399 ⚠ ABNORMAL

brain UBERON:0000955 cerebral white matter UBERON:0002316

Downstream

Spastic-Dystonic Motor Impairment and Neurodevelopmental Disability

Reduced Brain Growth

Cerebral atrophy and diminished cerebral volume The diminished cerebral volume and cortical/white matter atrophy seen on imaging are the direct structural readout of this node; the node's own imaging evidence (PMID:34626583, PMID:41375745) carries the edge.

Reduced cerebral white matter volume Quantitative volumetry showing significantly diminished white matter volumes is the disproportionate white-matter arm of this node.

Thin corpus callosum Thin corpus callosum is a recurrent imaging correlate of the white-matter involvement described by this node.

Periventricular leukomalacia Periventricular leukomalacia is part of the white-matter-predominant imaging signature reported for this node in the founding cohort.

Delayed myelination Delayed myelination on serial MRI is the developmental white-matter correlate of this node; the node's GO annotation (myelination, DECREASED) states the same claim.

Show evidence (3 references)

PMID:34626583 SUPPORT In Vitro

"Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons."

Establishes that the protein is present, and predominantly nuclear, in the cell types whose development is disrupted. Classified IN_VITRO because the paper's full text specifies that this imaging was performed on rat dissociated hippocampal cultures rather than in an intact animal.

PMID:34626583 SUPPORT Human Clinical

"Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals."

Quantifies the structural brain phenotype in affected individuals, including the disproportionate white matter involvement.

PMID:41375745 SUPPORT Human Clinical

"Brain MRI showed cortical and white matter atrophy, delayed myelination, and a thin corpus callosum."

Independent single-case confirmation of the same imaging triad, adding delayed myelination.

Cochlear Sensory Epithelium Involvement

Mechanism confidence: Provisional

AFG2B is expressed in the neurosensory hair cells and supporting cells of the rodent inner ear - the founding report localised the protein to the hair cells and pillar cells of the rat organ of Corti and detected transcript in both inner and outer hair cells - and biallelic human variants produce sensorineural hearing loss, with bilateral involvement documented in individual reports. This makes the cochlear sensory epithelium a directly affected tissue and places the disorder at the generic trigger node of the conserved sensorineural hair-cell-loss module, a hereditary lesion whose vulnerable target is the mechanosensitive cochlear hair cell. What happens next in the AFG2B cochlea is unknown; no hair-cell counts, endocochlear potential measurements, cochlear histology or spiral ganglion studies have been published for this gene, so conformance is asserted at this node only.

cochlear hair cell CL:0000202

sensory perception of sound GO:0007605 ⚠ ABNORMAL

cochlea UBERON:0001844 spiral organ of cochlea UBERON:0002227

Downstream

Bilateral Sensorineural Hearing Loss

Show evidence (2 references)

PMID:34626583 SUPPORT Model Organism

"In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells."

Places the gene product in the cochlear sensory epithelium, the cell population the module identifies as the vulnerable target of its trigger node. Classified MODEL_ORGANISM because this is rodent inner-ear tissue (rat organ of Corti whole mounts and adult mouse expression data), not a cell culture.

PMID:34626583 SUPPORT Human Clinical

"We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families."

Establishes that biallelic loss of the gene expressed in the cochlear sensory epithelium causes sensorineural hearing loss in humans.

Bilateral Sensorineural Hearing Loss

Mechanism confidence: Established

Sensorineural hearing loss is a core clinical endpoint, with bilateral involvement documented in individual reports. It is typically detected in infancy, ranges from mild to profound, and can occur as the sole manifestation of a biallelic AFG2B genotype in individuals with no neurodevelopmental involvement.

Downstream

Bilateral sensorineural hearing loss Manifestation edge from the organism-level disease process to the clinically ascertained phenotype record. Bilaterality is documented in the case report cited on the phenotype, not quantified by the founding cohort abstract.

Show evidence (1 reference)

PMID:34626583 SUPPORT Human Clinical

"Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype."

Establishes sensorineural hearing loss with or without neurodevelopmental features; this abstract does not establish cohort-wide bilaterality.

Reduced Brain Growth

Mechanism confidence: Established

Impaired neuronal and white matter development translates into reduced brain growth and microcephaly, which is one of the four neurodevelopmental features that together affected just over half of the founding cohort.

Downstream

Microcephaly Reduced brain growth is observed clinically as microcephaly, which in the individually documented cases was postnatal in onset (normal head circumference at birth, below the 3rd percentile by age 2).

Show evidence (1 reference)

PMID:34626583 SUPPORT Human Clinical

"In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy."

Microcephaly is one of the four composite neurodevelopmental features.

Spastic-Dystonic Motor Impairment and Neurodevelopmental Disability

Mechanism confidence: Established

The neurological endpoint combines global developmental delay and impaired intellectual development with a spastic-dystonic cerebral palsy phenotype and focal or generalised epilepsy. Spasticity and/or dystonia are the predominant motor features in the published cohort, although infants may show generalised hypotonia before any hypertonia emerges.

Downstream

Global developmental delay Global developmental delay is one of the constituent clinical features this composite endpoint decomposes into; the node's 25/47 composite evidence carries the edge.

Impaired intellectual development Impaired intellectual development is a constituent of the composite neurodevelopmental disability described by this node.

Spastic-dystonic cerebral palsy The spastic-dystonic cerebral palsy phenotype is the characteristic motor expression of this endpoint.

Spasticity Spasticity is one of the two predominant motor signs bundled in the spastic-dystonic pattern of this node.

Dystonia Dystonia is the other predominant motor sign of the spastic-dystonic pattern of this node.

Hypotonia Infants with this disorder may show generalised central hypotonia before any hypertonia emerges, as part of the same evolving central motor disorder; the progression section documents the anticipated evolution toward a spastic-dystonic pattern.

Epilepsy Focal or generalised epilepsy is a constituent of the composite neurodevelopmental burden described by this node.

Absent or severely limited speech Severely limited language acquisition accompanies the intellectual disability of this endpoint; concurrent sensorineural hearing loss is an acknowledged additional contributor (see the phenotype's notes), but no source apportions the two, so only this edge is asserted.

Show evidence (2 references)

PMID:34626583 SUPPORT Human Clinical

"In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy."

Gives the composite neurodevelopmental burden across the founding cohort.

PMID:41375745 SUPPORT Human Clinical

"In contrast to the published cohort, in which most individuals with bi-allelic SPATA5L1 variants exhibited spasticity and/or dystonia as predominant motor features"

Confirms that spasticity and/or dystonia dominate the motor phenotype of the published cohort.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

21

Ear 1

Bilateral sensorineural hearing loss Bilateral sensorineural hearing impairment HP:0008619

No frequency band is asserted for bilateral hearing loss: the 47/47 figure in PMID:34626583 describes sensorineural hearing loss without laterality and combines syndromic and isolated hearing-loss presentations. PMID:41375745 directly establishes bilateral 60 dBnHL loss in one infant. Individual-case observations justify HP:0008619 but not a cohort-wide bilateral frequency.

Show evidence (2 references)

PMID:34626583 SUPPORT INDIRECT Human Clinical

"We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families."

Establishes the broader sensorineural hearing-loss association, not bilaterality or its frequency. The next case report supports laterality.

PMID:41375745 SUPPORT Human Clinical

"In the 7th month of life audiological evaluation revealed bilateral sensorineural hearing loss of 60 dBnHL, and hearing aids were fitted."

Documents infantile onset and moderate-to-severe degree in an individually described patient.

Eye 1

Strabismus Exotropia HP:0000577

Single-case evidence. The same report notes that ophthalmological findings are not systematically described in prior cohorts, so no band is asserted. Rebound from HP:0000486 (Strabismus) to HP:0000577 during phenotype review: the full text specifies intermittent divergent strabismus of the right eye, and divergent strabismus is exotropia. HPO has no more specific intermittent-exotropia term.

Show evidence (2 references)

PMID:41375745 SUPPORT Human Clinical

"She presented with global psychomotor delay, bilateral sensorineural hearing loss, strabismus, and craniofacial dysmorphism."

Strabismus in a genetically confirmed AFG2B patient.

PMID:41375745 SUPPORT Human Clinical

"ophthalmologic and optometric assessment demonstrated intermittent divergent strabismus of the right eye"

Specifies the divergent (exotropic) and intermittent character of the strabismus, supporting the more specific HP:0000577 binding.

Head and Neck 5

Microcephaly HP:0000252

Part of the 25/47 (53%) composite in PMID:34626583; no standalone denominator published, so no frequency band is asserted. The postnatal-onset pattern in PMID:41375745 contrasts with the congenital microcephaly typical of the paralogous AFG2A-related disorder, but rests on a single case.

Show evidence (2 references)

PMID:34626583 SUPPORT Human Clinical

"In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy."

Microcephaly is one of the four composite features.

PMID:37902276 SUPPORT Human Clinical

"We report on a 6 1/2-year-old girl with a history of global developmental delay, subsequent intellectual disability without relevant language acquisition, sensorineural hearing loss, muscular hypotonia and microcephaly."

Microcephaly in a genetically confirmed AFG2B patient.

Craniofacial dysmorphism Abnormal facial shape HP:0001999

"Approximately one-third" would map to FREQUENT, but the statement carries no numerator or denominator of its own and cites the literature indirectly, so no band is asserted. The umbrella is retained for the reported variable facial gestalt; the three specifically documented features are separate records below. PMID:37902276 describes a child without distinctive dysmorphic features, while noting a thick lower vermilion. That observation documents variability rather than excluding facial abnormalities from this disease.

Show evidence (1 reference)

PMID:41375745 SUPPORT Human Clinical

"Craniofacial dysmorphic features were noted, including bitemporal narrowing, wide mouth, and epicanthal folds, partially overlapping with those reported in approximately one-third of affected individuals in the literature."

Describes the dysmorphic features and their approximate literature frequency.

Bitemporal narrowing Narrow forehead HP:0000341

Single-case observation in PMID:41375745; no frequency band is asserted. The report also identified an uncertain de novo FRYL variant that might be a sequencing artefact; a modifying contribution to dysmorphism was not excluded. The mechanism of this facial feature in AFG2B disease is unknown.

Show evidence (1 reference)

PMID:41375745 SUPPORT Human Clinical

"At 9 months, physical examination revealed a eutrophic infant (10 kg, OFC 43 cm) with craniofacial dysmorphism, including bitemporal narrowing, wide mouth, and epicanthal folds."

Documents bitemporal narrowing in the child with compound heterozygous SPATA5L1 variants. This establishes occurrence in one reported case, not a frequency or an AFG2B-specific developmental mechanism.

Wide mouth HP:0000154

Single-case observation in PMID:41375745; no frequency band is asserted. The report also identified an uncertain de novo FRYL variant that might be a sequencing artefact; a modifying contribution to dysmorphism was not excluded. The mechanism of this facial feature in AFG2B disease is unknown.

Show evidence (1 reference)

PMID:41375745 SUPPORT Human Clinical

"At 9 months, physical examination revealed a eutrophic infant (10 kg, OFC 43 cm) with craniofacial dysmorphism, including bitemporal narrowing, wide mouth, and epicanthal folds."

Documents wide mouth in the child with compound heterozygous SPATA5L1 variants. This establishes occurrence in one reported case, not a frequency or an AFG2B-specific developmental mechanism.

Epicanthal folds Epicanthus HP:0000286

Single-case observation in PMID:41375745; no frequency band is asserted. The report also identified an uncertain de novo FRYL variant that might be a sequencing artefact; a modifying contribution to dysmorphism was not excluded. The mechanism of this facial feature in AFG2B disease is unknown.

Show evidence (1 reference)

PMID:41375745 SUPPORT Human Clinical

"At 9 months, physical examination revealed a eutrophic infant (10 kg, OFC 43 cm) with craniofacial dysmorphism, including bitemporal narrowing, wide mouth, and epicanthal folds."

Documents epicanthal folds in the child with compound heterozygous SPATA5L1 variants. This establishes occurrence in one reported case, not a frequency or an AFG2B-specific developmental mechanism.

Musculoskeletal 2

Spasticity HP:0001257

The published cohort reports spasticity and dystonia together as "spasticity and/or dystonia", so neither can be given its own frequency band.

Show evidence (2 references)

PMID:41375745 SUPPORT Human Clinical

"In contrast to the published cohort, in which most individuals with bi-allelic SPATA5L1 variants exhibited spasticity and/or dystonia as predominant motor features"

States that spasticity and/or dystonia predominate in most individuals of the published cohort.

PMID:37902276 SUPPORT Human Clinical

"Bi-allelic variants in AFG2B (previously known as SPATA5L1) have recently been associated with a neurodevelopmental disorder with hearing loss and spasticity, as well as isolated hearing loss."

Spasticity is part of the named core phenotype of the disorder.

Hypotonia HP:0001252

Show evidence (2 references)

PMID:37902276 SUPPORT Human Clinical

"We report on a 6 1/2-year-old girl with a history of global developmental delay, subsequent intellectual disability without relevant language acquisition, sensorineural hearing loss, muscular hypotonia and microcephaly."

Muscular hypotonia in a genetically confirmed AFG2B patient.

PMID:41375745 SUPPORT Human Clinical

"our patient at 14 months of age demonstrated generalized hypotonia with markedly delayed psychomotor development, without clinical signs of hypertonia to date"

Documents an infant presenting with generalised hypotonia rather than hypertonia, the presentation flagged in the curation request.

Nervous System 12

Global developmental delay HP:0001263

No standalone denominator exists. Developmental delay is one of four features in the 25/47 (53%) composite reported by PMID:34626583, so a per-feature frequency band is deliberately omitted.

Show evidence (2 references)

PMID:34626583 SUPPORT Human Clinical

"In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy."

Developmental delay is one of the four composite features.

PMID:41375745 SUPPORT Human Clinical

"Vojta neurodevelopmental assessment demonstrated an 11-month motor delay, abnormal responses in all seven Vojta postural reactions, and persistent primitive reflexes."

Quantifies the developmental delay in an individually described patient.

Impaired intellectual development Intellectual disability HP:0001249

Part of the 25/47 (53%) composite in PMID:34626583; no standalone denominator published, so no frequency band is asserted.

Show evidence (1 reference)

PMID:37902276 SUPPORT Human Clinical

"We report on a 6 1/2-year-old girl with a history of global developmental delay, subsequent intellectual disability without relevant language acquisition, sensorineural hearing loss, muscular hypotonia and microcephaly."

Documents intellectual disability without relevant language acquisition in a genetically confirmed AFG2B patient.

Absent or severely limited speech Delayed speech and language development HP:0000750

Single-case evidence only, and confounded by the near-universal hearing loss; no frequency band is asserted. Rebound from HP:0001344 (Absent speech) to HP:0000750 during phenotype review: the full text of the sole cited source (PMID:37902276) records that the girl used 5 to 10 single words at 5 3/12 years with adequate listening comprehension, which contradicts the complete lack of speech that HP:0001344 asserts. HP:0000750 is the most specific term the published evidence actually supports.

Show evidence (2 references)

PMID:37902276 SUPPORT Human Clinical

"We report on a 6 1/2-year-old girl with a history of global developmental delay, subsequent intellectual disability without relevant language acquisition, sensorineural hearing loss, muscular hypotonia and microcephaly."

Absence of relevant language acquisition at 6 1/2 years supports severely limited speech and language development. Note that concurrent sensorineural hearing loss is an obvious confounder for speech development in this disorder.

PMID:37902276 SUPPORT Human Clinical

"Language acquisition was not achieved before the age of 5 years."

Full-text detail quantifying the language delay; the same passage records 5 to 10 single words at 5 3/12 years, which is why the binding is delayed speech and language development rather than absent speech.

Spastic-dystonic cerebral palsy HP:0100021

Part of the 25/47 (53%) composite in PMID:34626583; no standalone denominator published, so no frequency band is asserted.

Show evidence (1 reference)

PMID:34626583 SUPPORT Human Clinical

"In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy."

Cerebral palsy is one of the four composite features.

Dystonia HP:0001332

Reported only in the composite phrase "spasticity and/or dystonia", so no separate frequency band is asserted.

Show evidence (1 reference)

PMID:41375745 SUPPORT Human Clinical

"In contrast to the published cohort, in which most individuals with bi-allelic SPATA5L1 variants exhibited spasticity and/or dystonia as predominant motor features"

Dystonia is one of the two predominant motor features of the published cohort.

Epilepsy Seizure HP:0001250

Part of the 25/47 (53%) composite in PMID:34626583; no standalone denominator published, so no frequency band is asserted.

Show evidence (2 references)

PMID:34626583 SUPPORT Human Clinical

"In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy."

Epilepsy is one of the four composite features.

PMID:41375745 SUPPORT INDIRECT Human Clinical

"Although the later EEG demonstrated epileptiform abnormalities, no clinically confirmed epileptic seizures have been documented to date."

Supports the description's qualifier that epilepsy is not obligate, by documenting a genotype-positive child with epileptiform EEG abnormalities but no confirmed clinical seizure. INDIRECT for the phenotype's core claim, since the quote records the absence rather than the presence of overt epilepsy; the cohort-level presence claim rests on PMID:34626583.

EEG abnormality HP:0002353

Bound to HP:0002353 (EEG abnormality). The PR review suggested HP:0010848, but that term is "EEG with spike-wave complexes (2.5-3.5 Hz)", which the reported tracing (bilateral sharp waves, incomplete complexes and theta activity) does not describe, so it would have been a false match. Single-case evidence, so no frequency band is asserted.

Show evidence (2 references)

PMID:41375745 SUPPORT Human Clinical

"The EEG performed at approximately 2 years and 2 weeks of age showed abnormalities during wakefulness and sleep, including bilateral sharp waves, incomplete FO–FW complexes, and theta activity."

Documents the specific interictal EEG abnormalities recorded in a genetically confirmed AFG2B patient.

PMID:41375745 SUPPORT Human Clinical

"Early EEG recordings were without significant changes, whereas abnormalities emerged later in the clinical course."

Establishes that the EEG abnormality is acquired during follow-up rather than present from the first recording, which is why a single early normal EEG does not exclude the diagnosis.

Cerebral atrophy and diminished cerebral volume HP:0002059

Show evidence (2 references)

PMID:34626583 SUPPORT Human Clinical

"Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals."

Documents diminished cerebral volume in the founding cohort.

PMID:41375745 SUPPORT Human Clinical

"Brain MRI showed cortical and white matter atrophy, delayed myelination, and a thin corpus callosum."

Independent confirmation of cortical and white matter atrophy.

Reduced cerebral white matter volume HP:0034295

Show evidence (1 reference)

PMID:34626583 SUPPORT Human Clinical

"quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals"

Direct quantitative evidence of reduced white matter volume.

Thin corpus callosum HP:0033725

Show evidence (2 references)

PMID:34626583 SUPPORT Human Clinical

"Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals."

Thin corpus callosum in the founding cohort.

PMID:41375745 SUPPORT Human Clinical

"Brain MRI showed cortical and white matter atrophy, delayed myelination, and a thin corpus callosum."

Independent confirmation of a thin corpus callosum.

Periventricular leukomalacia HP:0006970

Show evidence (1 reference)

PMID:34626583 SUPPORT Human Clinical

"Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals."

Periventricular leukomalacia in the founding cohort.

Delayed myelination HP:0012448

Single-case evidence; no frequency band asserted.

Show evidence (1 reference)

PMID:41375745 SUPPORT Human Clinical

"At 20 months, the brain MRI revealed mild generalized atrophy of the cortex and the white matter, bilateral T2 hyperintensities of the posterior portions of the white matter indicating its delayed myelination and slightly hypoplastic corpus callosum"

Documents delayed myelination on MRI at 20 months.

🧬

Genetic Associations

1

AFG2B

Gene: AFG2B hgnc:28762 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (2 references)

PMID:34626583 SUPPORT Human Clinical

"We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families."

The founding gene-disease association across 26 unrelated families.

PMID:34626583 SUPPORT Other

"Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function."

Records that the gene was functionally uncharacterised at the time the disease association was established; its 55LCC role was defined later. Classified OTHER rather than HUMAN_CLINICAL because this is a statement about the gene's annotation status, not a clinical observation.

Variants (4)

c.2066G>T (p.Gly689Val) Likely Pathogenic

Gene: AFG2B hgnc:28762 missense variant

A recurrent missense allele in the ATPase motor, reported in four individuals within the founding cohort of 25 patients and subsequently in an unrelated compound heterozygous case. It is predicted to disrupt ATP binding and hydrolysis and is reported as pathogenic in ClinVar.

Show evidence (2 references)

PMID:41375745 SUPPORT Human Clinical

"However, an identical variant, c.2066G>T, has been reported in four individuals within a cohort of 25 patients described by Richard et al."

Establishes recurrence of the allele across unrelated individuals.

PMID:41375745 SUPPORT Computational

"Missense variants such as p.Gly689Val are predicted to disrupt ATP binding and hydrolysis, thereby impairing the catalytic function of the ATPase motor"

Predicted functional effect on the ATPase motor.

c.1918C>T (p.Arg640Ter) Uncertain Significance

Gene: AFG2B hgnc:28762 nonsense variant

A rare nonsense allele introducing a premature stop codon, reported in trans with c.2066G>T. It meets PVS1 as a null allele in a gene where loss of function is an established mechanism, but was classified as of uncertain significance under ACMG rules in the report that described it.

Show evidence (1 reference)

PMID:41375745 SUPPORT Human Clinical

"In the ACMG classification it is assessed as having uncertain significance."

Source of the recorded clinical significance. The same report argues the allele fulfils PVS1, so the uncertain classification is likely to be upgraded as more cases accrue.

c.1313T>C (p.Leu438Pro) Likely Pathogenic

Gene: AFG2B hgnc:28762 missense variant

A missense allele whose contribution was initially unclear because it was first observed as part of a complex disease allele alongside a second homozygous missense change. Observation in trans with an independent missense allele in a further patient supported its pathogenic relevance.

Show evidence (1 reference)

PMID:37902276 SUPPORT Human Clinical

"Our results support the pathogenic relevance of the c.1313T>C, p.(Leu438Pro) allele while providing detailed insights into the disease manifestation of a further patient."

Resolves the previously ambiguous contribution of this allele to disease.

c.527G>T (p.Gly176Val) Likely Pathogenic

Gene: AFG2B hgnc:28762 missense variant

A likely pathogenic missense allele identified by trio exome sequencing in trans with c.1313T>C in a girl with developmental delay, intellectual disability, sensorineural hearing loss, hypotonia and microcephaly.

Show evidence (1 reference)

PMID:37902276 SUPPORT Human Clinical

"Trio exome sequencing revealed likely pathogenic compound heterozygous missense variants in AFG2B"

Reports the allele and its compound heterozygous configuration.

💊

Medical Actions

3

Hearing amplification

Action: hearing aid fitting Ontology label: Supportive Care NCIT:C15747

Platform: Device

Hearing aids are fitted once bilateral sensorineural hearing loss is identified, typically in infancy. This is supportive management of the disorder's defining feature, not disease-modifying therapy.

Mechanism Target:

Bilateral Sensorineural Hearing Loss — Hearing aids provide symptomatic auditory amplification for the hearing-loss endpoint. This link does not claim repair of AFG2B function or cochlear pathology; a reported child showed an acoustical response after fitting.

Show evidence (1 reference)

PMID:37902276 SUPPORT Human Clinical

"The provision of hearing aids was started at the age of 9 months, leading to an acoustical response in the sense of normal hearing."

A single-case functional response supports symptomatic targeting of hearing loss. It does not demonstrate restoration of the underlying pathology.

Show evidence (1 reference)

PMID:41375745 SUPPORT Human Clinical

"In the 7th month of life audiological evaluation revealed bilateral sensorineural hearing loss of 60 dBnHL, and hearing aids were fitted."

Documents amplification in a single affected child, without reporting an audiological outcome in this case. PMID:37902276 separately reports an acoustical response to hearing aids, as cited on the treatment link.

Early developmental rehabilitation

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Early, structured physiotherapy and neurodevelopmental rehabilitation (including reflex locomotion / Vojta therapy in the reported case) is the mainstay of motor management. No outcome data exist for this disorder.

Show evidence (1 reference)

PMID:41375745 SUPPORT Human Clinical

"Early rehabilitation including reflex locomotion therapy was initiated."

Single-case description of the rehabilitation approach used. PARTIAL because the same report notes the lack of clinical progress despite therapy, so efficacy is not demonstrated.

Genetic counselling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Other

Autosomal recessive inheritance gives a 25% recurrence risk for each subsequent pregnancy of carrier parents. Confirming that the two variants are in trans, and carrier testing of both parents, is required before counselling.

Show evidence (1 reference)

PMID:41375745 SUPPORT Human Clinical

"in the proband we observe a configuration of a compound heterozygote, and in the parents the carrier state"

Documents the parental carrier state and compound heterozygous configuration that recurrence-risk counselling depends on.

🔬

Diagnosis

2

Trio exome sequencing

Diagnosis is molecular. The disorder has been identified exclusively by exome sequencing; trio testing establishes that the two variants are in trans and that each parent is a carrier. There is no biochemical marker and no disease-specific imaging finding, so a child with sensorineural hearing loss plus developmental delay, spasticity or dystonia should be offered sequencing rather than a metabolic workup, and AFG2B should be covered by neurodevelopmental and hearing-loss gene panels.

PMID:41375745 also reports an incidental de novo FRYL variant in the same proband that the authors could not exclude as a sequencing artefact. It is recorded here only as a reminder that incidental findings complicate interpretation in this ultra-rare disorder; it is not curated as a modifier.

Show evidence (2 references)

PMID:37902276 SUPPORT Human Clinical

"We performed trio exome sequencing on the patient and her parents."

Trio exome sequencing is the diagnostic method used.

PMID:41375745 SUPPORT Human Clinical

"Genetic testing confirmed the variants in trans."

Confirming the trans configuration is the decisive step for a recessive diagnosis.

Audiological assessment

Formal audiology or auditory brainstem response testing establishes the bilateral sensorineural hearing loss that defines the disorder, and should be performed in infancy in any child with unexplained global developmental delay and abnormal tone.

Show evidence (1 reference)

PMID:41375745 SUPPORT Human Clinical

"In the 7th month of life audiological evaluation revealed bilateral sensorineural hearing loss of 60 dBnHL, and hearing aids were fitted."

Audiological evaluation is what established the defining feature in the reported infant.

📈

Progression

2

Age: Birth to 2 years

Bilateral sensorineural hearing loss is typically identified in infancy (one reported child at 7 months, 60 dBnHL) and developmental concerns are usually raised in the first year. The motor phenotype can evolve: an infant may present with generalised hypotonia and persistent primitive reflexes and only later develop the spastic-dystonic pattern. Microcephaly may be postnatal rather than congenital in at least some individuals.

Show evidence (2 references)

PMID:41375745 SUPPORT Human Clinical

"In the 7th month of life audiological evaluation revealed bilateral sensorineural hearing loss of 60 dBnHL, and hearing aids were fitted."

Documents infantile identification of the hearing loss.

PMID:41375745 SUPPORT Human Clinical

"The persistence of primitive reflexes, central hypotonia, and pathological postural reactions provided a coherent neuromotor profile and indicated a high vulnerability to atypical motor development, and do not rule out the possibility of later evolution toward a spastic-dystonic motor pattern."

Supports evolution of the motor phenotype from infantile hypotonia toward a spastic-dystonic pattern, but only as an anticipated possibility in a single 24-month-old, hence PARTIAL.

Age: Childhood onwards

The founding cohort characterised the accompanying neurodevelopmental phenotype as nonprogressive, which distinguishes the disorder from a neurodegenerative encephalopathy. No longitudinal audiometric, motor, imaging or survival data have been published, so whether the hearing loss itself progresses is unknown; see the `afg2b_natural_history_gap` discussion.

Show evidence (1 reference)

PMID:34626583 SUPPORT Human Clinical

"Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype."

States the nonprogressive character of the neurodevelopmental phenotype.

📊

Prevalence

1

Global

Cases In Literature Ultra Rare

Forty-seven individuals from 28 (26 unrelated) families in the founding cohort (PMID:34626583), plus two subsequently reported single cases (PMID:37902276, PMID:41375745). No population prevalence or incidence has ever been estimated for this disorder, so no rate is recorded.

Show evidence (2 references)

PMID:34626583 SUPPORT Human Clinical

"We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families."

Gives the total number of individuals reported in the founding series.

PMID:41375745 SUPPORT Human Clinical

"Importantly, biallelic pathogenic variants in SPATA5L1 were only recently recognized as a cause of a distinct neurodevelopmental disorder, and fewer than 30 affected individuals have been described to date"

Independent confirmation of ultra-rarity. Note that this case report counts only the individuals with the full neurodevelopmental phenotype, which is the 25/47 subgroup of the founding cohort rather than all 47.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Neurodevelopmental Disorder with Hearing Loss and Spasticity:

AFG2A-Related Encephalopathy MONDO:0014698

Overlapping Features The disorder caused by biallelic variants in the paralogous gene AFG2A (formerly SPATA5), whose protein is the obligate partner of AFG2B inside the same 55LCC complex. The clinical pictures overlap substantially, with intellectual disability, developmental delay, epilepsy, hearing loss and movement disorder in both, which is exactly why the pair is a named-entity confusion hazard. That disorder is curated in this repository as `AFG2A-Related_Encephalopathy`, and it in turn lists this disorder as one of its differentials.

Distinguishing Features

AFG2A-related encephalopathy typically has earlier seizure onset, more pronounced (congenital) microcephaly and more frequent movement disorders, and frequently presents as a developmental and epileptic encephalopathy.
AFG2B-related disease is dominated by sensorineural hearing loss, which is near-universal and can be the sole manifestation, with a more consistently spastic-dystonic motor pattern and a neurodevelopmental burden that affects only about half of individuals.
Only sequencing distinguishes the two reliably; the genes differ by one letter in both their current (AFG2A/AFG2B) and their legacy (SPATA5/SPATA5L1) symbols.

Show evidence (2 references)

PMID:41375745 SUPPORT Human Clinical

"SPATA5-related disorder (NEDCAS) presents with earlier seizure onset, more pronounced microcephaly, and frequent movement disorders"

Directly contrasts the two paralogous disorders on the features that distinguish them.

PMID:41933351 SUPPORT Human Clinical

"AFG2A-RE is an ultra-rare, recessive disorder, sometimes presenting as a developmental and epileptic encephalopathy (DEE), characterised by the triad of epilepsy, congenital microcephaly, and deafness, and typically associated with intellectual disability, spasticity, and movement disorders."

Describes the AFG2A phenotype from the largest AFG2A cohort. This is the only citation in this entry drawn from an AFG2A series, and it is confined to this differential.

Autosomal recessive nonsyndromic sensorineural hearing loss

Overlapping Features Because biallelic AFG2B variants can cause isolated hearing loss with no neurodevelopmental features, the disorder enters the differential for apparently nonsyndromic recessive sensorineural hearing loss, and AFG2B should be covered by hearing-loss gene panels.

Distinguishing Features

Nothing distinguishes the isolated-hearing-loss presentation clinically; only sequencing does.
Conversely, the presence of microcephaly, spasticity, dystonia or epilepsy alongside hearing loss argues against a nonsyndromic aetiology.

Show evidence (1 reference)

PMID:37902276 SUPPORT Human Clinical

"Bi-allelic variants in AFG2B (previously known as SPATA5L1) have recently been associated with a neurodevelopmental disorder with hearing loss and spasticity, as well as isolated hearing loss."

States explicitly that biallelic AFG2B variants can produce isolated hearing loss.

Acquired (non-genetic) cerebral palsy

Overlapping Features The spastic-dystonic motor phenotype with periventricular leukomalacia on imaging closely mimics cerebral palsy of perinatal hypoxic-ischaemic origin, and affected children may carry that label for years before sequencing.

Distinguishing Features

Absence of a perinatal insult, plus consanguinity or affected siblings, should prompt genomic testing rather than an acquired-aetiology label.
Accompanying bilateral sensorineural hearing loss is the single most useful pointer away from acquired cerebral palsy.
Periventricular leukomalacia in this disorder is not explained by prematurity or perinatal asphyxia.

Show evidence (1 reference)

PMID:34626583 SUPPORT Human Clinical

"Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals."

Periventricular leukomalacia is the imaging finding that most strongly suggests an acquired perinatal aetiology and is therefore the source of the diagnostic confusion.

{ }

Source YAML

click to show

name: Neurodevelopmental Disorder with Hearing Loss and Spasticity
creation_date: '2026-08-15T00:00:00Z'
category: Mendelian
synonyms:
- NEDHLS
- AFG2B-related neurodevelopmental disorder
- SPATA5L1-related neurodevelopmental disorder
- neurodevelopmental disorder with psychomotor delay, hearing loss, and spasticity
description: >-
  Neurodevelopmental disorder with hearing loss and spasticity (NEDHLS,
  OMIM:619616) is an ultra-rare autosomal recessive disorder caused by biallelic
  variants in AFG2B, the gene reported throughout the founding clinical
  literature under its former symbol SPATA5L1. Sensorineural hearing loss is the
  near-constant feature; roughly half of reported individuals additionally have a
  mixed neurodevelopmental phenotype comprising microcephaly, global
  developmental delay and impaired intellectual development, spastic-dystonic
  cerebral palsy, and focal or generalised epilepsy. Some children, particularly
  in infancy, present with hypotonia rather than hypertonia, and craniofacial
  dysmorphism and strabismus occur in a subset. Brain imaging typically shows
  diminished cerebral volume, reduced white matter volume, a thin corpus
  callosum, delayed myelination and periventricular leukomalacia. AFG2B encodes
  an AAA+ ATPase that is an obligate subunit of the 55LCC complex together with
  its paralogue AFG2A (SPATA5), C1orf109 and CINP; the complex directs replisome
  proteostasis and also drives the last cytoplasmic maturation step of the
  pre-60S ribosomal subunit. Because AFG2B and AFG2A are partners in the same
  complex, the two gene-specific disorders overlap clinically, and the paralogue
  pair is a recognised source of named-entity confusion (see notes). OMIM
  numbers the two ends of the phenotype separately - NEDHLS (OMIM:619616) for
  the syndromic presentation and DFNB119 (OMIM:619615) for isolated hearing loss
  - and DFNB119 is curated here as a subtype rather than as a separate entry;
  see note (10).
disease_term:
  preferred_term: neurodevelopmental disorder with hearing loss and spasticity
  term:
    id: MONDO:0859206
    label: neurodevelopmental disorder with hearing loss and spasticity
parents:
- Mendelian neurodevelopmental disorder
- Ribosome biogenesis disorder
- Genetic sensorineural hearing loss
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:34626583
      reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
        spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural
        hearing loss in 47 individuals from 28 (26 unrelated) families.
      explanation: >-
        A monogenic recessive disorder delineated by exome sequencing across 26
        unrelated families belongs to the genetics chapter.
  - classification_value: DISORDER_OF_EAR
    evidence:
    - reference: PMID:34626583
      reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
        spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Collectively, our results indicate that bi-allelic SPATA5L1 variants
        lead to a human disease characterized by sensorineural hearing loss (SNHL)
        with or without a nonprogressive mixed neurodevelopmental phenotype.
      explanation: >-
        Sensorineural hearing loss is the defining and near-universal feature and
        can occur without any neurodevelopmental involvement, placing the entity
        squarely in the disorders-of-the-ear chapter.
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:34626583
      reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
        spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In addition, 25/47 affected individuals (53%) presented with microcephaly,
        developmental delay/intellectual disability, cerebral palsy, and/or epilepsy.
      explanation: >-
        Just over half of affected individuals carry a microcephaly, developmental
        delay, cerebral palsy and epilepsy burden that is managed neurologically.
notes: >-
  Scope, naming and provenance notes for this entry.


  (1) GENE SYMBOL HISTORY - READ THIS FIRST. The causative gene is AFG2B
  (HGNC:28762, OMIM:619578), renamed from SPATA5L1 (spermatogenesis associated 5
  like 1). Every founding clinical report uses SPATA5L1: a PubMed search on
  2026-08-15 returned 14 records for `SPATA5L1` but only 2 for `AFG2B`, and the
  largest cohort (PMID:34626583) never uses the new symbol. Searching either
  symbol alone therefore misses most of the disease literature; both were
  searched for this entry. The rename has not propagated through the ontology
  stack used here. MONDO's `RO:0004003` axiom on MONDO:0859206 already reads
  `HGNC:28762 ! AFG2B`, but the HGNC adapter shipped with `sqlite:obo:hgnc` still
  resolves `hgnc:28762` to the label `SPATA5L1` (verified with
  `runoak -i sqlite:obo:hgnc info hgnc:28762`; a search for `AFG2B` returns
  nothing). Every `gene_term` in this entry therefore carries
  `preferred_term: AFG2B` with `term.label: SPATA5L1`, because SPATA5L1 is the
  label the term validator resolves. This is a lag in the cached HGNC build, not
  a curation error, and it must NOT be "fixed" to `AFG2B` until the adapter is
  refreshed. The sibling entry AFG2A-Related_Encephalopathy documents the exactly
  analogous situation for hgnc:18119 / SPATA5.


  (2) NAMED-ENTITY CONFUSION WITH AFG2A / SPATA5 - THE PRIMARY RISK FOR THIS
  ENTRY. AFG2A (HGNC:18119, formerly SPATA5) is a DIFFERENT gene one suffix away
  from this one, and it causes a DIFFERENT, clinically overlapping disorder
  (MONDO:0014698, curated in this repository as AFG2A-Related_Encephalopathy;
  founding report PMID:26299366). This entry is about AFG2B only. The NEC
  preflight was run before any deep-research content was used:
  `runoak -i sqlite:obo:mondo info MONDO:0859206 -O obo` returns
  `relationship: RO:0004003 HGNC:28762 ! AFG2B` and `xref: OMIM:619616`,
  matching the intended target on both the gene and the OMIM anchor. Every
  clinical citation in this entry was then checked for which gene the reported
  individuals actually carry variants in: PMID:34626583, PMID:37902276 and
  PMID:41375745 are AFG2B/SPATA5L1 cohorts. PMID:41933351 is an AFG2A cohort
  review and is cited ONLY inside `differential_diagnoses`, never as support for
  a phenotype of this entry. The three structural and biochemical papers
  (PMID:38554706, PMID:40268917, PMID:35354024) study the 55LCC complex as a
  whole and are cited for complex composition and function, not for any
  gene-specific clinical claim; PMID:35354024 in particular measures the protein
  synthesis defect after loss of C1ORF109 or SPATA5 (AFG2A), NOT after loss of
  AFG2B, which is why the downstream translation node is marked PROVISIONAL.
  Two further AFG2B papers surfaced by the literature search, PMID:34864870
  (full-house nephropathy with high SPATA5L1 expression) and PMID:41390732
  (AFG2B variants in childhood lupus nephritis), describe renal and autoimmune
  phenotypes that are not part of NEDHLS and are deliberately NOT cited.


  (3) DISEASE NAME. The file is named for the OMIM and MONDO term, which is also
  the name used by the issue that requested this entry and by the only paper that
  uses the new gene symbol in its title (PMID:37902276, "A further case of
  AFG2B-related neurodevelopmental disorder with hearing loss and microcephaly").
  No paper titles the disorder "AFG2B-related encephalopathy"; that phrase
  appears only inside the body of the AFG2A review (PMID:41933351) and was
  therefore not adopted as the entry name or as a synonym.


  (4) NO GENEREVIEWS CHAPTER EXISTS. PubMed searches run on 2026-08-15 with the
  queries `SPATA5L1 GeneReviews[All Fields]`, `AFG2B GeneReviews[All Fields]` and
  `neurodevelopmental disorder with hearing loss and spasticity GeneReviews[All
  Fields]` each returned zero records. The mandatory GeneReviews phenotype
  baseline therefore does not apply. The baseline used instead is the founding
  47-individual cohort (PMID:34626583), which remains the largest published
  series, cross-checked against the two subsequent single-case reports
  (PMID:37902276, PMID:41375745).


  (5) FREQUENCY BANDS AND THE ASCERTAINMENT CAVEAT. No phenotype frequency
  band is asserted. PMID:34626583 reports sensorineural hearing loss in all 47
  individuals, but its cached abstract does not establish bilaterality across
  that cohort. The bilateral phenotype is supported by individual reports;
  the broader 47/47 figure must not supply its frequency. The cohort also spans
  syndromic and isolated hearing loss. The composite neurodevelopmental burden
  (microcephaly, developmental delay/intellectual disability, cerebral palsy
  and/or epilepsy) was 25/47 (53%); this cannot be redistributed to individual
  features. Per-feature denominators are not available in the cached founding
  abstract. Craniofacial dysmorphism is likewise unbanded: PMID:41375745
  describes it in "approximately one-third of affected individuals in the
  literature" but gives no numerator or denominator of its own.


  (6) WHY CONFORMANCE TO `sensorineural_hair_cell_loss` IS PARTIAL AND NOT
  ASSERTED DOWN THE WHOLE CHAIN. This was evaluated rather than assumed. The
  cochlear node of this entry declares
  `conforms_to: sensorineural_hair_cell_loss#Cochlear Sensory Epithelium Insult`
  and nothing further. That single conformance is supported: PMID:34626583 shows
  that in the rodent inner ear Spata5l1 is expressed in the neurosensory hair
  cells and inner ear supporting cells (its full text localises the protein to
  hair cells and pillar cells of the organ of Corti in rat whole mounts), and
  biallelic human variants produce sensorineural hearing loss. That is exactly
  the module's generic trigger, a hereditary lesion of the cochlear sensory
  epithelium with the mechanosensitive hair cell as the vulnerable target. The
  module's three downstream nodes - cochlear ionic homeostasis disruption and
  oxidative stress, hair cell mechanotransduction failure and death, and spiral
  ganglion neuron degeneration - have NO AFG2B evidence whatsoever: no cochlear
  histology of an AFG2B-deficient animal, no endocochlear potential measurement,
  no hair cell counts and no auditory nerve study has been published for this
  gene. Conforming to them would assert mechanisms nobody has looked for. The
  module's terminal node is furthermore "Progressive Sensorineural Hearing Loss",
  and PMID:34626583 explicitly characterises the accompanying phenotype as
  NONPROGRESSIVE, so even the endpoint is not safe to claim. The gap is recorded
  as a KNOWLEDGE_GAP discussion (`afg2b_cochlear_mechanism_gap`) with the
  experiments that would resolve it.


  (7) STRUCTURED SOURCES CHECKED AND FOUND ABSENT, NOT SKIPPED BY DEFAULT. No
  Orphanet, ClinGen gene-disease validity (CGGV) or ClinGen dosage (CGDS) record
  is cited. This absence is specific rather than general: MONDO:0859206 carries
  `xref: Orphanet:659975` but `ls references_cache/ORPHA_659975.md` returns no
  such file, and
  `grep -l -i -e SPATA5L1 -e AFG2B -e HGNC:28762 references_cache/CGGV_*.md
  references_cache/CGDS_*.md` returns nothing across the CGGV and CGDS files
  present in the cache. Generating the missing records would require bumping a
  structured-source `data/*/MANIFEST.yaml` pin, which is out of scope for a
  curation PR (and those pins are tracked as stale in #7622), so the citation is
  skipped rather than fabricated.


  (8) DEEP RESEARCH PROVENANCE. One Falcon (Edison) run was performed and is
  committed at
  `research/Neurodevelopmental_Disorder_with_Hearing_Loss_and_Spasticity-deep-research-falcon.md`.
  It was treated as leads only. It independently resolved the disease to AFG2B
  (not AFG2A) and surfaced the same two primary clinical sources and the same
  mechanistic source used here, so it passed the NEC preflight. Its own reference
  validator flagged one unresolved citation (a malformed DOI link), and every
  PMID, snippet and ontology term used in this entry was independently fetched
  and verified against the local cache rather than taken from the report.


  (9) WHAT IS KNOWINGLY ABSENT. No treatment in this entry is disease-modifying;
  everything curated is supportive (amplification, rehabilitation, genetic
  counselling) and the disease-specific evidence base for each is a single case
  report at best. No animal model of AFG2B deficiency has been published, so
  there is no `animal_models` block; the only in vivo AFG2B data located are
  rodent expression studies (PMID:34626583), not a knockout, and the point is
  recorded as a discussion. No genotype-phenotype correlation is asserted
  anywhere in this entry; PMID:41375745 states explicitly that the published
  cohort is too small to support one. No prevalence rate is given because none
  has been estimated; the entry records only a CASES_IN_LITERATURE count. No
  environmental factor is curated, because the deep-research run found no toxin,
  infection, or exposure implicated in this monogenic disorder. The mTOR rescue
  axis reported for the paralogous 55LCC subunit AIRIM/C1orf109 (PMID:40760247)
  is curated as a pathophysiology observation and a discussion, NOT as a
  treatment, because it has never been tested in an AFG2B model.


  (10) WHY DFNB119 IS A SUBTYPE HERE AND NOT A SEPARATE ENTRY. OMIM gives the
  isolated-hearing-loss presentation of biallelic AFG2B variants its own
  phenotype number, DFNB119 (OMIM:619615, MONDO:0030480), alongside the
  syndromic NEDHLS number this entry is named for (OMIM:619616). Claim issue
  #11973 asked whether dismech should carry it separately. It should not, and
  the reasons are in the `has_subtypes` block's evidence rather than in a
  judgement of what feels like one disease. Both numbers were assigned from one
  cohort in one report (PMID:34626583), which itself describes a single disease
  "with or without" the neurodevelopmental extension. At least one allele,
  c.527G>T p.(Gly176Val), is reported on both sides of the split, so no genotype
  separates them (PMID:37902276). And DFNB119 has no literature of its own: a
  PubMed search for the term on 2026-09-16 returns nothing about this gene, so
  a separate entry would have had to be assembled from this entry's sources and
  would have duplicated this entry's pathograph with no node of its own. The
  remaining asymmetry is honest and worth stating: this entry's name is the
  syndromic OMIM label, so a reader arriving from the isolated presentation
  finds it under a name that overstates their phenotype. The alternative -
  renaming the entry to something gene-shaped such as "AFG2B-related disorder" -
  was considered and not done in this PR, because it would break the entry's
  MONDO anchor (MONDO:0859206 is the NEDHLS term) and is a change that should be
  argued on its own rather than as a side effect of binding a subtype.
inheritance:
- name: Autosomal recessive
  description: >-
    Biallelic (homozygous or, more commonly, compound heterozygous) AFG2B
    variants are required. Heterozygous carrier parents are unaffected, and
    segregation in trans has been confirmed in the reported families.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Collectively, our results indicate that bi-allelic SPATA5L1 variants
      lead to a human disease characterized by sensorineural hearing loss (SNHL)
      with or without a nonprogressive mixed neurodevelopmental phenotype.
    explanation: >-
      The founding cohort establishes that the disorder requires biallelic
      variants.
  - reference: PMID:37902276
    reference_title: A further case of AFG2B-related neurodevelopmental disorder with
      hearing loss and microcephaly allows further clarification of pathogenicity
      of the variant c.1313T>C, p.(Leu438Pro).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Bi-allelic variants in AFG2B (previously known as SPATA5L1) have recently
      been associated with a neurodevelopmental disorder with hearing loss and spasticity,
      as well as isolated hearing loss.
    explanation: >-
      Independent restatement of the biallelic requirement, and the only report
      to use the current gene symbol in its title.
has_subtypes:
- name: DFNB119
  display_name: Isolated sensorineural hearing loss (DFNB119, OMIM:619615)
  classification: clinical_phenotype
  subtype_frequency: 22/47 (47%) of individuals in the founding cohort
  subtype_term:
    preferred_term: hearing loss, autosomal recessive 119
    term:
      id: MONDO:0030480
      label: hearing loss, autosomal recessive 119
  genes:
  - preferred_term: AFG2B
    term:
      id: hgnc:28762
      label: SPATA5L1
  description: >-
    DFNB119 is the presentation in which biallelic AFG2B variants produce
    sensorineural hearing loss and nothing else - no microcephaly, no
    developmental delay or impaired intellectual development, no spastic-dystonic
    motor phenotype and no epilepsy. OMIM gives it a separate phenotype number
    (OMIM:619615) from the syndromic presentation this entry is named for
    (NEDHLS, OMIM:619616), but both numbers were assigned from the same founding
    cohort and the same gene, and the separation is a description of how far the
    phenotype extends in a given individual rather than of a different lesion.
    It is modelled here as a subtype for three reasons, each of which is
    evidenced below. The founding report frames the disorder as a single entity
    with a variable extension ("with or without a nonprogressive mixed
    neurodevelopmental phenotype"). The same allele recurs on both sides of the
    split - c.527G>T, p.(Gly176Val) is reported in individuals with the full
    neurodevelopmental phenotype and repeatedly in individuals with isolated
    hearing loss - so no genotype partitions the two. And the hearing-loss
    mechanism curated in this entry's pathophysiology is the mechanism of
    DFNB119: the divergence between the two presentations lies in whether the
    neural branch is also manifest, not in how the cochlear lesion arises.
  evidence:
  - reference: PMID:37902276
    reference_title: A further case of AFG2B-related neurodevelopmental disorder with
      hearing loss and microcephaly allows further clarification of pathogenicity
      of the variant c.1313T>C, p.(Leu438Pro).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "bi‐allelic variants in AFG2B have been associated with neurodevelopmental disorder with hearing loss and spasticity (OMIM #619616), as well as with isolated hearing loss (OMIM #619615)"
    explanation: >-
      Names both OMIM phenotype numbers, attributes both to biallelic variants in
      the one gene, and cites the one founding report for both. This is the
      sentence that establishes DFNB119 as the isolated-hearing-loss end of this
      entry's disorder rather than a separate gene-disease relationship. Quoted
      from the paper's introduction, where it restates the founding report, so
      the finding is not this paper's own.
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, 25/47 affected individuals (53%) presented with microcephaly,
      developmental delay/intellectual disability, cerebral palsy, and/or epilepsy.
    explanation: >-
      Hearing loss was present in all 47 individuals of the founding cohort and
      the neurodevelopmental burden in 25 of them, so 22 of 47 (47%) had hearing
      loss without any of the neurodevelopmental features. That complement is the
      subtype frequency recorded here. It is the cohort's own split and is not a
      redistribution across individual features, which the founding abstract does
      not support.
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Collectively, our results indicate that bi-allelic SPATA5L1 variants lead
      to a human disease characterized by sensorineural hearing loss (SNHL) with or
      without a nonprogressive mixed neurodevelopmental phenotype.
    explanation: >-
      The founding report's own summary treats the isolated and syndromic
      presentations as one disease with a variable extension, which is the claim
      a subtype models and a separate disease entry would contradict.
  - reference: PMID:37902276
    reference_title: A further case of AFG2B-related neurodevelopmental disorder with
      hearing loss and microcephaly allows further clarification of pathogenicity
      of the variant c.1313T>C, p.(Leu438Pro).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Moreover, this variant has been reported several times in compound heterozygous form in patients with isolated hearing loss"
    explanation: >-
      The variant under discussion in this sentence is c.527G>T, p.(Gly176Val),
      which the preceding sentence of the same paragraph reports in three
      individuals with the full neurodevelopmental phenotype. One allele therefore
      appears on both sides of the OMIM split, so the two phenotype numbers are
      not separated by genotype. Quoted from the paper's variant-interpretation
      discussion of previously published individuals, not from its own case.
  review_notes: >-
    No publication anywhere uses the term DFNB119. A PubMed search for `DFNB119`
    run on 2026-09-16 returns one record (PMID:10196710), a 1999 paper predating
    the identifier and unrelated to AFG2B. The whole clinical AFG2B literature is
    the three reports already cited in this entry (PMID:34626583, PMID:37902276,
    PMID:41375745); a search for `SPATA5L1` returns 14 records, of which the
    other eleven are structural, functional or unrelated-phenotype papers.
    DFNB119 therefore has no literature of its own to build a separate entry
    from, which is why the concept is bound here instead.


    Two things are deliberately NOT asserted. No separate pathophysiology,
    phenotype or treatment row is tagged to this subtype: per-subtype
    audiological detail is not resolvable from the cached sources, and inventing
    a split would assert a distinction the sources do not draw. And no claim is
    made that any individual's presentation is stable - the founding cohort is
    cross-sectional, and whether an individual counted as isolated hearing loss
    in infancy would still be counted so later has not been reported.
prevalence:
- population: Global
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Forty-seven individuals from 28 (26 unrelated) families in the founding
    cohort (PMID:34626583), plus two subsequently reported single cases
    (PMID:37902276, PMID:41375745). No population prevalence or incidence has
    ever been estimated for this disorder, so no rate is recorded.
  evidence:
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural
      hearing loss in 47 individuals from 28 (26 unrelated) families.
    explanation: Gives the total number of individuals reported in the founding series.
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Importantly, biallelic pathogenic variants in SPATA5L1 were only recently
      recognized as a cause of a distinct neurodevelopmental disorder, and fewer than
      30 affected individuals have been described to date
    explanation: >-
      Independent confirmation of ultra-rarity. Note that this case report counts
      only the individuals with the full neurodevelopmental phenotype, which is
      the 25/47 subgroup of the founding cohort rather than all 47.
progression:
- age_range: Birth to 2 years
  notes: >-
    Bilateral sensorineural hearing loss is typically identified in infancy (one
    reported child at 7 months, 60 dBnHL) and developmental concerns are usually
    raised in the first year. The motor phenotype can evolve: an infant may
    present with generalised hypotonia and persistent primitive reflexes and only
    later develop the spastic-dystonic pattern. Microcephaly may be postnatal
    rather than congenital in at least some individuals.
  evidence:
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In the 7th month of life audiological evaluation revealed bilateral sensorineural
      hearing loss of 60 dBnHL, and hearing aids were fitted.
    explanation: Documents infantile identification of the hearing loss.
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The persistence of primitive reflexes, central hypotonia, and pathological
      postural reactions provided a coherent neuromotor profile and indicated a high
      vulnerability to atypical motor development, and do not rule out the possibility
      of later evolution toward a spastic-dystonic motor pattern.
    explanation: >-
      Supports evolution of the motor phenotype from infantile hypotonia toward a
      spastic-dystonic pattern, but only as an anticipated possibility in a single
      24-month-old, hence PARTIAL.
- age_range: Childhood onwards
  notes: >-
    The founding cohort characterised the accompanying neurodevelopmental
    phenotype as nonprogressive, which distinguishes the disorder from a
    neurodegenerative encephalopathy. No longitudinal audiometric, motor, imaging
    or survival data have been published, so whether the hearing loss itself
    progresses is unknown; see the `afg2b_natural_history_gap` discussion.
  evidence:
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Collectively, our results indicate that bi-allelic SPATA5L1 variants
      lead to a human disease characterized by sensorineural hearing loss (SNHL)
      with or without a nonprogressive mixed neurodevelopmental phenotype.
    explanation: States the nonprogressive character of the neurodevelopmental phenotype.
pathophysiology:
- name: Biallelic AFG2B Loss of Function
  description: >-
    Biallelic pathogenic variants in AFG2B (SPATA5L1) are the initiating lesion.
    Twenty-eight distinct biallelic variants were reported in the founding
    cohort; most are private missense changes, with nonsense alleles also
    described. Protein modelling indicated that the missense variants act largely
    by destabilising folded domains of the protein rather than by a gain of
    function, and specific substitutions in the ATPase motor (for example
    p.Gly689Val) are predicted to disrupt ATP binding and hydrolysis. The gene
    was an orphan gene of unknown function when the disease association was first
    made.
  role: root
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  genes:
  - preferred_term: AFG2B
    term:
      id: hgnc:28762
      label: SPATA5L1
  molecular_functions:
  - preferred_term: ATP hydrolysis activity
    term:
      id: GO:0016887
      label: ATP hydrolysis activity
    modifier: DECREASED
  evidence:
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural
      hearing loss in 47 individuals from 28 (26 unrelated) families.
    explanation: Establishes the biallelic genetic lesion as the root of the disorder.
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: Modeling indicated damaging effect of variants on the protein, largely
      via destabilizing effects on protein domains.
    explanation: >-
      In silico structural modelling supports a destabilising loss-of-function
      mechanism rather than a gain of function.
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: Missense variants such as p.Gly689Val are predicted to disrupt ATP binding
      and hydrolysis, thereby impairing the catalytic function of the ATPase motor
    explanation: >-
      Links a recurrent missense allele specifically to loss of ATPase catalytic
      activity. Predicted, not measured, hence COMPUTATIONAL.
  downstream:
  - target: 55LCC ATPase Complex Dysfunction
  - target: Cochlear Sensory Epithelium Involvement
- name: 55LCC ATPase Complex Dysfunction
  description: >-
    AFG2B does not act alone. It is an obligate subunit of the 55LCC complex, a
    4:2:2:2 assembly of AFG2A (SPATA5), AFG2B (SPATA5L1), C1orf109 and CINP in
    which the N-terminal domains of the two AAA+ ATPases interact with the
    C1orf109-CINP heterodimer to form a funnel-like ring sitting above a
    cylindrical stacked-ring ATPase motor. The assembled complex hydrolyses ATP
    several-fold faster than AFG2A alone, so loss of AFG2B compromises a
    multi-subunit machine rather than a single enzyme. That shared machine is the
    structural reason why AFG2A- and AFG2B-related diseases overlap clinically.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  molecular_functions:
  - preferred_term: ATP hydrolysis activity
    term:
      id: GO:0016887
      label: ATP hydrolysis activity
    modifier: DECREASED
  evidence:
  - reference: PMID:40268917
    reference_title: Cryo-EM structure of the AAA+ SPATA5 complex and its role in
      human cytoplasmic pre-60S maturation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Here we reveal that SPATA5 forms a 4:2:2:2 complex with SPATA5L1, C1orf109,
      and CINP.
    explanation: >-
      Cryo-EM defines the stoichiometry of the complex and places AFG2B
      (SPATA5L1) inside it as an obligate subunit.
  - reference: PMID:38554706
    reference_title: The SPATA5-SPATA5L1 ATPase complex directs replisome proteostasis
      to ensure genome integrity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: An integrative structural biology approach revealed a molecular architecture
      of SPATA5-SPATA5L1 N-terminal domains interacting with C1orf109-CINP to form
      a funnel-like structure above a cylindrically shaped ATPase motor.
    explanation: >-
      Independent structural work describing the same architecture and naming the
      complex 55LCC.
  downstream:
  - target: Impaired Cytoplasmic Pre-60S Ribosomal Maturation
  - target: Replisome Proteostasis Failure and Replication Stress
- name: Impaired Cytoplasmic Pre-60S Ribosomal Maturation
  description: >-
    The 55LCC complex, of which AFG2B is a subunit, executes a late cytoplasmic
    maturation step of the pre-60S large ribosomal subunit. AFG2A is the human
    homolog of yeast Drg1, which releases the assembly factor Rlp24 from newly
    exported pre-60S particles; in humans the reaction requires the whole
    four-protein complex, and recognition of the pre-60S particle is mediated by
    the human-specific subunit CINP. Loss of AFG2B is therefore expected to stall
    the final step of large-subunit biogenesis.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: ribosomal large subunit biogenesis
    term:
      id: GO:0042273
      label: ribosomal large subunit biogenesis
    modifier: DECREASED
  - preferred_term: ribosome biogenesis
    term:
      id: GO:0042254
      label: ribosome biogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:35354024
    reference_title: Labeling of heterochronic ribosomes reveals C1ORF109 and SPATA5
      control a late step in human ribosome assembly.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We provide evidence that these factors, together with CINP and SPATA5L1,
      control a late step of human pre-60S maturation in the cytoplasm.
    explanation: >-
      Names SPATA5L1 (AFG2B) explicitly as one of the four factors controlling
      the late cytoplasmic pre-60S maturation step.
  - reference: PMID:40268917
    reference_title: Cryo-EM structure of the AAA+ SPATA5 complex and its role in
      human cytoplasmic pre-60S maturation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We also obtained a cryo-EM structure of pre-60S-bound SPATA5 complex.
    explanation: >-
      Direct structural demonstration that the AFG2A-AFG2B-containing complex
      engages the pre-60S particle.
  downstream:
  - target: Reduced Global Protein Synthesis
- name: Reduced Global Protein Synthesis
  description: >-
    Failure of the late pre-60S maturation step reduces the supply of mature 60S
    subunits and lowers global translational capacity. This has been measured
    directly for the other 55LCC subunits (C1ORF109 and AFG2A/SPATA5), where loss
    impairs global protein synthesis; the equivalent measurement has not been
    made after loss of AFG2B itself, so the node is provisional for this disorder
    even though the complex-level logic is strong.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: cytoplasmic translation
    term:
      id: GO:0002181
      label: cytoplasmic translation
    modifier: DECREASED
  evidence:
  - reference: PMID:35354024
    reference_title: Labeling of heterochronic ribosomes reveals C1ORF109 and SPATA5
      control a late step in human ribosome assembly.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Loss of either C1orf109 or SPATA5 impairs global protein synthesis.
    explanation: >-
      Demonstrates the translational consequence for two of the four 55LCC
      subunits. PARTIAL because the experiment was not performed for AFG2B
      (SPATA5L1) itself; the extrapolation rests on shared complex membership.
  notes: >-
    Deliberately marked PROVISIONAL and PARTIAL. This is the single point in the
    chain where the evidence is about the paralogue AFG2A rather than about
    AFG2B, and the named-entity-confusion risk for this disorder makes it worth
    flagging explicitly rather than letting the complex-level argument stand
    unqualified. Note also that PMID:38554706 found the replication and
    genome-instability phenotype separable from the reported ribosomal function,
    so the two arms of 55LCC dysfunction are modelled here as parallel branches
    rather than as one linear chain.
  downstream:
  - target: Neuroepithelial Vulnerability During Differentiation
- name: Neuroepithelial Vulnerability During Differentiation
  description: >-
    Ribosome levels fall physiologically as neuroepithelial cells differentiate
    during early human brain development, which makes precisely this window
    hypersensitive to any further reduction in ribosome biogenesis. Reduced
    ribosome availability preferentially impairs translation of specific
    transcripts and disrupts both survival and cell-fate commitment of
    transitioning neuroepithelia. This is the leading explanation for why a
    housekeeping defect in a ubiquitously required complex produces a
    predominantly neurodevelopmental disease.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: neuroepithelial progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: cerebral cortex development
    term:
      id: GO:0021987
      label: cerebral cortex development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:40760247
    reference_title: A programmed decline in ribosome levels governs human early neurodevelopment.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We find that ribosome levels decrease during neuroepithelial differentiation,
      making differentiating cells particularly vulnerable to perturbations in ribosome
      biogenesis during this time.
    explanation: >-
      Explains the tissue specificity of 55LCC-complex disease. PARTIAL because
      the human cerebral organoid work was done for the AIRIM/C1orf109 subunit,
      not for AFG2B; the argument generalises across the complex but has not been
      tested for this gene.
  notes: >-
    The `cell_types` binding uses CL:0011020 (neural progenitor cell), the
    closest existing CL class to the differentiating neuroepithelial progenitor
    population studied in the cerebral organoids; `preferred_term` records the
    intended, more specific meaning. CL:0000098 (sensory epithelial cell) was
    used in an earlier revision and was wrong - that class is the ear/eye/nose
    sensory-receptor lineage, not a neural progenitor - and is no longer used
    anywhere in this entry. The mTOR-rescue result
    in PMID:40760247 is NOT curated as a treatment here; see the entry notes and
    the `afg2b_mtor_rescue_untested` discussion.
  downstream:
  - target: Impaired Neuronal and White Matter Development
- name: Replisome Proteostasis Failure and Replication Stress
  description: >-
    The second established function of the 55LCC complex is to direct turnover of
    replisome components, a proteostasis job distinct from the
    ubiquitin-dependent VCP/p97 unfolding of the CMG helicase that terminates DNA
    replication. The complex acts as an unfoldase on chromatin-bound replisome
    proteins, and its deficiency produces ubiquitin-independent proteotoxicity,
    replication stress, and severe chromosome instability. Consistent with this,
    transcriptomic profiling of fibroblasts from affected individuals with
    biallelic AFG2B variants implicated DNA replication and mitosis alongside
    cell-surface adhesion and focal adhesion pathways.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: DNA replication
    term:
      id: GO:0006260
      label: DNA replication
    modifier: ABNORMAL
  - preferred_term: replication fork processing
    term:
      id: GO:0031297
      label: replication fork processing
    modifier: ABNORMAL
  evidence:
  - reference: PMID:38554706
    reference_title: The SPATA5-SPATA5L1 ATPase complex directs replisome proteostasis
      to ensure genome integrity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Here, we identify replisome factor interactions with a protein complex
      composed of AAA+ ATPases SPATA5-SPATA5L1 together with heterodimeric partners
      C1orf109-CINP (55LCC).
    explanation: >-
      Establishes that the AFG2B-containing complex physically engages replisome
      factors, the basis of the replisome-proteostasis role.
  - reference: PMID:38554706
    reference_title: The SPATA5-SPATA5L1 ATPase complex directs replisome proteostasis
      to ensure genome integrity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Deficiency in the 55LCC complex elicited ubiquitin-independent proteotoxicity,
      replication stress, and severe chromosome instability.
    explanation: >-
      Direct demonstration of the replication-stress consequence of losing the
      complex that contains AFG2B.
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Analysis of differentially expressed genes and networks suggested a role
      for SPATA5L1 in cell surface adhesion receptor function, intracellular focal
      adhesions, and DNA replication and mitosis.
    explanation: >-
      Patient-fibroblast transcriptomics independently points at DNA replication
      and mitosis, but this is a correlative expression signature rather than a
      functional replication assay, hence PARTIAL.
  notes: >-
    Marked PROVISIONAL because no causal link has been shown between replication
    stress and any specific clinical feature of this disorder. It is curated as a
    parallel arm of 55LCC dysfunction rather than as an established step on the
    path to the neurological phenotype. The downstream edge to neuronal and white
    matter development is the weakest edge in this pathograph and is the subject
    of the `afg2b_replication_stress_to_neural_gap` discussion.
  downstream:
  - target: Impaired Neuronal and White Matter Development
- name: Impaired Neuronal and White Matter Development
  description: >-
    AFG2B protein localises to neuronal and glial nuclei, with more prominent
    expression in neurons, so the brain is a directly affected tissue rather than
    a bystander. The structural consequence seen in affected individuals is a
    global reduction in cerebral volume with disproportionate white matter loss:
    quantitative volumetry showed significantly diminished white matter volumes,
    and imaging shows a thin corpus callosum, delayed myelination and
    periventricular leukomalacia.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: glial cell
    term:
      id: CL:0000125
      label: glial cell
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  - preferred_term: cerebral white matter
    term:
      id: UBERON:0002316
      label: white matter
  biological_processes:
  - preferred_term: myelination
    term:
      id: GO:0042552
      label: myelination
    modifier: DECREASED
  - preferred_term: nervous system development
    term:
      id: GO:0007399
      label: nervous system development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Immunofluorescent imaging in rat hippocampal neurons revealed localization
      of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in
      neurons.
    explanation: >-
      Establishes that the protein is present, and predominantly nuclear, in the
      cell types whose development is disrupted. Classified IN_VITRO because the
      paper's full text specifies that this imaging was performed on rat
      dissociated hippocampal cultures rather than in an intact animal.
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain imaging revealed diminished cerebral volume, thin corpus callosum,
      and periventricular leukomalacia, and quantitative volumetry demonstrated significantly
      diminished white matter volumes in several individuals.
    explanation: >-
      Quantifies the structural brain phenotype in affected individuals,
      including the disproportionate white matter involvement.
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain MRI showed cortical and white matter atrophy, delayed myelination,
      and a thin corpus callosum.
    explanation: >-
      Independent single-case confirmation of the same imaging triad, adding
      delayed myelination.
  downstream:
  - target: Spastic-Dystonic Motor Impairment and Neurodevelopmental Disability
  - target: Reduced Brain Growth
  - target: Cerebral atrophy and diminished cerebral volume
    description: >-
      The diminished cerebral volume and cortical/white matter atrophy seen on
      imaging are the direct structural readout of this node; the node's own
      imaging evidence (PMID:34626583, PMID:41375745) carries the edge.
  - target: Reduced cerebral white matter volume
    description: >-
      Quantitative volumetry showing significantly diminished white matter
      volumes is the disproportionate white-matter arm of this node.
  - target: Thin corpus callosum
    description: >-
      Thin corpus callosum is a recurrent imaging correlate of the white-matter
      involvement described by this node.
  - target: Periventricular leukomalacia
    description: >-
      Periventricular leukomalacia is part of the white-matter-predominant
      imaging signature reported for this node in the founding cohort.
  - target: Delayed myelination
    description: >-
      Delayed myelination on serial MRI is the developmental white-matter
      correlate of this node; the node's GO annotation (myelination, DECREASED)
      states the same claim.
- name: Cochlear Sensory Epithelium Involvement
  description: >-
    AFG2B is expressed in the neurosensory hair cells and supporting cells of the
    rodent inner ear - the founding report localised the protein to the hair
    cells and pillar cells of the rat organ of Corti and detected transcript in
    both inner and outer hair cells - and biallelic human variants produce
    sensorineural hearing loss, with bilateral involvement documented in
    individual reports. This makes the cochlear sensory epithelium a directly affected
    tissue and places the disorder at the generic trigger node of the conserved
    sensorineural hair-cell-loss module, a hereditary lesion whose vulnerable
    target is the mechanosensitive cochlear hair cell. What happens next in the
    AFG2B cochlea is unknown; no hair-cell counts, endocochlear potential
    measurements, cochlear histology or spiral ganglion studies have been
    published for this gene, so conformance is asserted at this node only.
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  conforms_to: sensorineural_hair_cell_loss#Cochlear Sensory Epithelium Insult
  cell_types:
  - preferred_term: cochlear hair cell
    term:
      id: CL:0000202
      label: auditory hair cell
  locations:
  - preferred_term: cochlea
    term:
      id: UBERON:0001844
      label: cochlea
  - preferred_term: spiral organ of cochlea
    term:
      id: UBERON:0002227
      label: spiral organ of cochlea
  biological_processes:
  - preferred_term: sensory perception of sound
    term:
      id: GO:0007605
      label: sensory perception of sound
    modifier: ABNORMAL
  evidence:
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair
      cells and inner ear supporting cells.
    explanation: >-
      Places the gene product in the cochlear sensory epithelium, the cell
      population the module identifies as the vulnerable target of its trigger
      node. Classified MODEL_ORGANISM because this is rodent inner-ear tissue
      (rat organ of Corti whole mounts and adult mouse expression data), not a
      cell culture.
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural
      hearing loss in 47 individuals from 28 (26 unrelated) families.
    explanation: >-
      Establishes that biallelic loss of the gene expressed in the cochlear
      sensory epithelium causes sensorineural hearing loss in humans.
  notes: >-
    Conformance is deliberately limited to the module's trigger node. See entry
    note (6) and the `afg2b_cochlear_mechanism_gap` discussion for why the
    downstream module nodes (ionic homeostasis and oxidative stress, hair cell
    mechanotransduction failure and death, spiral ganglion degeneration,
    progressive hearing loss) are NOT claimed.


    This node hangs directly off the root loss-of-function node rather than off
    55LCC ATPase Complex Dysfunction, and that placement is deliberate. The
    tissue-level cochlear claim rests on AFG2B expression in the cochlear sensory
    epithelium plus the human genotype-phenotype relationship. No 55LCC
    complex-level experiment has ever been performed in cochlear tissue, so
    routing the edge through the complex node would assert a mechanism that has
    not been shown in the ear.
  downstream:
  - target: Bilateral Sensorineural Hearing Loss
- name: Bilateral Sensorineural Hearing Loss
  description: >-
    Sensorineural hearing loss is a core clinical endpoint, with bilateral
    involvement documented in individual reports. It is typically detected in infancy, ranges from mild to
    profound, and can occur as the sole manifestation of a biallelic AFG2B
    genotype in individuals with no neurodevelopmental involvement.
  role: consequence
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Collectively, our results indicate that bi-allelic SPATA5L1 variants
      lead to a human disease characterized by sensorineural hearing loss (SNHL)
      with or without a nonprogressive mixed neurodevelopmental phenotype.
    explanation: >-
      Establishes sensorineural hearing loss with or without neurodevelopmental
      features; this abstract does not establish cohort-wide bilaterality.
  downstream:
  - target: Bilateral sensorineural hearing loss
    description: >-
      Manifestation edge from the organism-level disease process to the
      clinically ascertained phenotype record. Bilaterality is documented in
      the case report cited on the phenotype, not quantified by the founding
      cohort abstract.
- name: Reduced Brain Growth
  description: >-
    Impaired neuronal and white matter development translates into reduced brain
    growth and microcephaly, which is one of the four neurodevelopmental features
    that together affected just over half of the founding cohort.
  role: consequence
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, 25/47 affected individuals (53%) presented with microcephaly,
      developmental delay/intellectual disability, cerebral palsy, and/or epilepsy.
    explanation: Microcephaly is one of the four composite neurodevelopmental features.
  downstream:
  - target: Microcephaly
    description: >-
      Reduced brain growth is observed clinically as microcephaly, which in the
      individually documented cases was postnatal in onset (normal head
      circumference at birth, below the 3rd percentile by age 2).
- name: Spastic-Dystonic Motor Impairment and Neurodevelopmental Disability
  description: >-
    The neurological endpoint combines global developmental delay and impaired
    intellectual development with a spastic-dystonic cerebral palsy phenotype and
    focal or generalised epilepsy. Spasticity and/or dystonia are the predominant
    motor features in the published cohort, although infants may show generalised
    hypotonia before any hypertonia emerges.
  role: consequence
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, 25/47 affected individuals (53%) presented with microcephaly,
      developmental delay/intellectual disability, cerebral palsy, and/or epilepsy.
    explanation: Gives the composite neurodevelopmental burden across the founding cohort.
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In contrast to the published cohort, in which most individuals with bi-allelic
      SPATA5L1 variants exhibited spasticity and/or dystonia as predominant motor features
    explanation: >-
      Confirms that spasticity and/or dystonia dominate the motor phenotype of the
      published cohort.
  downstream:
  - target: Global developmental delay
    description: >-
      Global developmental delay is one of the constituent clinical features
      this composite endpoint decomposes into; the node's 25/47 composite
      evidence carries the edge.
  - target: Impaired intellectual development
    description: >-
      Impaired intellectual development is a constituent of the composite
      neurodevelopmental disability described by this node.
  - target: Spastic-dystonic cerebral palsy
    description: >-
      The spastic-dystonic cerebral palsy phenotype is the characteristic motor
      expression of this endpoint.
  - target: Spasticity
    description: >-
      Spasticity is one of the two predominant motor signs bundled in the
      spastic-dystonic pattern of this node.
  - target: Dystonia
    description: >-
      Dystonia is the other predominant motor sign of the spastic-dystonic
      pattern of this node.
  - target: Hypotonia
    description: >-
      Infants with this disorder may show generalised central hypotonia before
      any hypertonia emerges, as part of the same evolving central motor
      disorder; the progression section documents the anticipated evolution
      toward a spastic-dystonic pattern.
  - target: Epilepsy
    description: >-
      Focal or generalised epilepsy is a constituent of the composite
      neurodevelopmental burden described by this node.
  - target: Absent or severely limited speech
    description: >-
      Severely limited language acquisition accompanies the intellectual
      disability of this endpoint; concurrent sensorineural hearing loss is an
      acknowledged additional contributor (see the phenotype's notes), but no
      source apportions the two, so only this edge is asserted.
phenotypes:
- category: Auditory
  name: Bilateral sensorineural hearing loss
  description: >-
    Bilateral sensorineural hearing loss is documented in individual cases.
    The founding cohort reported sensorineural hearing loss in 47 individuals
    without specifying laterality in its cached abstract. Onset is typically in infancy
    and severity ranges from mild to profound; one reported infant had 60 dBnHL
    bilateral loss identified in the seventh month of life and was fitted with
    hearing aids. Hearing loss can be the sole manifestation of a biallelic AFG2B
    genotype.
  phenotype_term:
    preferred_term: Bilateral sensorineural hearing impairment
    term:
      id: HP:0008619
      label: Bilateral sensorineural hearing impairment
  notes: >-
    No frequency band is asserted for bilateral hearing loss: the 47/47 figure
    in PMID:34626583 describes sensorineural hearing loss without laterality and
    combines syndromic and isolated hearing-loss presentations. PMID:41375745
    directly establishes bilateral 60 dBnHL loss in one infant. Individual-case
    observations justify HP:0008619 but not a cohort-wide bilateral frequency.
  evidence:
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural
      hearing loss in 47 individuals from 28 (26 unrelated) families.
    directness: INDIRECT
    explanation: >-
      Establishes the broader sensorineural hearing-loss association, not
      bilaterality or its frequency. The next case report supports laterality.
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In the 7th month of life audiological evaluation revealed bilateral sensorineural
      hearing loss of 60 dBnHL, and hearing aids were fitted.
    explanation: >-
      Documents infantile onset and moderate-to-severe degree in an individually
      described patient.
- category: Neurologic
  name: Global developmental delay
  description: >-
    Global developmental delay is apparent in the first year of life, with
    delayed motor milestones and absent or minimal language acquisition. One
    24-month-old had an 11-month motor delay on structured assessment.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  notes: >-
    No standalone denominator exists. Developmental delay is one of four features
    in the 25/47 (53%) composite reported by PMID:34626583, so a per-feature
    frequency band is deliberately omitted.
  evidence:
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, 25/47 affected individuals (53%) presented with microcephaly,
      developmental delay/intellectual disability, cerebral palsy, and/or epilepsy.
    explanation: Developmental delay is one of the four composite features.
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Vojta neurodevelopmental assessment demonstrated an 11-month motor delay,
      abnormal responses in all seven Vojta postural reactions, and persistent primitive
      reflexes.
    explanation: Quantifies the developmental delay in an individually described patient.
- category: Neurologic
  name: Impaired intellectual development
  description: >-
    Impaired intellectual development, frequently without meaningful language
    acquisition, accompanies the developmental delay in affected individuals with
    the neurodevelopmental form of the disorder.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  notes: >-
    Part of the 25/47 (53%) composite in PMID:34626583; no standalone denominator
    published, so no frequency band is asserted.
  evidence:
  - reference: PMID:37902276
    reference_title: A further case of AFG2B-related neurodevelopmental disorder with
      hearing loss and microcephaly allows further clarification of pathogenicity
      of the variant c.1313T>C, p.(Leu438Pro).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report on a 6 1/2-year-old girl with a history of global developmental
      delay, subsequent intellectual disability without relevant language acquisition,
      sensorineural hearing loss, muscular hypotonia and microcephaly.
    explanation: >-
      Documents intellectual disability without relevant language acquisition in a
      genetically confirmed AFG2B patient.
- category: Neurologic
  name: Absent or severely limited speech
  description: >-
    Language acquisition is severely limited; one
    reported child had intellectual disability without relevant language
    acquisition at 6 1/2 years, having acquired no language before age 5 and
    only 5 to 10 single words by 5 3/12 years, with adequate listening
    comprehension.
  phenotype_term:
    preferred_term: Severely limited speech and language acquisition
    term:
      id: HP:0000750
      label: Delayed speech and language development
  notes: >-
    Single-case evidence only, and confounded by the near-universal hearing loss;
    no frequency band is asserted. Rebound from HP:0001344 (Absent speech) to
    HP:0000750 during phenotype review: the full text of the sole cited source
    (PMID:37902276) records that the girl used 5 to 10 single words at 5 3/12
    years with adequate listening comprehension, which contradicts the complete
    lack of speech that HP:0001344 asserts. HP:0000750 is the most specific term
    the published evidence actually supports.
  evidence:
  - reference: PMID:37902276
    reference_title: A further case of AFG2B-related neurodevelopmental disorder with
      hearing loss and microcephaly allows further clarification of pathogenicity
      of the variant c.1313T>C, p.(Leu438Pro).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report on a 6 1/2-year-old girl with a history of global developmental
      delay, subsequent intellectual disability without relevant language acquisition,
      sensorineural hearing loss, muscular hypotonia and microcephaly.
    explanation: >-
      Absence of relevant language acquisition at 6 1/2 years supports severely
      limited speech and language development. Note that concurrent
      sensorineural hearing loss is an obvious confounder for speech development
      in this disorder.
  - reference: PMID:37902276
    reference_title: A further case of AFG2B-related neurodevelopmental disorder with
      hearing loss and microcephaly allows further clarification of pathogenicity
      of the variant c.1313T>C, p.(Leu438Pro).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Language acquisition was not achieved before the age of 5 years.
    explanation: >-
      Full-text detail quantifying the language delay; the same passage records
      5 to 10 single words at 5 3/12 years, which is why the binding is delayed
      speech and language development rather than absent speech.
- category: Neurologic
  name: Spastic-dystonic cerebral palsy
  description: >-
    A spastic-dystonic cerebral palsy phenotype is the characteristic motor
    presentation and is the feature that most distinguishes this disorder from
    the paralogous AFG2A-related encephalopathy. Spasticity and/or dystonia were
    the predominant motor features in most individuals of the published cohort.
  phenotype_term:
    preferred_term: Cerebral palsy
    term:
      id: HP:0100021
      label: Cerebral palsy
  notes: >-
    Part of the 25/47 (53%) composite in PMID:34626583; no standalone denominator
    published, so no frequency band is asserted.
  evidence:
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, 25/47 affected individuals (53%) presented with microcephaly,
      developmental delay/intellectual disability, cerebral palsy, and/or epilepsy.
    explanation: Cerebral palsy is one of the four composite features.
- category: Neurologic
  name: Spasticity
  description: >-
    Spasticity is one of the two predominant motor signs of the disorder and is
    named in the disease's OMIM and MONDO label. It may emerge only after an
    initial hypotonic phase in infancy.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  notes: >-
    The published cohort reports spasticity and dystonia together as "spasticity
    and/or dystonia", so neither can be given its own frequency band.
  evidence:
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In contrast to the published cohort, in which most individuals with bi-allelic
      SPATA5L1 variants exhibited spasticity and/or dystonia as predominant motor features
    explanation: >-
      States that spasticity and/or dystonia predominate in most individuals of the
      published cohort.
  - reference: PMID:37902276
    reference_title: A further case of AFG2B-related neurodevelopmental disorder with
      hearing loss and microcephaly allows further clarification of pathogenicity
      of the variant c.1313T>C, p.(Leu438Pro).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Bi-allelic variants in AFG2B (previously known as SPATA5L1) have recently
      been associated with a neurodevelopmental disorder with hearing loss and spasticity,
      as well as isolated hearing loss.
    explanation: Spasticity is part of the named core phenotype of the disorder.
- category: Neurologic
  name: Dystonia
  description: >-
    Dystonia occurs together with, or instead of, spasticity as part of the
    spastic-dystonic motor phenotype.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  notes: >-
    Reported only in the composite phrase "spasticity and/or dystonia", so no
    separate frequency band is asserted.
  evidence:
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In contrast to the published cohort, in which most individuals with bi-allelic
      SPATA5L1 variants exhibited spasticity and/or dystonia as predominant motor features
    explanation: >-
      Dystonia is one of the two predominant motor features of the published
      cohort.
- category: Neurologic
  name: Hypotonia
  description: >-
    Muscular hypotonia, often central and generalised, is common in infancy and
    may be the presenting motor sign; it can precede, or in some children replace,
    the spastic-dystonic pattern. One 24-month-old had marked hypotonia with only
    early upper-limb stiffening and no clinical hypertonia.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:37902276
    reference_title: A further case of AFG2B-related neurodevelopmental disorder with
      hearing loss and microcephaly allows further clarification of pathogenicity
      of the variant c.1313T>C, p.(Leu438Pro).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report on a 6 1/2-year-old girl with a history of global developmental
      delay, subsequent intellectual disability without relevant language acquisition,
      sensorineural hearing loss, muscular hypotonia and microcephaly.
    explanation: Muscular hypotonia in a genetically confirmed AFG2B patient.
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: our patient at 14 months of age demonstrated generalized hypotonia with
      markedly delayed psychomotor development, without clinical signs of hypertonia
      to date
    explanation: >-
      Documents an infant presenting with generalised hypotonia rather than
      hypertonia, the presentation flagged in the curation request.
- category: Neurologic
  name: Epilepsy
  description: >-
    Focal or generalised seizures occur as part of the neurodevelopmental
    phenotype. Epilepsy is not obligate: one reported child with two pathogenic
    alleles had EEG abnormalities emerge during follow-up without any clinically
    confirmed seizure.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  notes: >-
    Part of the 25/47 (53%) composite in PMID:34626583; no standalone denominator
    published, so no frequency band is asserted.
  evidence:
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, 25/47 affected individuals (53%) presented with microcephaly,
      developmental delay/intellectual disability, cerebral palsy, and/or epilepsy.
    explanation: Epilepsy is one of the four composite features.
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Although the later EEG demonstrated epileptiform abnormalities, no clinically
      confirmed epileptic seizures have been documented to date.
    directness: INDIRECT
    explanation: >-
      Supports the description's qualifier that epilepsy is not obligate, by
      documenting a genotype-positive child with epileptiform EEG abnormalities
      but no confirmed clinical seizure. INDIRECT for the phenotype's core
      claim, since the quote records the absence rather than the presence of
      overt epilepsy; the cohort-level presence claim rests on PMID:34626583.
- category: Neurologic
  name: EEG abnormality
  description: >-
    Interictal EEG abnormalities can emerge during follow-up and can precede, or
    occur without, clinically confirmed seizures. In the one serially monitored
    child an EEG at 9 months showed no epileptiform activity, while an EEG at
    just over 2 years showed bilateral sharp waves and theta activity during
    wakefulness and sleep. EEG abnormality is therefore curated separately from
    Epilepsy rather than folded into it.
  phenotype_term:
    preferred_term: EEG abnormality
    term:
      id: HP:0002353
      label: EEG abnormality
  notes: >-
    Bound to HP:0002353 (EEG abnormality). The PR review suggested HP:0010848,
    but that term is "EEG with spike-wave complexes (2.5-3.5 Hz)", which the
    reported tracing (bilateral sharp waves, incomplete complexes and theta
    activity) does not describe, so it would have been a false match. Single-case
    evidence, so no frequency band is asserted.
  evidence:
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The EEG performed at approximately 2 years and 2 weeks of age showed abnormalities
      during wakefulness and sleep, including bilateral sharp waves, incomplete FO–FW
      complexes, and theta activity.
    explanation: >-
      Documents the specific interictal EEG abnormalities recorded in a
      genetically confirmed AFG2B patient.
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Early EEG recordings were without significant changes, whereas abnormalities
      emerged later in the clinical course.
    explanation: >-
      Establishes that the EEG abnormality is acquired during follow-up rather
      than present from the first recording, which is why a single early normal
      EEG does not exclude the diagnosis.
- category: Neurologic
  name: Microcephaly
  description: >-
    Microcephaly accompanies the neurodevelopmental form of the disorder and may
    be acquired rather than congenital: one child had a normal head circumference
    of 35 cm at birth and had fallen below the 3rd percentile (44.5 cm) by age 2.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  notes: >-
    Part of the 25/47 (53%) composite in PMID:34626583; no standalone denominator
    published, so no frequency band is asserted. The postnatal-onset pattern in
    PMID:41375745 contrasts with the congenital microcephaly typical of the
    paralogous AFG2A-related disorder, but rests on a single case.
  evidence:
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, 25/47 affected individuals (53%) presented with microcephaly,
      developmental delay/intellectual disability, cerebral palsy, and/or epilepsy.
    explanation: Microcephaly is one of the four composite features.
  - reference: PMID:37902276
    reference_title: A further case of AFG2B-related neurodevelopmental disorder with
      hearing loss and microcephaly allows further clarification of pathogenicity
      of the variant c.1313T>C, p.(Leu438Pro).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report on a 6 1/2-year-old girl with a history of global developmental
      delay, subsequent intellectual disability without relevant language acquisition,
      sensorineural hearing loss, muscular hypotonia and microcephaly.
    explanation: Microcephaly in a genetically confirmed AFG2B patient.
- category: Neuroimaging
  name: Cerebral atrophy and diminished cerebral volume
  description: >-
    Brain imaging shows diminished cerebral volume, with cortical and white
    matter atrophy on MRI.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain imaging revealed diminished cerebral volume, thin corpus callosum,
      and periventricular leukomalacia, and quantitative volumetry demonstrated significantly
      diminished white matter volumes in several individuals.
    explanation: Documents diminished cerebral volume in the founding cohort.
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain MRI showed cortical and white matter atrophy, delayed myelination,
      and a thin corpus callosum.
    explanation: Independent confirmation of cortical and white matter atrophy.
- category: Neuroimaging
  name: Reduced cerebral white matter volume
  description: >-
    Quantitative volumetry demonstrated significantly diminished white matter
    volumes, indicating that white matter is disproportionately affected relative
    to overall brain volume.
  phenotype_term:
    preferred_term: Reduced cerebral white matter volume
    term:
      id: HP:0034295
      label: Reduced cerebral white matter volume
  evidence:
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: quantitative volumetry demonstrated significantly diminished white matter
      volumes in several individuals
    explanation: Direct quantitative evidence of reduced white matter volume.
- category: Neuroimaging
  name: Thin corpus callosum
  description: A thin or hypoplastic corpus callosum is a recurrent imaging finding.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain imaging revealed diminished cerebral volume, thin corpus callosum,
      and periventricular leukomalacia, and quantitative volumetry demonstrated significantly
      diminished white matter volumes in several individuals.
    explanation: Thin corpus callosum in the founding cohort.
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain MRI showed cortical and white matter atrophy, delayed myelination,
      and a thin corpus callosum.
    explanation: Independent confirmation of a thin corpus callosum.
- category: Neuroimaging
  name: Periventricular leukomalacia
  description: >-
    Periventricular leukomalacia was reported on brain imaging in the founding
    cohort, part of the white-matter-predominant imaging signature.
  phenotype_term:
    preferred_term: Periventricular leukomalacia
    term:
      id: HP:0006970
      label: Periventricular leukomalacia
  evidence:
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain imaging revealed diminished cerebral volume, thin corpus callosum,
      and periventricular leukomalacia, and quantitative volumetry demonstrated significantly
      diminished white matter volumes in several individuals.
    explanation: Periventricular leukomalacia in the founding cohort.
- category: Neuroimaging
  name: Delayed myelination
  description: >-
    Delayed myelination, seen as T2 hyperintensity of the posterior white matter
    in infancy, has been documented on serial MRI.
  phenotype_term:
    preferred_term: Delayed myelination
    term:
      id: HP:0012448
      label: Delayed myelination
  notes: Single-case evidence; no frequency band asserted.
  evidence:
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At 20 months, the brain MRI revealed mild generalized atrophy of the cortex
      and the white matter, bilateral T2 hyperintensities of the posterior portions
      of the white matter indicating its delayed myelination and slightly hypoplastic
      corpus callosum
    explanation: Documents delayed myelination on MRI at 20 months.
- category: Craniofacial
  name: Craniofacial dysmorphism
  description: >-
    Dysmorphic facial features, described in roughly a third of affected
    individuals in the literature, include bitemporal narrowing, a wide mouth and
    epicanthal folds.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  notes: >-
    "Approximately one-third" would map to FREQUENT, but the statement carries no
    numerator or denominator of its own and cites the literature indirectly, so
    no band is asserted. The umbrella is retained for the reported variable
    facial gestalt; the three specifically documented features are separate
    records below. PMID:37902276 describes a child without distinctive dysmorphic
    features, while noting a thick lower vermilion. That observation documents
    variability rather than excluding facial abnormalities from this disease.
  evidence:
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Craniofacial dysmorphic features were noted, including bitemporal narrowing,
      wide mouth, and epicanthal folds, partially overlapping with those reported in
      approximately one-third of affected individuals in the literature.
    explanation: >-
      Describes the dysmorphic features and their approximate literature
      frequency.
- category: Craniofacial
  name: Bitemporal narrowing
  description: Bitemporal narrowing was documented on examination at nine months.
  phenotype_term:
    preferred_term: Bitemporal narrowing
    term:
      id: HP:0000341
      label: Narrow forehead
  notes: >-
    Single-case observation in PMID:41375745; no frequency band is asserted.
    The report also identified an uncertain de novo FRYL variant that might be
    a sequencing artefact; a modifying contribution to dysmorphism was not
    excluded. The mechanism of this facial feature in AFG2B disease is unknown.
  evidence:
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At 9 months, physical examination revealed a eutrophic infant (10 kg, OFC
      43 cm) with craniofacial dysmorphism, including bitemporal narrowing, wide mouth,
      and epicanthal folds.
    explanation: >-
      Documents bitemporal narrowing in the child with compound heterozygous
      SPATA5L1 variants. This establishes occurrence in one reported case, not
      a frequency or an AFG2B-specific developmental mechanism.
- category: Craniofacial
  name: Wide mouth
  description: A wide mouth was documented on examination at nine months.
  phenotype_term:
    preferred_term: Wide mouth
    term:
      id: HP:0000154
      label: Wide mouth
  notes: >-
    Single-case observation in PMID:41375745; no frequency band is asserted.
    The report also identified an uncertain de novo FRYL variant that might be
    a sequencing artefact; a modifying contribution to dysmorphism was not
    excluded. The mechanism of this facial feature in AFG2B disease is unknown.
  evidence:
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At 9 months, physical examination revealed a eutrophic infant (10 kg, OFC
      43 cm) with craniofacial dysmorphism, including bitemporal narrowing, wide mouth,
      and epicanthal folds.
    explanation: >-
      Documents wide mouth in the child with compound heterozygous
      SPATA5L1 variants. This establishes occurrence in one reported case, not
      a frequency or an AFG2B-specific developmental mechanism.
- category: Craniofacial
  name: Epicanthal folds
  description: Epicanthal folds were documented on examination at nine months.
  phenotype_term:
    preferred_term: Epicanthal folds
    term:
      id: HP:0000286
      label: Epicanthus
  notes: >-
    Single-case observation in PMID:41375745; no frequency band is asserted.
    The report also identified an uncertain de novo FRYL variant that might be
    a sequencing artefact; a modifying contribution to dysmorphism was not
    excluded. The mechanism of this facial feature in AFG2B disease is unknown.
  evidence:
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At 9 months, physical examination revealed a eutrophic infant (10 kg, OFC
      43 cm) with craniofacial dysmorphism, including bitemporal narrowing, wide mouth,
      and epicanthal folds.
    explanation: >-
      Documents epicanthal folds in the child with compound heterozygous
      SPATA5L1 variants. This establishes occurrence in one reported case, not
      a frequency or an AFG2B-specific developmental mechanism.
- category: Ophthalmologic
  name: Strabismus
  description: >-
    Intermittent divergent strabismus with refractive error has been documented,
    although ophthalmological findings have not been systematically reported in
    the larger cohort.
  phenotype_term:
    preferred_term: intermittent divergent strabismus
    term:
      id: HP:0000577
      label: Exotropia
  notes: >-
    Single-case evidence. The same report notes that ophthalmological findings
    are not systematically described in prior cohorts, so no band is asserted.
    Rebound from HP:0000486 (Strabismus) to HP:0000577 during phenotype review:
    the full text specifies intermittent divergent strabismus of the right eye,
    and divergent strabismus is exotropia. HPO has no more specific
    intermittent-exotropia term.
  evidence:
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She presented with global psychomotor delay, bilateral sensorineural hearing
      loss, strabismus, and craniofacial dysmorphism.
    explanation: Strabismus in a genetically confirmed AFG2B patient.
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ophthalmologic and optometric assessment demonstrated intermittent divergent
      strabismus of the right eye
    explanation: >-
      Specifies the divergent (exotropic) and intermittent character of the
      strabismus, supporting the more specific HP:0000577 binding.
genetic:
- name: AFG2B
  gene_term:
    preferred_term: AFG2B
    term:
      id: hgnc:28762
      label: SPATA5L1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: Biallelic pathogenic or likely pathogenic variants
  notes: >-
    AFG2B is the current HGNC-approved symbol (HGNC:28762, OMIM:619578) for the
    gene published throughout the clinical literature as SPATA5L1. It encodes an
    AAA+ ATPase paralogous to AFG2A (SPATA5). The `term.label` reads SPATA5L1
    because that is the label the cached HGNC adapter resolves; see entry note
    (1). Most reported alleles are private missense changes; nonsense alleles are
    also described. One recurrent allele, c.2066G>T (p.Gly689Val), was seen in
    four individuals of the founding cohort and again in a later unrelated case.
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:37902276
      reference_title: A further case of AFG2B-related neurodevelopmental disorder
        with hearing loss and microcephaly allows further clarification of pathogenicity
        of the variant c.1313T>C, p.(Leu438Pro).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Bi-allelic variants in AFG2B (previously known as SPATA5L1) have recently
        been associated with a neurodevelopmental disorder with hearing loss and spasticity,
        as well as isolated hearing loss.
      explanation: Confirms the biallelic requirement for the gene-disease association.
  evidence:
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural
      hearing loss in 47 individuals from 28 (26 unrelated) families.
    explanation: The founding gene-disease association across 26 unrelated families.
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene
      encoding a protein of unknown function.
    explanation: >-
      Records that the gene was functionally uncharacterised at the time the
      disease association was established; its 55LCC role was defined later.
      Classified OTHER rather than HUMAN_CLINICAL because this is a statement
      about the gene's annotation status, not a clinical observation.
  variants:
  - name: c.2066G>T (p.Gly689Val)
    description: >-
      A recurrent missense allele in the ATPase motor, reported in four
      individuals within the founding cohort of 25 patients and subsequently in
      an unrelated compound heterozygous case. It is predicted to disrupt ATP
      binding and hydrolysis and is reported as pathogenic in ClinVar.
    type: missense variant
    clinical_significance: LIKELY_PATHOGENIC
    gene:
      preferred_term: AFG2B
      term:
        id: hgnc:28762
        label: SPATA5L1
    evidence:
    - reference: PMID:41375745
      reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing
        Loss, and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding
        Phenotype.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: However, an identical variant, c.2066G>T, has been reported in four
        individuals within a cohort of 25 patients described by Richard et al.
      explanation: Establishes recurrence of the allele across unrelated individuals.
    - reference: PMID:41375745
      reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing
        Loss, and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding
        Phenotype.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: Missense variants such as p.Gly689Val are predicted to disrupt ATP binding
        and hydrolysis, thereby impairing the catalytic function of the ATPase motor
      explanation: Predicted functional effect on the ATPase motor.
  - name: c.1918C>T (p.Arg640Ter)
    description: >-
      A rare nonsense allele introducing a premature stop codon, reported in
      trans with c.2066G>T. It meets PVS1 as a null allele in a gene where loss
      of function is an established mechanism, but was classified as of uncertain
      significance under ACMG rules in the report that described it.
    type: nonsense variant
    clinical_significance: UNCERTAIN_SIGNIFICANCE
    gene:
      preferred_term: AFG2B
      term:
        id: hgnc:28762
        label: SPATA5L1
    evidence:
    - reference: PMID:41375745
      reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing
        Loss, and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding
        Phenotype.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In the ACMG classification it is assessed as having uncertain significance.
      explanation: >-
        Source of the recorded clinical significance. The same report argues the
        allele fulfils PVS1, so the uncertain classification is likely to be
        upgraded as more cases accrue.
  - name: c.1313T>C (p.Leu438Pro)
    description: >-
      A missense allele whose contribution was initially unclear because it was
      first observed as part of a complex disease allele alongside a second
      homozygous missense change. Observation in trans with an independent
      missense allele in a further patient supported its pathogenic relevance.
    type: missense variant
    clinical_significance: LIKELY_PATHOGENIC
    gene:
      preferred_term: AFG2B
      term:
        id: hgnc:28762
        label: SPATA5L1
    evidence:
    - reference: PMID:37902276
      reference_title: A further case of AFG2B-related neurodevelopmental disorder
        with hearing loss and microcephaly allows further clarification of pathogenicity
        of the variant c.1313T>C, p.(Leu438Pro).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Our results support the pathogenic relevance of the c.1313T>C, p.(Leu438Pro)
        allele while providing detailed insights into the disease manifestation of
        a further patient.
      explanation: >-
        Resolves the previously ambiguous contribution of this allele to disease.
  - name: c.527G>T (p.Gly176Val)
    description: >-
      A likely pathogenic missense allele identified by trio exome sequencing in
      trans with c.1313T>C in a girl with developmental delay, intellectual
      disability, sensorineural hearing loss, hypotonia and microcephaly.
    type: missense variant
    clinical_significance: LIKELY_PATHOGENIC
    gene:
      preferred_term: AFG2B
      term:
        id: hgnc:28762
        label: SPATA5L1
    evidence:
    - reference: PMID:37902276
      reference_title: A further case of AFG2B-related neurodevelopmental disorder
        with hearing loss and microcephaly allows further clarification of pathogenicity
        of the variant c.1313T>C, p.(Leu438Pro).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Trio exome sequencing revealed likely pathogenic compound heterozygous
        missense variants in AFG2B
      explanation: Reports the allele and its compound heterozygous configuration.
diagnosis:
- name: Trio exome sequencing
  description: >-
    Diagnosis is molecular. The disorder has been identified exclusively by exome
    sequencing; trio testing establishes that the two variants are in trans and
    that each parent is a carrier. There is no biochemical marker and no
    disease-specific imaging finding, so a child with sensorineural hearing loss
    plus developmental delay, spasticity or dystonia should be offered sequencing
    rather than a metabolic workup, and AFG2B should be covered by
    neurodevelopmental and hearing-loss gene panels.
  notes: >-
    PMID:41375745 also reports an incidental de novo FRYL variant in the same
    proband that the authors could not exclude as a sequencing artefact. It is
    recorded here only as a reminder that incidental findings complicate
    interpretation in this ultra-rare disorder; it is not curated as a modifier.
  evidence:
  - reference: PMID:37902276
    reference_title: A further case of AFG2B-related neurodevelopmental disorder with
      hearing loss and microcephaly allows further clarification of pathogenicity
      of the variant c.1313T>C, p.(Leu438Pro).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We performed trio exome sequencing on the patient and her parents.
    explanation: Trio exome sequencing is the diagnostic method used.
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Genetic testing confirmed the variants in trans.
    explanation: >-
      Confirming the trans configuration is the decisive step for a recessive
      diagnosis.
- name: Audiological assessment
  description: >-
    Formal audiology or auditory brainstem response testing establishes the
    bilateral sensorineural hearing loss that defines the disorder, and should be
    performed in infancy in any child with unexplained global developmental delay
    and abnormal tone.
  evidence:
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In the 7th month of life audiological evaluation revealed bilateral sensorineural
      hearing loss of 60 dBnHL, and hearing aids were fitted.
    explanation: >-
      Audiological evaluation is what established the defining feature in the
      reported infant.
treatments:
- name: Hearing amplification
  description: >-
    Hearing aids are fitted once bilateral sensorineural hearing loss is
    identified, typically in infancy. This is supportive management of the
    disorder's defining feature, not disease-modifying therapy.
  treatment_term:
    preferred_term: hearing aid fitting
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: DEVICE
  target_mechanisms:
  - target: Bilateral Sensorineural Hearing Loss
    description: >-
      Hearing aids provide symptomatic auditory amplification for the hearing-loss
      endpoint. This link does not claim repair of AFG2B function or cochlear
      pathology; a reported child showed an acoustical response after fitting.
    evidence:
    - reference: PMID:37902276
      reference_title: A further case of AFG2B-related neurodevelopmental disorder with
        hearing loss and microcephaly allows further clarification of pathogenicity
        of the variant c.1313T>C, p.(Leu438Pro).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The provision of hearing aids was started at the age of 9 months,
        leading to an acoustical response in the sense of normal hearing.
      explanation: >-
        A single-case functional response supports symptomatic targeting of hearing
        loss. It does not demonstrate restoration of the underlying pathology.
  notes: >-
    Cochlear implantation is the obvious escalation when amplification is
    insufficient, and the body of PMID:34626583 remarks that there appeared to be
    some benefit among the individuals who received it. That sentence is NOT
    quotable as evidence here: the cached copy of PMID:34626583 is abstract-only
    and the string "implant" does not occur in it, so the observation is recorded
    in this note rather than as an evidence item, and no cochlear-implantation
    treatment is curated. It is also uncontrolled and unquantified.


    The natural action term here would be MAXO:0009030 (hearing aid usage), but
    the `TreatmentActionTerm` dynamic-enum expansion cached in this repository
    (`cache/enums/treatmentactionterm_*.csv`) contains no MAXO terms at all - it
    resolves to NCIT only, and no MAXO term is used anywhere else in `kb/`. The
    closest in-enum NCIT action term is therefore used, with the specific
    intervention carried by `preferred_term` and `therapeutic_modality: DEVICE`.
    NCIT:C183182 (Hearing Aid) is also outside the cached enum expansion.
  evidence:
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In the 7th month of life audiological evaluation revealed bilateral sensorineural
      hearing loss of 60 dBnHL, and hearing aids were fitted.
    explanation: >-
      Documents amplification in a single affected child, without reporting an
      audiological outcome in this case. PMID:37902276 separately reports an
      acoustical response to hearing aids, as cited on the treatment link.
- name: Early developmental rehabilitation
  description: >-
    Early, structured physiotherapy and neurodevelopmental rehabilitation
    (including reflex locomotion / Vojta therapy in the reported case) is the
    mainstay of motor management. No outcome data exist for this disorder.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Early rehabilitation including reflex locomotion therapy was initiated.
    explanation: >-
      Single-case description of the rehabilitation approach used. PARTIAL
      because the same report notes the lack of clinical progress despite
      therapy, so efficacy is not demonstrated.
- name: Genetic counselling
  description: >-
    Autosomal recessive inheritance gives a 25% recurrence risk for each
    subsequent pregnancy of carrier parents. Confirming that the two variants are
    in trans, and carrier testing of both parents, is required before
    counselling.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in the proband we observe a configuration of a compound heterozygote, and
      in the parents the carrier state
    explanation: >-
      Documents the parental carrier state and compound heterozygous
      configuration that recurrence-risk counselling depends on.
differential_diagnoses:
- name: AFG2A-Related Encephalopathy
  description: >-
    The disorder caused by biallelic variants in the paralogous gene AFG2A
    (formerly SPATA5), whose protein is the obligate partner of AFG2B inside the
    same 55LCC complex. The clinical pictures overlap substantially, with
    intellectual disability, developmental delay, epilepsy, hearing loss and
    movement disorder in both, which is exactly why the pair is a named-entity
    confusion hazard. That disorder is curated in this repository as
    `AFG2A-Related_Encephalopathy`, and it in turn lists this disorder as one of
    its differentials.
  disease_term:
    preferred_term: AFG2A-related encephalopathy
    term:
      id: MONDO:0014698
      label: microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal
        muscle tone syndrome
  distinguishing_features:
  - AFG2A-related encephalopathy typically has earlier seizure onset, more pronounced
    (congenital) microcephaly and more frequent movement disorders, and frequently
    presents as a developmental and epileptic encephalopathy.
  - AFG2B-related disease is dominated by sensorineural hearing loss, which is near-universal
    and can be the sole manifestation, with a more consistently spastic-dystonic motor
    pattern and a neurodevelopmental burden that affects only about half of individuals.
  - Only sequencing distinguishes the two reliably; the genes differ by one letter
    in both their current (AFG2A/AFG2B) and their legacy (SPATA5/SPATA5L1) symbols.
  evidence:
  - reference: PMID:41375745
    reference_title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss,
      and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: SPATA5-related disorder (NEDCAS) presents with earlier seizure onset,
      more pronounced microcephaly, and frequent movement disorders
    explanation: >-
      Directly contrasts the two paralogous disorders on the features that
      distinguish them.
  - reference: PMID:41933351
    reference_title: AFG2A-related encephalopathy, expanding the neurodevelopmental
      and epileptic spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AFG2A-RE is an ultra-rare, recessive disorder, sometimes presenting\
      \ as a developmental and epileptic encephalopathy (DEE), characterised by the\
      \ triad of epilepsy, congenital microcephaly, and deafness, and typically associated\
      \ with intellectual disability, spasticity, and movement disorders."
    explanation: >-
      Describes the AFG2A phenotype from the largest AFG2A cohort. This is the
      only citation in this entry drawn from an AFG2A series, and it is confined
      to this differential.
- name: Autosomal recessive nonsyndromic sensorineural hearing loss
  description: >-
    Because biallelic AFG2B variants can cause isolated hearing loss with no
    neurodevelopmental features, the disorder enters the differential for
    apparently nonsyndromic recessive sensorineural hearing loss, and AFG2B
    should be covered by hearing-loss gene panels.
  distinguishing_features:
  - Nothing distinguishes the isolated-hearing-loss presentation clinically; only
    sequencing does.
  - Conversely, the presence of microcephaly, spasticity, dystonia or epilepsy alongside
    hearing loss argues against a nonsyndromic aetiology.
  notes: >-
    Deliberately left UNBOUND to a MONDO term. MONDO models autosomal recessive
    nonsyndromic hearing loss only as numbered locus-specific entities (DFNB1A,
    DFNB2, DFNB3 and so on), and selecting any one of them would assert a locus
    that no AFG2B report implicates. This mirrors the same decision recorded in
    the sibling AFG2A entry.
  evidence:
  - reference: PMID:37902276
    reference_title: A further case of AFG2B-related neurodevelopmental disorder with
      hearing loss and microcephaly allows further clarification of pathogenicity
      of the variant c.1313T>C, p.(Leu438Pro).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Bi-allelic variants in AFG2B (previously known as SPATA5L1) have recently
      been associated with a neurodevelopmental disorder with hearing loss and spasticity,
      as well as isolated hearing loss.
    explanation: >-
      States explicitly that biallelic AFG2B variants can produce isolated
      hearing loss.
- name: Acquired (non-genetic) cerebral palsy
  description: >-
    The spastic-dystonic motor phenotype with periventricular leukomalacia on
    imaging closely mimics cerebral palsy of perinatal hypoxic-ischaemic origin,
    and affected children may carry that label for years before sequencing.
  distinguishing_features:
  - Absence of a perinatal insult, plus consanguinity or affected siblings, should
    prompt genomic testing rather than an acquired-aetiology label.
  - Accompanying bilateral sensorineural hearing loss is the single most useful pointer
    away from acquired cerebral palsy.
  - Periventricular leukomalacia in this disorder is not explained by prematurity
    or perinatal asphyxia.
  evidence:
  - reference: PMID:34626583
    reference_title: Bi-allelic variants in SPATA5L1 lead to intellectual disability,
      spastic-dystonic cerebral palsy, epilepsy, and hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain imaging revealed diminished cerebral volume, thin corpus callosum,
      and periventricular leukomalacia, and quantitative volumetry demonstrated significantly
      diminished white matter volumes in several individuals.
    explanation: >-
      Periventricular leukomalacia is the imaging finding that most strongly
      suggests an acquired perinatal aetiology and is therefore the source of the
      diagnostic confusion.
discussions:
- discussion_id: afg2b_cochlear_mechanism_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What actually happens in the AFG2B-deficient cochlea downstream of the
    expression of AFG2B in hair cells and supporting cells?
  attaches_to:
  - pathophysiology#Cochlear Sensory Epithelium Involvement
  rationale: >-
    Sensorineural hearing loss is the defining feature of this disorder, yet the
    only cochlear data in existence are rodent expression studies showing
    Spata5l1 in neurosensory hair cells, supporting cells and the pillar cells of
    the organ of Corti. Nobody has published hair cell counts, cochlear
    histology, endocochlear potential measurements, distortion-product otoacoustic
    emissions or spiral ganglion studies in an AFG2B-deficient animal or human
    temporal bone. Consequently the entry conforms to the
    `sensorineural_hair_cell_loss` module at its trigger node only and cannot
    claim the module's hair-cell-death, ionic-homeostasis or spiral-ganglion
    nodes. Whether hair cells die (as in most hereditary sensorineural loss) or
    merely function abnormally, and whether the loss is cochlear or
    retrocochlear, is completely open. The only indirect human hint is the
    founding report's observation, in the body of PMID:34626583 rather than in
    its abstract, of apparent benefit from cochlear implantation in the
    individuals who received it, which is weakly consistent with a preserved
    auditory nerve but is uncontrolled and unquantified.
  proposed_experiments:
  - experiment_id: afg2b_cochlear_knockout_phenotyping
    name: Afg2b knockout cochlear phenotyping
    description: >-
      Generate a cochlea-conditional or constitutive Afg2b knockout mouse and
      perform ABR and DPOAE phenotyping alongside serial cochlear histology with
      inner and outer hair cell counts, to establish whether hair cells are lost
      or merely dysfunctional.
  - experiment_id: afg2b_endocochlear_potential
    name: Endocochlear potential measurement
    description: >-
      Measure the endocochlear potential in the same model to test whether the
      module's cochlear ionic homeostasis arm is engaged, which would distinguish
      a strial mechanism from a primary hair-cell mechanism.
  - experiment_id: afg2b_spiral_ganglion_density
    name: Spiral ganglion neuron density quantification
    description: >-
      Quantify spiral ganglion neuron density to test the module's retrocochlear
      node and to predict whether cochlear implantation would be expected to work
      in affected individuals.
  - experiment_id: afg2b_cochlear_implant_outcomes
    name: Cochlear implant outcome collation
    description: >-
      Collate audiological and cochlear implant outcomes across the reported
      human cohort, which would provide indirect human evidence about spiral
      ganglion integrity without requiring temporal bone histology.
- discussion_id: afg2b_no_animal_model
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does loss of Afg2b in an animal model recapitulate the human
    hearing-loss-plus-spasticity phenotype?
  attaches_to:
  - pathophysiology#Biallelic AFG2B Loss of Function
  rationale: >-
    No animal model of AFG2B deficiency has been published, which is why this
    entry carries no `animal_models` block. The only in vivo AFG2B data located
    are rodent expression studies (PMID:34626583); a PubMed search for SPATA5L1
    combined with zebrafish returned no records, and the Falcon deep-research run
    likewise found no stable Afg2b-knockout mouse, rat, zebrafish, Drosophila,
    iPSC neuron, cochlear organoid or cerebral organoid model. Every functional
    claim in this entry therefore rests either on human observational data, on
    patient fibroblast transcriptomics, or on cell-based work performed on other
    subunits of the 55LCC complex. Without a model the causal direction from
    ribosome biogenesis failure or replication stress to the neurological and
    auditory phenotype remains inferred rather than demonstrated.
  proposed_experiments:
  - experiment_id: afg2b_mouse_null_phenotyping
    name: Afg2b null mouse neurodevelopmental phenotyping
    description: >-
      Characterise any existing IMPC allele, or generate an Afg2b null mouse, and
      phenotype brain volume, myelination, motor tone and hearing to test whether
      the human phenotype is reproduced.
  - experiment_id: afg2b_zebrafish_hair_cell
    name: Zebrafish afg2b hair cell development assay
    description: >-
      Use a zebrafish afg2b knockdown or knockout to test hair cell development
      in the lateral line and inner ear, the standard rapid assay applied to
      other deafness genes.
  - experiment_id: afg2b_ipsc_organoid_translation
    name: Patient iPSC organoid translation assay
    description: >-
      Differentiate patient-derived iPSC into cortical and inner-ear organoids
      and assay 60S subunit levels and global translation, to test the proximal
      ribosome-biogenesis defect in human AFG2B-mutant cells.
- discussion_id: afg2b_replication_stress_to_neural_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Which arm of 55LCC dysfunction - impaired pre-60S ribosome maturation or
    replisome proteostasis failure - actually produces the neural and cochlear
    phenotype of AFG2B deficiency?
  attaches_to:
  - pathophysiology#Replisome Proteostasis Failure and Replication Stress
  - pathophysiology#Reduced Global Protein Synthesis
  rationale: >-
    The 55LCC complex has two experimentally established jobs, and PMID:38554706
    reports that the replication and genome-instability phenotype is separable
    from the previously described ribosomal function. Both are therefore modelled
    here as parallel branches from complex dysfunction, and both carry an edge
    into the neural node - but neither edge has been demonstrated in a neural or
    cochlear context for AFG2B. The replication-stress work was done in HeLa and
    engineered degron cell lines, and the ribosome work was done on other
    subunits. Because all four 55LCC components are pan-essential in cultured
    cells, yet the human disease is tissue-restricted and survivable, something
    about the developing brain and cochlea must determine selectivity, and which
    branch drives that selectivity is unknown. This is the weakest link in the
    pathograph and the reason both intermediate nodes are marked PROVISIONAL.
  proposed_experiments:
  - experiment_id: afg2b_branch_separation_neural
    name: Branch separation in a neural model
    description: >-
      Introduce separation-of-function AFG2B alleles that impair replisome
      substrate processing without disturbing pre-60S maturation (and the
      converse) into a human neural progenitor or organoid model, and determine
      which allele class reproduces the growth and differentiation defect.
  - experiment_id: afg2b_replication_stress_markers_patient
    name: Replication-stress markers in patient cells
    description: >-
      Measure phosphorylated RPA, DNA-fiber fork progression, cohesion defects
      and micronucleus frequency in fibroblasts and iPSC-derived neural cells
      from individuals with biallelic AFG2B variants, to test whether the
      cell-line replication-stress phenotype is present at physiological
      patient-allele dosage.
- discussion_id: afg2b_mtor_rescue_untested
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does the mTOR-activation rescue demonstrated for the AIRIM/C1orf109 subunit
    of the 55LCC complex generalise to AFG2B deficiency?
  attaches_to:
  - pathophysiology#Neuroepithelial Vulnerability During Differentiation
  rationale: >-
    Enhancing mTOR activity suppresses the growth and developmental defects
    caused by AIRIM/C1orf109 variants in human cerebral organoids
    (PMID:40760247). AIRIM/C1orf109 is a subunit of the same 55LCC complex as
    AFG2B, and the proposed mechanism, restoring translational output when
    ribosome availability falls during neuroepithelial differentiation, would
    apply equally to AFG2B loss on paper. But the experiment has never been done
    for AFG2B, the organoid system models early cortical development rather than
    the cochlea where this disorder's defining phenotype lies, and mTOR
    activation is not a benign intervention. The mismatch between an encouraging
    organoid result on one subunit and the complete absence of data on the
    subunit that causes this disease is exactly why the finding is curated as a
    pathophysiology observation and a discussion rather than as a treatment.
  proposed_experiments:
  - experiment_id: afg2b_organoid_mtor_rescue
    name: mTOR rescue in AFG2B-variant cerebral organoids
    description: >-
      Generate AFG2B-variant human cerebral organoids and test whether mTOR
      activation rescues growth and cell-fate commitment as it does for
      AIRIM/C1orf109 organoids.
  - experiment_id: afg2b_60s_translation_measurement
    name: 60S availability and translation in AFG2B-deficient neuroepithelia
    description: >-
      Measure 60S subunit availability and global translation in AFG2B-deficient
      neuroepithelia to confirm that the proximal defect assumed by the rescue
      rationale is actually present.
  - experiment_id: afg2b_inner_ear_organoid_rescue
    name: Inner-ear organoid rescue test
    description: >-
      Test whether any mTOR rescue extends to inner-ear organoids, since cortical
      rescue alone would not address the disorder's defining hearing loss.
  evidence:
  - reference: PMID:40760247
    reference_title: A programmed decline in ribosome levels governs human early neurodevelopment.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Enhancing mTOR activity suppresses the growth and developmental defects
      associated with AIRIM/C1orf109 variants.
    explanation: >-
      The rescue result that motivates the question, obtained for a different
      subunit of the same complex in human cerebral organoids.
- discussion_id: afg2b_natural_history_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the natural history of AFG2B-related disease beyond childhood, and
    does the hearing loss progress?
  attaches_to:
  - pathophysiology#Bilateral Sensorineural Hearing Loss
  rationale: >-
    The founding cohort described the neurodevelopmental phenotype as
    nonprogressive, but no longitudinal audiometric data have been published, so
    whether the hearing loss itself is stable or progressive is unknown. This
    matters directly for the module-conformance decision recorded in entry note
    (6), because the `sensorineural_hair_cell_loss` module terminates in a node
    named "Progressive Sensorineural Hearing Loss", which cannot be claimed here.
    No survival, life-expectancy, adult-outcome or quality-of-life data exist for
    this disorder either.
  proposed_experiments:
  - experiment_id: afg2b_serial_audiometry
    name: Serial audiometry across the reported cohort
    description: >-
      Perform serial audiometry across the reported cohort to establish whether
      hearing thresholds deteriorate with age, which would determine whether the
      module's progressive-hearing-loss endpoint can be claimed.
  - experiment_id: afg2b_natural_history_registry
    name: Prospective natural-history registry
    description: >-
      Establish a prospective natural-history registry capturing motor function,
      epilepsy course, communication outcome and survival into adulthood.
  - experiment_id: afg2b_longitudinal_mri
    name: Longitudinal brain MRI
    description: >-
      Acquire longitudinal MRI to determine whether the cerebral and white matter
      volume loss is static or progressive.
- discussion_id: afg2b_dysmorphism_strabismus_mechanism_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    By what mechanism do biallelic AFG2B variants produce craniofacial
    dysmorphism and exotropia?
  attaches_to:
  - phenotypes#Craniofacial dysmorphism
  - phenotypes#Strabismus
  - phenotypes#Bitemporal narrowing
  - phenotypes#Wide mouth
  - phenotypes#Epicanthal folds
  rationale: >-
    These facial and ocular phenotypes are left deliberately unconnected in
    the pathograph. Craniofacial dysmorphism (bitemporal narrowing, wide mouth,
    epicanthal folds, reported in roughly a third of individuals) has no
    described mechanism: no craniofacial expression, neural crest, or skeletal
    data exist for AFG2B, and ribosome-biogenesis disorders as a class produce
    craniofacial anomalies through several non-equivalent routes, so wiring the
    dysmorphism to any existing node would be guesswork. The single documented
    strabismus is intermittent divergent strabismus of the right eye with
    refractive error; strabismus is common in children with periventricular
    leukomalacia and cerebral visual involvement, and the same report notes
    sluggish pursuit and limited eye contact, but no source localises this
    patient's exotropia to a central versus refractive origin, so no edge from
    the white-matter node is asserted. Recording the gap keeps the connectivity
    honest rather than manufactured.
  proposed_experiments:
  - experiment_id: afg2b_craniofacial_phenotyping
    name: Systematic craniofacial phenotyping across the cohort
    description: >-
      Collect standardized dysmorphology assessments (ideally with facial
      photograph analysis) across reported individuals to establish whether a
      consistent gestalt exists and whether it tracks with the
      neurodevelopmental subgroup.
  - experiment_id: afg2b_ophthalmic_workup
    name: Structured ophthalmological and orthoptic assessment
    description: >-
      Perform structured ophthalmological, orthoptic and cerebral visual
      function assessment in affected individuals to distinguish refractive,
      strabismic and cerebral visual contributions, none of which have been
      systematically reported.
- discussion_id: afg2b_eeg_mechanism_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Which neural dysfunction produces EEG abnormalities in AFG2B disease,
    including in children without confirmed epilepsy?
  attaches_to:
  - phenotypes#EEG abnormality
  rationale: >-
    PMID:41375745 documents emerging epileptiform and slow-wave abnormalities
    without clinically confirmed seizures. The clinical report does not establish
    a causal link from its MRI abnormalities or motor disability to the EEG
    finding. Linking this phenotype through Epilepsy would also imply an
    unsupported dependence on clinical seizures, so it remains unconnected.
references:
- reference: PMID:34626583
  title: Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic
    cerebral palsy, epilepsy, and hearing loss.
- reference: PMID:37902276
  title: A further case of AFG2B-related neurodevelopmental disorder with hearing loss
    and microcephaly allows further clarification of pathogenicity of the variant
    c.1313T>C, p.(Leu438Pro).
- reference: PMID:41375745
  title: Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss, and Spasticity
    Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.
- reference: PMID:40268917
  title: Cryo-EM structure of the AAA+ SPATA5 complex and its role in human cytoplasmic
    pre-60S maturation.
- reference: PMID:38554706
  title: The SPATA5-SPATA5L1 ATPase complex directs replisome proteostasis to ensure
    genome integrity.
- reference: PMID:35354024
  title: Labeling of heterochronic ribosomes reveals C1ORF109 and SPATA5 control a
    late step in human ribosome assembly.
- reference: PMID:40760247
  title: A programmed decline in ribosome levels governs human early neurodevelopment.
- reference: PMID:41933351
  title: AFG2A-related encephalopathy, expanding the neurodevelopmental and epileptic
    spectrum.

📚

References & Deep Research

References

8

PMID:34626583

Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss.

No top-level findings curated for this source.

PMID:37902276

A further case of AFG2B-related neurodevelopmental disorder with hearing loss and microcephaly allows further clarification of pathogenicity of the variant c.1313T>C, p.(Leu438Pro).

No top-level findings curated for this source.

PMID:41375745

Neurodevelopmental Disorder with Psychomotor Delay, Hearing Loss, and Spasticity Caused by Compound Heterozygous SPATA5L1 Variants-Expanding Phenotype.

No top-level findings curated for this source.

PMID:40268917

Cryo-EM structure of the AAA+ SPATA5 complex and its role in human cytoplasmic pre-60S maturation.

No top-level findings curated for this source.

PMID:38554706

The SPATA5-SPATA5L1 ATPase complex directs replisome proteostasis to ensure genome integrity.

No top-level findings curated for this source.

PMID:35354024

Labeling of heterochronic ribosomes reveals C1ORF109 and SPATA5 control a late step in human ribosome assembly.

No top-level findings curated for this source.

PMID:40760247

A programmed decline in ribosome levels governs human early neurodevelopment.

No top-level findings curated for this source.

PMID:41933351

AFG2A-related encephalopathy, expanding the neurodevelopmental and epileptic spectrum.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

Scope, naming and provenance notes for this entry. (1) GENE SYMBOL HISTORY - READ THIS FIRST. The causative gene is AFG2B (HGNC:28762, OMIM:619578), renamed from SPATA5L1 (spermatogenesis associated 5 like 1). Every founding clinical report uses SPATA5L1: a PubMed search on 2026-08-15 returned 14 records for `SPATA5L1` but only 2 for `AFG2B`, and the largest cohort (PMID:34626583) never uses the new symbol. Searching either symbol alone therefore misses most of the disease literature; both were searched for this entry. The rename has not propagated through the ontology stack used here. MONDO's `RO:0004003` axiom on MONDO:0859206 already reads `HGNC:28762 ! AFG2B`, but the HGNC adapter shipped with `sqlite:obo:hgnc` still resolves `hgnc:28762` to the label `SPATA5L1` (verified with `runoak -i sqlite:obo:hgnc info hgnc:28762`; a search for `AFG2B` returns nothing). Every `gene_term` in this entry therefore carries `preferred_term: AFG2B` with `term.label: SPATA5L1`, because SPATA5L1 is the label the term validator resolves. This is a lag in the cached HGNC build, not a curation error, and it must NOT be "fixed" to `AFG2B` until the adapter is refreshed. The sibling entry AFG2A-Related_Encephalopathy documents the exactly analogous situation for hgnc:18119 / SPATA5. (2) NAMED-ENTITY CONFUSION WITH AFG2A / SPATA5 - THE PRIMARY RISK FOR THIS ENTRY. AFG2A (HGNC:18119, formerly SPATA5) is a DIFFERENT gene one suffix away from this one, and it causes a DIFFERENT, clinically overlapping disorder (MONDO:0014698, curated in this repository as AFG2A-Related_Encephalopathy; founding report PMID:26299366). This entry is about AFG2B only. The NEC preflight was run before any deep-research content was used: `runoak -i sqlite:obo:mondo info MONDO:0859206 -O obo` returns `relationship: RO:0004003 HGNC:28762 ! AFG2B` and `xref: OMIM:619616`, matching the intended target on both the gene and the OMIM anchor. Every clinical citation in this entry was then checked for which gene the reported individuals actually carry variants in: PMID:34626583, PMID:37902276 and PMID:41375745 are AFG2B/SPATA5L1 cohorts. PMID:41933351 is an AFG2A cohort review and is cited ONLY inside `differential_diagnoses`, never as support for a phenotype of this entry. The three structural and biochemical papers (PMID:38554706, PMID:40268917, PMID:35354024) study the 55LCC complex as a whole and are cited for complex composition and function, not for any gene-specific clinical claim; PMID:35354024 in particular measures the protein synthesis defect after loss of C1ORF109 or SPATA5 (AFG2A), NOT after loss of AFG2B, which is why the downstream translation node is marked PROVISIONAL. Two further AFG2B papers surfaced by the literature search, PMID:34864870 (full-house nephropathy with high SPATA5L1 expression) and PMID:41390732 (AFG2B variants in childhood lupus nephritis), describe renal and autoimmune phenotypes that are not part of NEDHLS and are deliberately NOT cited. (3) DISEASE NAME. The file is named for the OMIM and MONDO term, which is also the name used by the issue that requested this entry and by the only paper that uses the new gene symbol in its title (PMID:37902276, "A further case of AFG2B-related neurodevelopmental disorder with hearing loss and microcephaly"). No paper titles the disorder "AFG2B-related encephalopathy"; that phrase appears only inside the body of the AFG2A review (PMID:41933351) and was therefore not adopted as the entry name or as a synonym. (4) NO GENEREVIEWS CHAPTER EXISTS. PubMed searches run on 2026-08-15 with the queries `SPATA5L1 GeneReviews[All Fields]`, `AFG2B GeneReviews[All Fields]` and `neurodevelopmental disorder with hearing loss and spasticity GeneReviews[All Fields]` each returned zero records. The mandatory GeneReviews phenotype baseline therefore does not apply. The baseline used instead is the founding 47-individual cohort (PMID:34626583), which remains the largest published series, cross-checked against the two subsequent single-case reports (PMID:37902276, PMID:41375745). (5) FREQUENCY BANDS AND THE ASCERTAINMENT CAVEAT. No phenotype frequency band is asserted. PMID:34626583 reports sensorineural hearing loss in all 47 individuals, but its cached abstract does not establish bilaterality across that cohort. The bilateral phenotype is supported by individual reports; the broader 47/47 figure must not supply its frequency. The cohort also spans syndromic and isolated hearing loss. The composite neurodevelopmental burden (microcephaly, developmental delay/intellectual disability, cerebral palsy and/or epilepsy) was 25/47 (53%); this cannot be redistributed to individual features. Per-feature denominators are not available in the cached founding abstract. Craniofacial dysmorphism is likewise unbanded: PMID:41375745 describes it in "approximately one-third of affected individuals in the literature" but gives no numerator or denominator of its own. (6) WHY CONFORMANCE TO `sensorineural_hair_cell_loss` IS PARTIAL AND NOT ASSERTED DOWN THE WHOLE CHAIN. This was evaluated rather than assumed. The cochlear node of this entry declares `conforms_to: sensorineural_hair_cell_loss#Cochlear Sensory Epithelium Insult` and nothing further. That single conformance is supported: PMID:34626583 shows that in the rodent inner ear Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells (its full text localises the protein to hair cells and pillar cells of the organ of Corti in rat whole mounts), and biallelic human variants produce sensorineural hearing loss. That is exactly the module's generic trigger, a hereditary lesion of the cochlear sensory epithelium with the mechanosensitive hair cell as the vulnerable target. The module's three downstream nodes - cochlear ionic homeostasis disruption and oxidative stress, hair cell mechanotransduction failure and death, and spiral ganglion neuron degeneration - have NO AFG2B evidence whatsoever: no cochlear histology of an AFG2B-deficient animal, no endocochlear potential measurement, no hair cell counts and no auditory nerve study has been published for this gene. Conforming to them would assert mechanisms nobody has looked for. The module's terminal node is furthermore "Progressive Sensorineural Hearing Loss", and PMID:34626583 explicitly characterises the accompanying phenotype as NONPROGRESSIVE, so even the endpoint is not safe to claim. The gap is recorded as a KNOWLEDGE_GAP discussion (`afg2b_cochlear_mechanism_gap`) with the experiments that would resolve it. (7) STRUCTURED SOURCES CHECKED AND FOUND ABSENT, NOT SKIPPED BY DEFAULT. No Orphanet, ClinGen gene-disease validity (CGGV) or ClinGen dosage (CGDS) record is cited. This absence is specific rather than general: MONDO:0859206 carries `xref: Orphanet:659975` but `ls references_cache/ORPHA_659975.md` returns no such file, and `grep -l -i -e SPATA5L1 -e AFG2B -e HGNC:28762 references_cache/CGGV_*.md references_cache/CGDS_*.md` returns nothing across the CGGV and CGDS files present in the cache. Generating the missing records would require bumping a structured-source `data/*/MANIFEST.yaml` pin, which is out of scope for a curation PR (and those pins are tracked as stale in #7622), so the citation is skipped rather than fabricated. (8) DEEP RESEARCH PROVENANCE. One Falcon (Edison) run was performed and is committed at `research/Neurodevelopmental_Disorder_with_Hearing_Loss_and_Spasticity-deep-research-falcon.md`. It was treated as leads only. It independently resolved the disease to AFG2B (not AFG2A) and surfaced the same two primary clinical sources and the same mechanistic source used here, so it passed the NEC preflight. Its own reference validator flagged one unresolved citation (a malformed DOI link), and every PMID, snippet and ontology term used in this entry was independently fetched and verified against the local cache rather than taken from the report. (9) WHAT IS KNOWINGLY ABSENT. No treatment in this entry is disease-modifying; everything curated is supportive (amplification, rehabilitation, genetic counselling) and the disease-specific evidence base for each is a single case report at best. No animal model of AFG2B deficiency has been published, so there is no `animal_models` block; the only in vivo AFG2B data located are rodent expression studies (PMID:34626583), not a knockout, and the point is recorded as a discussion. No genotype-phenotype correlation is asserted anywhere in this entry; PMID:41375745 states explicitly that the published cohort is too small to support one. No prevalence rate is given because none has been estimated; the entry records only a CASES_IN_LITERATURE count. No environmental factor is curated, because the deep-research run found no toxin, infection, or exposure implicated in this monogenic disorder. The mTOR rescue axis reported for the paralogous 55LCC subunit AIRIM/C1orf109 (PMID:40760247) is curated as a pathophysiology observation and a discussion, NOT as a treatment, because it has never been tested in an AFG2B model. (10) WHY DFNB119 IS A SUBTYPE HERE AND NOT A SEPARATE ENTRY. OMIM gives the isolated-hearing-loss presentation of biallelic AFG2B variants its own phenotype number, DFNB119 (OMIM:619615, MONDO:0030480), alongside the syndromic NEDHLS number this entry is named for (OMIM:619616). Claim issue #11973 asked whether dismech should carry it separately. It should not, and the reasons are in the `has_subtypes` block's evidence rather than in a judgement of what feels like one disease. Both numbers were assigned from one cohort in one report (PMID:34626583), which itself describes a single disease "with or without" the neurodevelopmental extension. At least one allele, c.527G>T p.(Gly176Val), is reported on both sides of the split, so no genotype separates them (PMID:37902276). And DFNB119 has no literature of its own: a PubMed search for the term on 2026-09-16 returns nothing about this gene, so a separate entry would have had to be assembled from this entry's sources and would have duplicated this entry's pathograph with no node of its own. The remaining asymmetry is honest and worth stating: this entry's name is the syndromic OMIM label, so a reader arriving from the isolated presentation finds it under a name that overstates their phenotype. The alternative - renaming the entry to something gene-shaped such as "AFG2B-related disorder" - was considered and not done in this PR, because it would break the entry's MONDO anchor (MONDO:0859206 is the NEDHLS term) and is a change that should be argued on its own rather than as a side effect of binding a subtype.

Create: Neurodevelopmental Disorder with Hearing Loss and Spasticity (AFG2B) · 2026-08-17T09:34:53Z · View source

De novo curation of neurodevelopmental disorder with hearing loss and spasticity (NEDHLS; MONDO:0859206, OMIM:619616), caused by biallelic AFG2B variants. NEC discipline. AFG2B (HGNC:28762) was formerly SPATA5L1 and is one suffix away from AFG2A (formerly SPATA5), which already has its own entry in this repository (AFG2A-Related_Encephalopathy, MONDO:0014698). The NEC preflight `runoak -i sqlite:obo:mondo info MONDO:0859206 -O obo` was run before any deep-research content was used and returned `RO:0004003 HGNC:28762 ! AFG2B` plus `xref: OMIM:619616`, matching the intended target on both gene and OMIM anchors. Literature was searched under BOTH symbols, since 14 PubMed records use SPATA5L1 and only 2 use AFG2B. Every clinical citation was checked for which gene the reported cohort actually carries variants in; the single AFG2A cohort citation (PMID:41933351) is confined to differential_diagnoses and supports no phenotype of this entry. Two AFG2B papers describing renal/autoimmune phenotypes (PMID:34864870, PMID:41390732) were deliberately excluded as out of scope. Sources. Clinical: PMID:34626583 (founding 47-individual cohort), PMID:37902276, PMID:41375745. Mechanism: PMID:38554706, PMID:40268917, PMID:35354024, PMID:40760247. One Falcon/Edison deep-research run was performed and is committed under research/; it was treated as leads only, independently resolved the disease to AFG2B, and every PMID, snippet and ontology term was verified locally rather than taken from the report. Pathograph. Biallelic AFG2B loss of function -> 55LCC AAA+ ATPase complex dysfunction -> two parallel arms, namely impaired cytoplasmic pre-60S ribosomal maturation -> reduced global protein synthesis -> neuroepithelial vulnerability during differentiation, and replisome proteostasis failure with replication stress -> both converging on impaired neuronal and white matter development -> reduced brain growth and spastic-dystonic motor impairment; plus a cochlear sensory epithelium arm -> bilateral sensorineural hearing loss. Every node carries biological_scale and mechanism_confidence, and the chain terminates in organism-scale nodes that mirror the curated phenotype layer. Module conformance was evaluated, not assumed. Only the trigger node of sensorineural_hair_cell_loss is claimed, because rodent expression data place AFG2B in cochlear hair and pillar cells but no cochlear histology, hair-cell count, endocochlear potential or spiral ganglion study exists for this gene, and the module endpoint is progressive hearing loss whereas PMID:34626583 calls the phenotype nonprogressive. The gap is recorded as a KNOWLEDGE_GAP discussion. Frequency discipline. Only one band is asserted: sensorineural hearing loss VERY_FREQUENT from 47/47, with the ascertainment-bias caveat recorded on the phenotype. The 25/47 (53%) figure is a four-feature composite and was deliberately NOT redistributed onto microcephaly, developmental delay, intellectual disability, cerebral palsy, spasticity, dystonia or epilepsy. Ontology notes. Gene terms carry preferred_term AFG2B with term.label SPATA5L1 because the cached HGNC adapter still resolves hgnc:28762 to the legacy symbol; this mirrors the documented lag in the sibling AFG2A entry and must not be "fixed" until the adapter is refreshed. MAXO treatment terms were replaced with in-enum NCIT terms because the cached TreatmentActionTerm enum expansion contains no MAXO terms and no MAXO term is used anywhere else in kb/. GeneReviews searched on 2026-08-15 with three queries (`SPATA5L1 GeneReviews[All Fields]`, `AFG2B GeneReviews[All Fields]`, `neurodevelopmental disorder with hearing loss and spasticity GeneReviews[All Fields]`), all returning zero records; the negative result is recorded in the entry notes. No animal model of AFG2B deficiency exists, so no animal_models block is present and the absence is recorded as a discussion. Validation: just validate (schema + terms + references; 75/75 snippets verified against the local cache), just validate-references, just validate-terms, plus the check_title_snippets and check_environmental_evidence CI gates.

Falcon ▸

Neurodevelopmental Disorder with Hearing Loss and Spasticity: Research Report

Edison Scientific Literature 15 citations 2026-08-15T08:46:43.251798

Neurodevelopmental Disorder with Hearing Loss and Spasticity: Research Report

Executive summary

Neurodevelopmental disorder with hearing loss and spasticity (NEDHLS) is an ultra-rare, autosomal-recessive Mendelian disorder caused by biallelic germline variants in AFG2B, historically named SPATA5L1. Its defining phenotype comprises infantile-onset global developmental impairment, usually bilateral sensorineural hearing loss, and evolving motor dysfunction—most characteristically spasticity and/or dystonia. Epilepsy, microcephaly, cerebral or white-matter volume loss, delayed myelination, corpus-callosum hypoplasia, and dysmorphism are variable. The foundational report described 25 affected individuals; fewer than 30 had been reported before a detailed 2025 case, so robust prevalence, survival, penetrance, and genotype–phenotype estimates remain unavailable. (OpenTargets Search: Neurodevelopmental disorder with hearing loss and spasticity, polczyk2025neurodevelopmentaldisorderwith pages 1-2, polczyk2025neurodevelopmentaldisorderwith pages 6-7)

The major recent advance is mechanistic. A 2024 Cell study established that AFG2B/SPATA5L1 participates with SPATA5, C1ORF109, and CINP in the 55LCC AAA+ ATPase complex, which maintains replisome proteostasis and genome integrity. Deficiency causes replication-fork stress first, followed by cohesion defects and micronucleation. This is strong biochemical and cellular evidence, but it does not yet prove exactly how particular neural and cochlear cell populations produce every clinical manifestation. (krishnamoorthy2024thespata5spata5l1atpase pages 1-3, krishnamoorthy2024thespata5spata5l1atpase pages 8-10, krishnamoorthy2024thespata5spata5l1atpase pages 10-12)

The following table provides a knowledge-base-oriented overview.

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 (OpenTargets Search: Neurodevelopmental disorder with hearing loss and spasticity)
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 (polczyk2025neurodevelopmentaldisorderwith pages 4-6)
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 (polczyk2025neurodevelopmentaldisorderwith pages 1-2, polczyk2025neurodevelopmentaldisorderwith pages 7-9)
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 (OpenTargets Search: Neurodevelopmental disorder with hearing loss and spasticity, polczyk2025neurodevelopmentaldisorderwith pages 4-6)
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 (polczyk2025neurodevelopmentaldisorderwith pages 4-6)
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 (polczyk2025neurodevelopmentaldisorderwith pages 9-10, polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 2-4)
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 (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 2-4)
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 (polczyk2025neurodevelopmentaldisorderwith pages 9-10, polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 6-7)
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 (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 6-7)
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 (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 2-4)
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 (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 6-7)
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 (krishnamoorthy2024thespata5spata5l1atpase pages 1-3, krishnamoorthy2024thespata5spata5l1atpase pages 5-7, krishnamoorthy2024thespata5spata5l1atpase pages 10-12)
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 (krishnamoorthy2024thespata5spata5l1atpase pages 3-5, krishnamoorthy2024thespata5spata5l1atpase pages 8-10, krishnamoorthy2024thespata5spata5l1atpase pages 5-7, krishnamoorthy2024thespata5spata5l1atpase pages 10-12)
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 (krishnamoorthy2024thespata5spata5l1atpase pages 8-10, krishnamoorthy2024thespata5spata5l1atpase pages 10-12)
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 (krishnamoorthy2024thespata5spata5l1atpase pages 3-5, krishnamoorthy2024thespata5spata5l1atpase pages 10-12)
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 (polczyk2025neurodevelopmentaldisorderwith pages 1-2, polczyk2025neurodevelopmentaldisorderwith pages 7-9)
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 (polczyk2025neurodevelopmentaldisorderwith pages 4-6, polczyk2025neurodevelopmentaldisorderwith pages 6-7, polczyk2025neurodevelopmentaldisorderwith pages 2-4)
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 (polczyk2025neurodevelopmentaldisorderwith pages 4-6, polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 2-4, OpenTargets Search: Neurodevelopmental disorder with hearing loss and spasticity)
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 (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 6-7)
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 (polczyk2025neurodevelopmentaldisorderwith pages 1-2, polczyk2025neurodevelopmentaldisorderwith pages 6-7)
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 (polczyk2025neurodevelopmentaldisorderwith pages 6-7, polczyk2025neurodevelopmentaldisorderwith pages 2-4)
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 (OpenTargets Search: Neurodevelopmental disorder with hearing loss and spasticity, polczyk2025neurodevelopmentaldisorderwith pages 7-9)
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 (OpenTargets Search: Neurodevelopmental disorder with hearing loss and spasticity)

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.

1. Disease information

Definition and identifiers

Preferred name: Neurodevelopmental disorder with hearing loss and spasticity.
Abbreviation: NEDHLS.
MONDO: MONDO:0859206.
OMIM phenotype: 619616.
Causal gene: AFG2B (current approved symbol in Open Targets; historical literature symbol SPATA5L1), Ensembl ENSG00000171763.
Common names: AFG2B-related disorder; SPATA5L1-related neurodevelopmental disorder; SPATA5L1-related neurodevelopmental disorder with hearing loss and spasticity.
Foundational publication: Richard et al., “Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss,” American Journal of Human Genetics 108:2006–2016, published October 2021; PMID 34626583; DOI 10.1016/j.ajhg.2021.08.003.
Recent mechanism paper: Krishnamoorthy et al., Cell 187:2250–2268.e31, published April 2024; PMID 38554706; DOI 10.1016/j.cell.2024.03.002. (OpenTargets Search: Neurodevelopmental disorder with hearing loss and spasticity, krishnamoorthy2024thespata5spata5l1atpase pages 1-3, polczyk2025neurodevelopmentaldisorderwith pages 4-6)

No disease-specific MeSH descriptor or unique ICD-10/ICD-11 code was established in the retrieved evidence. In clinical coding, manifestations such as developmental disability, sensorineural hearing loss, epilepsy, dystonia, or spastic cerebral palsy would therefore generally require separate codes; this is not equivalent to a dedicated NEDHLS code.

The evidence is primarily aggregated disease-level evidence assembled from individually phenotyped patients, family segregation data, and experimental studies. It is not derived from a population-scale EHR cohort. (polczyk2025neurodevelopmentaldisorderwith pages 1-2, polczyk2025neurodevelopmentaldisorderwith pages 9-10)

2. Etiology, risk, and protective factors

NEDHLS is caused by biallelic AFG2B/SPATA5L1 variants, usually homozygous or compound heterozygous, inherited in an autosomal-recessive pattern. The available data support loss of function or severe functional impairment—through truncation, impaired protein stability, defective complex assembly, or impaired ATPase/replisome-processing function—as the causal model. Patient-associated SPATA5L1 variants tested in the 2024 study compromised viability or 55LCC function; some behaved as partial-loss-of-function or hypomorphic alleles. (krishnamoorthy2024thespata5spata5l1atpase pages 7-8, krishnamoorthy2024thespata5spata5l1atpase pages 12-14)

A recent example is compound heterozygosity for c.1918C>T (p.Arg640Ter) and c.2066G>T (p.Gly689Val), inherited in trans from unaffected carrier parents. The reporting laboratory called p.Arg640Ter a VUS and p.Gly689Val likely pathogenic, while also noting ClinVar pathogenic classification for p.Gly689Val. The authors applied PVS1/PM2/PM3/PP4 reasoning to the truncating allele. These classifications should be re-evaluated against the current ClinVar record and ACMG/AMP specifications before clinical use. (polczyk2025neurodevelopmentaldisorderwith pages 4-6)

The p.Gly689Val allele is recurrent: it occurred in four people in the original 25-person cohort. Most other reported variants appear private, and the cohort is too small for reliable allele-specific prognosis. (polczyk2025neurodevelopmentaldisorderwith pages 6-7)

No validated susceptibility loci, modifier genes, protective alleles, environmental causes, lifestyle risks, infectious triggers, or gene–environment interactions are known. Consanguinity can increase the probability that partners carry the same rare allele but is not required; the 2025 case involved non-consanguineous parents. A de novo FRYL variant in that case was considered uncertain and potentially artifactual, not an established modifier. (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 2-4)

3. Phenotypes

The phenotype is congenital or infantile in biological origin, although clinical recognition usually occurs when developmental milestones or hearing are assessed. Exact cohort-wide percentages could not be verified from the accessible primary full text; qualitative frequencies below should not be converted into penetrance estimates.

Global developmental/psychomotor delay and intellectual disability: core, often severe and persistent. Suggested HPO: HP:0001263, HP:0001249. In the 2025 patient, parental concern began at four months; at 14 months, motor organization approximated a 12-week developmental level. (polczyk2025neurodevelopmentaldisorderwith pages 1-2, polczyk2025neurodevelopmentaldisorderwith pages 2-4)
Sensorineural hearing impairment: core and described as nearly universal in the literature summary. Suggested HPO: HP:0000407 and bilateral hearing impairment HP:0008619. The recent patient had bilateral 60-dBnHL loss diagnosed at seven months and received hearing aids. Hearing loss substantially affects speech-language acquisition and communication. (polczyk2025neurodevelopmentaldisorderwith pages 1-2, polczyk2025neurodevelopmentaldisorderwith pages 2-4)
Motor disorder: spasticity and/or dystonia predominated in most members of the original cohort, producing a spastic-dystonic cerebral-palsy phenotype. Suggested HPO: HP:0001257, HP:0001332. Early hypotonia may precede hypertonia: the recent child remained centrally hypotonic at 14 months, later developing upper-limb stiffening. This supports age-dependent evolution rather than requiring spasticity in infancy. (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 6-7)
Hypotonia: variable, particularly early. Suggested HPO: HP:0001252. It impairs antigravity posture, rolling, sitting, and mobility. (polczyk2025neurodevelopmentaldisorderwith pages 6-7, polczyk2025neurodevelopmentaldisorderwith pages 2-4)
Epilepsy/EEG abnormality: common but not obligatory. Suggested HPO: HP:0001250, abnormal EEG HP:0010848. The recent child had no epileptiform activity at nine months; at approximately two years, bilateral sharp waves and other abnormalities appeared, but clinical epilepsy remained unconfirmed. (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 6-7)
Microcephaly: variable. Suggested HPO: HP:0000252. The recent child’s head circumference was below the third percentile after age two. (polczyk2025neurodevelopmentaldisorderwith pages 1-2, polczyk2025neurodevelopmentaldisorderwith pages 6-7)
MRI abnormalities: cerebral/cortical and white-matter volume loss, delayed myelination, periventricular T2 hyperintensity, mild ventriculomegaly, and thin/hypoplastic corpus callosum. Suggested HPO: HP:0002078, HP:0007058, HP:0002079, HP:0001273. (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 6-7)
Dysmorphism: variable and reported in roughly one-third according to the later literature summary; findings can include bitemporal narrowing, wide mouth, and epicanthal folds. Suggested HPO: HP:0001999, HP:0000286, and broad/wide mouth mapping after ontology validation. (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 2-4)
Ophthalmic findings: strabismus, refractive errors, and occasionally cortical visual impairment. Suggested HPO: HP:0000486, hypermetropia HP:0000540, astigmatism HP:0000483. (polczyk2025neurodevelopmentaldisorderwith pages 1-2, polczyk2025neurodevelopmentaldisorderwith pages 2-4)
Primitive reflex persistence/abnormal postural reactions: potentially useful early motor signs, but not validated as disease-specific biomarkers. In one child, all seven Vojta postural reactions were abnormal at 11 and 14 months, and Moro, rooting, and Babkin reflexes persisted. (polczyk2025neurodevelopmentaldisorderwith pages 6-7)

No NEDHLS-specific EQ-5D, SF-36, PROMIS, or caregiver-burden study was found. Nevertheless, severe impairment of communication, mobility, self-care, education, and independent living is clinically foreseeable from the documented combined hearing and neurodevelopmental disabilities; this is an inference rather than a quantified disease-specific result.

4. Genetic and molecular information

AFG2B/SPATA5L1 encodes an AAA+ ATPase-family protein. Open Targets assigns an exact disease–target association score of approximately 0.726 and links the association to PMIDs 34626583 and 38554706. (OpenTargets Search: Neurodevelopmental disorder with hearing loss and spasticity)

Reported pathogenic classes include missense, nonsense, frameshift, and likely splice-disrupting alleles, although a definitive exhaustive variant table and current gnomAD frequencies were not recoverable from the available primary text. Variants are germline, not somatic. The recessive inheritance and unaffected heterozygous parents are consistent with disease requiring two damaging alleles. (polczyk2025neurodevelopmentaldisorderwith pages 9-10, polczyk2025neurodevelopmentaldisorderwith pages 4-6)

Functional studies show several routes to pathogenicity:

reduced protein stability;
defective interaction or assembly within 55LCC;
reduced ATP binding/hydrolysis or pore-mediated unfoldase activity;
impaired replisome-substrate processing;
cellular replication stress and chromosome instability. (krishnamoorthy2024thespata5spata5l1atpase pages 7-8, krishnamoorthy2024thespata5spata5l1atpase pages 12-14)

Most patient mutants in the 2024 experiments were unstable after endogenous wild-type protein was removed. I466M and G689V were exceptions in retaining stability, although preserved abundance does not establish normal function. The patient-associated V245E allele severely compromised viability in CRISPR-rescue assays. (krishnamoorthy2024thespata5spata5l1atpase pages 7-8, krishnamoorthy2024thespata5spata5l1atpase pages 8-10)

No validated modifier gene, disease-specific methylation signature, chromosomal rearrangement, repeat expansion, mitochondrial-DNA defect, or somatic mechanism has been established. Large CNVs and uniparental disomy were specifically not explanatory in the recent patient. (polczyk2025neurodevelopmentaldisorderwith pages 4-6)

5. Environmental information

No toxin, radiation, pollution, occupation, diet, smoking, alcohol, exercise pattern, or infectious agent has been implicated causally. Prenatal history was uneventful in the detailed recent case. NEDHLS is not infectious, environmentally acquired, or zoonotic. Environmental and lifestyle measures may improve general health but are not known to alter the primary molecular defect. (polczyk2025neurodevelopmentaldisorderwith pages 2-4)

6. Mechanism and pathophysiology

Upstream molecular defect

SPATA5 and AFG2B/SPATA5L1 are type-II AAA+ ATPases related to the CDC48/p97 family. Together with C1ORF109 and CINP they form the stable four-member 55LCC complex. Cryo-EM and orthogonal interaction studies indicate a 4:2:2:2 stoichiometry—four SPATA5, two SPATA5L1, two C1ORF109, and two CINP subunits—forming a funnel/lid over a stacked-ring ATPase motor. ATP binding stabilizes the complex. (krishnamoorthy2024thespata5spata5l1atpase pages 3-5, krishnamoorthy2024thespata5spata5l1atpase pages 5-7)

The complete complex has 3.6-fold greater ATP hydrolysis than SPATA5 alone, and replication-fork DNA specifically increases its ATPase activity. Mutating conserved Walker-B residues abolishes hydrolysis. Suggested annotations include ATP hydrolysis activity, DNA binding, protein unfolding, GO:0006260 DNA replication, GO:0005657 replication fork, and GO:0000785 chromatin. (krishnamoorthy2024thespata5spata5l1atpase pages 5-7)

Replisome proteostasis

55LCC interacts with POLD1/POLD3, RFC1, cohesin components, and other nuclear and cytoplasmic complexes. In S phase and after replication damage, its ATPase/pore activity appears to unfold replisome proteins, making them accessible to calpain-family or related cysteine proteases. Processed substrates include POLD3, RFC1, POLA1, POLD1, ATR, ATRIP, and RAD21. This turnover is largely ubiquitin- and proteasome-independent. The authors’ mechanistic conclusion was that 55LCC “acts as an unfoldase,” facilitating cleavage and removal of replisome proteins from chromatin. (krishnamoorthy2024thespata5spata5l1atpase pages 8-10, krishnamoorthy2024thespata5spata5l1atpase pages 10-12)

Downstream causal chain

Biallelic damaging AFG2B variants → impaired 55LCC abundance/assembly/ATPase activity → defective replisome-protein remodeling → replication-fork slowing, stalling, and defective restart → exposed single-stranded DNA and replication stress → later ATR checkpoint activation, cohesion loss, and micronuclei → impaired survival or development of vulnerable neural and auditory cells → developmental disability, motor-system dysfunction, epilepsy, and hearing loss.

In engineered cells, phosphorylated RPA and fork shortening appeared within 18–24 hours; mitotic abnormalities emerged around 48–72 hours; approximately 25% of cells had micronuclei after 72 hours of induced depletion. Thus, replication stress is experimentally upstream of chromosomal instability. (krishnamoorthy2024thespata5spata5l1atpase pages 8-10)

An unfolded-protein response, including increased CHOP and spliced XBP1, also followed 55LCC loss. Earlier work additionally links complex members to late ribosome assembly, but the 2024 study found the replication/genome-instability phenotype separable from the reported ribosomal function. No disease-specific patient tissue transcriptome, proteome, metabolome, lipidome, single-cell atlas, spatial transcriptome, or integrated multi-omic signature has yet been established. (krishnamoorthy2024thespata5spata5l1atpase pages 3-5, krishnamoorthy2024thespata5spata5l1atpase pages 8-10)

Suggested cell terms are neuron, glial cell, and inner-ear sensory hair cell; these should be mapped to exact CL identifiers during curation. The evidence for enrichment in neurons, glial nuclei, and neurosensory hair cells comes from later synthesis, whereas the causal replication experiments used cultured cells rather than patient neural tissue. (polczyk2025neurodevelopmentaldisorderwith pages 1-2)

7. Anatomical structures affected

The primary systems are the central nervous system and auditory system. Brain structures implicated by imaging include cerebral cortex, white matter, corpus callosum, periventricular regions, and anterior temporal regions. Motor manifestations implicate corticospinal and extrapyramidal networks, although tract-specific pathology has not been demonstrated. Suggested UBERON mappings include brain, cerebral cortex, cerebral white matter, corpus callosum, inner ear, and cochlea. (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 6-7)

Hearing loss is bilateral in the reported detailed case and generally sensorineural, supporting cochlear hair-cell and/or auditory-neural involvement. At the subcellular level, the relevant compartments include nucleus, chromatin, replication fork, and the 55LCC macromolecular complex. (krishnamoorthy2024thespata5spata5l1atpase pages 3-5, polczyk2025neurodevelopmentaldisorderwith pages 2-4)

No consistent primary cardiovascular, pulmonary, renal, hepatic, gastrointestinal, endocrine, immune, or hematologic phenotype has been established for NEDHLS. Thrombocytopenia appears in the broader SPATA5/55LCC disease discussion but should not be assigned to AFG2B-related NEDHLS without patient-level confirmation. (krishnamoorthy2024thespata5spata5l1atpase pages 12-14)

8. Temporal development

Onset is infantile and insidious, not acute. Developmental delay and hypotonia can be evident by four months; hearing loss may be recognized within the first year; spasticity/dystonia and EEG abnormalities may emerge later. (polczyk2025neurodevelopmentaldisorderwith pages 6-7, polczyk2025neurodevelopmentaldisorderwith pages 2-4)

The course is chronic and lifelong. A practical—not formally validated—staging model is:

Early infancy: hypotonia, abnormal visual/social engagement, delayed motor milestones, hearing impairment.
Later infancy/childhood: persistent global delay, abnormal postural control, possible microcephaly and MRI abnormalities.
Evolving course: spastic-dystonic motor disorder and possible epilepsy/EEG abnormalities.

No relapsing-remitting pattern, spontaneous remission, or disease-defined end stage is known. Early auditory and developmental intervention is rational because infancy is a critical period for language and motor development, but no study has quantified a disease-specific window for modifying the underlying disorder. (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 2-4)

9. Inheritance and population

Inheritance is autosomal recessive. For two confirmed heterozygous carrier parents, standard Mendelian recurrence expectations are 25% affected, 50% carrier, and 25% unaffected/non-carrier per pregnancy, subject to confirmation that both alleles are truly pathogenic. No anticipation is expected, and no founder effect, germline mosaicism rate, carrier frequency, ethnic enrichment, geographic concentration, or sex bias has been demonstrated.

The foundational cohort contained 25 patients, and a 2025 report described the total literature as fewer than 30 affected individuals. Prevalence, incidence, mortality, and population carrier frequency are unknown; absence from epidemiologic registries should not be interpreted as zero prevalence. (polczyk2025neurodevelopmentaldisorderwith pages 1-2, polczyk2025neurodevelopmentaldisorderwith pages 6-7)

Penetrance among individuals with clearly pathogenic biallelic genotypes appears high for neurodevelopmental impairment, but exact penetrance is not calculable. Expressivity is variable, particularly for epilepsy, microcephaly, imaging abnormalities, and the timing of hypertonia. (polczyk2025neurodevelopmentaldisorderwith pages 7-9)

10. Diagnostics

Clinical workup

The recognizable combination is developmental delay plus bilateral sensorineural hearing loss and hypotonia or evolving spastic-dystonic motor dysfunction. Evaluation should include detailed neurologic/developmental examination, formal audiology or auditory brainstem response, ophthalmology, brain MRI, and EEG when seizures or episodic unresponsiveness are suspected. Serial assessment is important because EEG and tone abnormalities may evolve. (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 6-7)

There is no validated blood, urine, enzyme, metabolite, proteomic, epigenetic, biopsy, or liquid-biopsy biomarker. Replication-stress measurements remain research assays.

Molecular diagnosis

Preferred testing is trio WES or WGS with copy-number calling and confirmation of two rare, plausibly damaging AFG2B variants in trans. A neurodevelopmental/hearing-loss/spasticity panel that includes AFG2B is reasonable when rapid targeted testing is preferred. Sanger or equivalent orthogonal confirmation and parental segregation are appropriate. The recent real-world workflow used trio WES, mitochondrial-genome analysis, noncoding ClinVar-variant analysis, CNV assessment, and UPD assessment. (polczyk2025neurodevelopmentaldisorderwith pages 4-6)

WGS may identify noncoding, structural, or poorly captured variants missed by WES, although NEDHLS-specific incremental yield is unknown. RNA sequencing may help resolve suspected splice variants, but no validated disease-specific RNA diagnostic was identified. CMA can exclude alternative pathogenic CNVs but cannot reliably detect most causal single-nucleotide or small indel alleles. Karyotype, FISH, mitochondrial testing, and repeat-expansion testing are not first-line disease-specific tests unless the phenotype suggests another diagnosis.

Differential diagnosis

Key genetic differentials include SPATA5/AFG2A-related neurodevelopmental disorder, HPDL-related neurodegeneration/spasticity, hereditary spastic paraplegias, mitochondrial disorders, congenital infections, and other syndromic hearing-loss/epileptic encephalopathies. SPATA5-related disease reportedly has earlier seizures, more marked microcephaly, and frequent movement disorders, while AFG2B disease more consistently features sensorineural hearing loss and spastic-dystonic cerebral palsy; substantial overlap prevents clinical distinction without molecular testing. (polczyk2025neurodevelopmentaldisorderwith pages 7-9)

No population or newborn genetic screening program exists. Audiologic newborn screening may detect hearing loss but is neither sensitive nor specific for NEDHLS.

11. Outcome and prognosis

No 5- or 10-year survival estimates, life-expectancy data, mortality rates, or validated prognostic biomarkers exist. Available reports support persistent developmental and motor disability rather than recovery to typical development. Hearing amplification can improve sound access but does not reverse the genetic neurodevelopmental disorder. (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 2-4)

Potential long-term morbidity includes severe communication impairment, limited mobility, contractures from spasticity, epilepsy, feeding or nutritional difficulty secondary to neurologic disability, and caregiver burden, although NEDHLS-specific complication rates are unavailable. Younger age without seizures or spasticity cannot be assumed to predict a mild course because these features may emerge later. (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 6-7)

12. Treatment and current implementation

There is no approved disease-modifying pharmacotherapy, gene therapy, RNA therapy, cell therapy, or genotype-guided drug. No relevant disease-specific interventional trial was identified by searching the disease name and AFG2B/SPATA5L1.

Current treatment is multidisciplinary and phenotype-directed:

hearing aids; cochlear-implant assessment if hearing loss meets standard audiologic criteria;
early communication intervention, including speech-language and hearing rehabilitation;
physical and occupational therapy, positioning, mobility devices, and contracture prevention;
standard spasticity management where needed, potentially including oral antispastic medication, botulinum toxin, orthoses, or specialist procedures;
standard antiseizure medication selected according to seizure type if epilepsy is confirmed;
nutritional/feeding, ophthalmologic, orthopedic, and psychosocial support.

The detailed 2025 case used hearing aids and early reflex-locomotion/Vojta-oriented rehabilitation. The report documented persistent abnormalities, not a controlled treatment-response estimate. Suggested NCIT concepts include hearing-aid intervention, physical therapy, occupational therapy, speech therapy, rehabilitation, anticonvulsant therapy, and botulinum-toxin treatment; exact NCIT identifiers require terminology-service validation. (polczyk2025neurodevelopmentaldisorderwith pages 4-6, polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 2-4)

The 2024 mechanism identifies 55LCC, calpain-linked processing, replication stress, and proteostasis as research targets, but directly inhibiting this essential complex would be biologically risky: all four components were pan-essential across several cell lines. Mechanistic rescue or gene-replacement approaches remain preclinical concepts, not current clinical applications. (krishnamoorthy2024thespata5spata5l1atpase pages 3-5, krishnamoorthy2024thespata5spata5l1atpase pages 10-12)

13. Prevention

There is no vaccine, behavioral prevention, environmental prophylaxis, or medication that prevents disease in a person with a causal biallelic genotype.

Primary genetic prevention/reproductive options include carrier testing of parents and adult relatives, genetic counseling, partner testing, preimplantation genetic testing for monogenic disease, and prenatal diagnosis by chorionic-villus sampling or amniocentesis once familial variants are established. Secondary prevention consists of early molecular diagnosis, audiology, developmental surveillance, and seizure monitoring. Tertiary prevention targets complications through rehabilitation, hearing support, spasticity management, orthopedic surveillance, and epilepsy treatment.

Variant interpretation must be finalized before using a familial allele for reproductive testing, particularly when one allele remains a VUS. (polczyk2025neurodevelopmentaldisorderwith pages 4-6)

14. Other species and natural disease

No naturally occurring AFG2B-equivalent syndrome in a companion animal, livestock species, or wildlife population was identified. Consequently, breed ontology identifiers, veterinary prevalence, and zoonotic transmission are not applicable. The disorder is inherited rather than transmissible.

AFG2B/SPATA5L1 orthologs and the ATPase/proteostasis machinery are evolutionarily conserved, enabling experimental modeling, but conservation alone does not establish a spontaneous veterinary disease.

15. Model organisms and experimental systems

The strongest disease-relevant models currently retrieved are in vitro biochemical and engineered human-cell systems, not a fully validated organismal NEDHLS model.

Recombinant 55LCC supported ATPase, nucleic-acid-binding, thermal-stability, mass-photometry, native-mass-spectrometry, and cryo-EM studies.
HeLa S3 and engineered degron/CRISPR-rescue systems established complex essentiality, patient-variant effects, replication-fork defects, stress responses, cohesion loss, and micronucleation.
DNA-fiber assays, iPOND, chromatin fractionation, co-immunoprecipitation, and mass spectrometry defined replisome interactions and temporal effects. (krishnamoorthy2024thespata5spata5l1atpase pages 7-8, krishnamoorthy2024thespata5spata5l1atpase pages 41-46, krishnamoorthy2024thespata5spata5l1atpase pages 3-5, krishnamoorthy2024thespata5spata5l1atpase pages 8-10)

These models reproduce the molecular defect—impaired replisome proteostasis and genome stability—but cannot by themselves reproduce cognition, spastic-dystonic cerebral palsy, hearing behavior, or developmental trajectories. No retrieved evidence established a stable Afg2b-knockout mouse, rat, zebrafish, Drosophila, patient-derived iPSC neuron, cochlear organoid, or cerebral organoid that recapitulates NEDHLS. Such models are priorities for resolving tissue selectivity and testing allele-specific rescue.

Evidence appraisal and principal knowledge gaps

The human disease association is strong because multiple unrelated patients carry recessive biallelic variants with compatible phenotypes and familial segregation. The molecular mechanism is supported by high-quality structural, biochemical, and cell-biological experiments published in 2024. However, the bridge from replication stress to selective human brain and cochlear pathology remains inferential. (OpenTargets Search: Neurodevelopmental disorder with hearing loss and spasticity, krishnamoorthy2024thespata5spata5l1atpase pages 7-8, krishnamoorthy2024thespata5spata5l1atpase pages 1-3)

The most important gaps are: reliable phenotype frequencies from expanded cohorts; longitudinal natural history; variant-level penetrance and functional calibration; population carrier frequency; validated neural/cochlear models; patient-derived multi-omics; quantitative quality-of-life outcomes; treatment-response data; and disease-specific clinical trials.

Key abstract-supported statements

The foundational paper’s title itself states the principal human conclusion: “Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss.” PMID 34626583; October 2021; DOI URL. (OpenTargets Search: Neurodevelopmental disorder with hearing loss and spasticity, polczyk2025neurodevelopmentaldisorderwith pages 9-10)

The 2024 mechanistic study concluded that the complex processes replisome substrates and regulates genome stability, proposing that “55LCC acts as an unfoldase” and facilitates subsequent cysteine-protease cleavage and removal of replisome proteins from chromatin. PMID 38554706; April 2024; DOI URL. (krishnamoorthy2024thespata5spata5l1atpase pages 10-12)

A 2025 detailed case report concluded that integrating genomic sequencing with structured motor assessment can refine recognition and management; it also documented that biallelic disease may initially present with hypotonia and no confirmed epilepsy, illustrating age-dependent and variable expression. Published November 2025; DOI 10.3390/jcm14238442. (polczyk2025neurodevelopmentaldisorderwith pages 1-2, polczyk2025neurodevelopmentaldisorderwith pages 7-9)

References

(OpenTargets Search: Neurodevelopmental disorder with hearing loss and spasticity): Open Targets Query (Neurodevelopmental disorder with hearing loss and spasticity, 6 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(polczyk2025neurodevelopmentaldisorderwith pages 1-2): Artur Polczyk, Ewelina Wolańska, Anna Zimny, Agnieszka Zubkiewicz-Kucharska, Mateusz Biela, Agnieszka Pawelak, and Robert Śmigiel. Neurodevelopmental disorder with psychomotor delay, hearing loss, and spasticity caused by compound heterozygous spata5l1 variants—expanding phenotype. Journal of Clinical Medicine, 14:8442, Nov 2025. URL: https://doi.org/10.3390/jcm14238442, doi:10.3390/jcm14238442. This article has 1 citations.
(polczyk2025neurodevelopmentaldisorderwith pages 6-7): Artur Polczyk, Ewelina Wolańska, Anna Zimny, Agnieszka Zubkiewicz-Kucharska, Mateusz Biela, Agnieszka Pawelak, and Robert Śmigiel. Neurodevelopmental disorder with psychomotor delay, hearing loss, and spasticity caused by compound heterozygous spata5l1 variants—expanding phenotype. Journal of Clinical Medicine, 14:8442, Nov 2025. URL: https://doi.org/10.3390/jcm14238442, doi:10.3390/jcm14238442. This article has 1 citations.
(krishnamoorthy2024thespata5spata5l1atpase pages 1-3): Vidhya Krishnamoorthy, Martina Foglizzo, Robert L. Dilley, Angela Wu, Arindam Datta, Parul Dutta, Lisa J. Campbell, Oksana Degtjarik, Laura J. Musgrove, Antonio N. Calabrese, Elton Zeqiraj, and Roger A. Greenberg. The spata5-spata5l1 atpase complex directs replisome proteostasis to ensure genome integrity. Cell, 187:2250-2268.e31, Apr 2024. URL: https://doi.org/10.1016/j.cell.2024.03.002, doi:10.1016/j.cell.2024.03.002. This article has 18 citations and is from a highest quality peer-reviewed journal.
(krishnamoorthy2024thespata5spata5l1atpase pages 8-10): Vidhya Krishnamoorthy, Martina Foglizzo, Robert L. Dilley, Angela Wu, Arindam Datta, Parul Dutta, Lisa J. Campbell, Oksana Degtjarik, Laura J. Musgrove, Antonio N. Calabrese, Elton Zeqiraj, and Roger A. Greenberg. The spata5-spata5l1 atpase complex directs replisome proteostasis to ensure genome integrity. Cell, 187:2250-2268.e31, Apr 2024. URL: https://doi.org/10.1016/j.cell.2024.03.002, doi:10.1016/j.cell.2024.03.002. This article has 18 citations and is from a highest quality peer-reviewed journal.
(krishnamoorthy2024thespata5spata5l1atpase pages 10-12): Vidhya Krishnamoorthy, Martina Foglizzo, Robert L. Dilley, Angela Wu, Arindam Datta, Parul Dutta, Lisa J. Campbell, Oksana Degtjarik, Laura J. Musgrove, Antonio N. Calabrese, Elton Zeqiraj, and Roger A. Greenberg. The spata5-spata5l1 atpase complex directs replisome proteostasis to ensure genome integrity. Cell, 187:2250-2268.e31, Apr 2024. URL: https://doi.org/10.1016/j.cell.2024.03.002, doi:10.1016/j.cell.2024.03.002. This article has 18 citations and is from a highest quality peer-reviewed journal.
(polczyk2025neurodevelopmentaldisorderwith pages 4-6): Artur Polczyk, Ewelina Wolańska, Anna Zimny, Agnieszka Zubkiewicz-Kucharska, Mateusz Biela, Agnieszka Pawelak, and Robert Śmigiel. Neurodevelopmental disorder with psychomotor delay, hearing loss, and spasticity caused by compound heterozygous spata5l1 variants—expanding phenotype. Journal of Clinical Medicine, 14:8442, Nov 2025. URL: https://doi.org/10.3390/jcm14238442, doi:10.3390/jcm14238442. This article has 1 citations.
(polczyk2025neurodevelopmentaldisorderwith pages 7-9): Artur Polczyk, Ewelina Wolańska, Anna Zimny, Agnieszka Zubkiewicz-Kucharska, Mateusz Biela, Agnieszka Pawelak, and Robert Śmigiel. Neurodevelopmental disorder with psychomotor delay, hearing loss, and spasticity caused by compound heterozygous spata5l1 variants—expanding phenotype. Journal of Clinical Medicine, 14:8442, Nov 2025. URL: https://doi.org/10.3390/jcm14238442, doi:10.3390/jcm14238442. This article has 1 citations.
(polczyk2025neurodevelopmentaldisorderwith pages 9-10): Artur Polczyk, Ewelina Wolańska, Anna Zimny, Agnieszka Zubkiewicz-Kucharska, Mateusz Biela, Agnieszka Pawelak, and Robert Śmigiel. Neurodevelopmental disorder with psychomotor delay, hearing loss, and spasticity caused by compound heterozygous spata5l1 variants—expanding phenotype. Journal of Clinical Medicine, 14:8442, Nov 2025. URL: https://doi.org/10.3390/jcm14238442, doi:10.3390/jcm14238442. This article has 1 citations.
(polczyk2025neurodevelopmentaldisorderwith pages 2-4): Artur Polczyk, Ewelina Wolańska, Anna Zimny, Agnieszka Zubkiewicz-Kucharska, Mateusz Biela, Agnieszka Pawelak, and Robert Śmigiel. Neurodevelopmental disorder with psychomotor delay, hearing loss, and spasticity caused by compound heterozygous spata5l1 variants—expanding phenotype. Journal of Clinical Medicine, 14:8442, Nov 2025. URL: https://doi.org/10.3390/jcm14238442, doi:10.3390/jcm14238442. This article has 1 citations.
(krishnamoorthy2024thespata5spata5l1atpase pages 5-7): Vidhya Krishnamoorthy, Martina Foglizzo, Robert L. Dilley, Angela Wu, Arindam Datta, Parul Dutta, Lisa J. Campbell, Oksana Degtjarik, Laura J. Musgrove, Antonio N. Calabrese, Elton Zeqiraj, and Roger A. Greenberg. The spata5-spata5l1 atpase complex directs replisome proteostasis to ensure genome integrity. Cell, 187:2250-2268.e31, Apr 2024. URL: https://doi.org/10.1016/j.cell.2024.03.002, doi:10.1016/j.cell.2024.03.002. This article has 18 citations and is from a highest quality peer-reviewed journal.
(krishnamoorthy2024thespata5spata5l1atpase pages 3-5): Vidhya Krishnamoorthy, Martina Foglizzo, Robert L. Dilley, Angela Wu, Arindam Datta, Parul Dutta, Lisa J. Campbell, Oksana Degtjarik, Laura J. Musgrove, Antonio N. Calabrese, Elton Zeqiraj, and Roger A. Greenberg. The spata5-spata5l1 atpase complex directs replisome proteostasis to ensure genome integrity. Cell, 187:2250-2268.e31, Apr 2024. URL: https://doi.org/10.1016/j.cell.2024.03.002, doi:10.1016/j.cell.2024.03.002. This article has 18 citations and is from a highest quality peer-reviewed journal.
(krishnamoorthy2024thespata5spata5l1atpase pages 7-8): Vidhya Krishnamoorthy, Martina Foglizzo, Robert L. Dilley, Angela Wu, Arindam Datta, Parul Dutta, Lisa J. Campbell, Oksana Degtjarik, Laura J. Musgrove, Antonio N. Calabrese, Elton Zeqiraj, and Roger A. Greenberg. The spata5-spata5l1 atpase complex directs replisome proteostasis to ensure genome integrity. Cell, 187:2250-2268.e31, Apr 2024. URL: https://doi.org/10.1016/j.cell.2024.03.002, doi:10.1016/j.cell.2024.03.002. This article has 18 citations and is from a highest quality peer-reviewed journal.
(krishnamoorthy2024thespata5spata5l1atpase pages 12-14): Vidhya Krishnamoorthy, Martina Foglizzo, Robert L. Dilley, Angela Wu, Arindam Datta, Parul Dutta, Lisa J. Campbell, Oksana Degtjarik, Laura J. Musgrove, Antonio N. Calabrese, Elton Zeqiraj, and Roger A. Greenberg. The spata5-spata5l1 atpase complex directs replisome proteostasis to ensure genome integrity. Cell, 187:2250-2268.e31, Apr 2024. URL: https://doi.org/10.1016/j.cell.2024.03.002, doi:10.1016/j.cell.2024.03.002. This article has 18 citations and is from a highest quality peer-reviewed journal.
(krishnamoorthy2024thespata5spata5l1atpase pages 41-46): Vidhya Krishnamoorthy, Martina Foglizzo, Robert L. Dilley, Angela Wu, Arindam Datta, Parul Dutta, Lisa J. Campbell, Oksana Degtjarik, Laura J. Musgrove, Antonio N. Calabrese, Elton Zeqiraj, and Roger A. Greenberg. The spata5-spata5l1 atpase complex directs replisome proteostasis to ensure genome integrity. Cell, 187:2250-2268.e31, Apr 2024. URL: https://doi.org/10.1016/j.cell.2024.03.002, doi:10.1016/j.cell.2024.03.002. This article has 18 citations and is from a highest quality peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	6
Resolved	5
Unresolved (possible confabulation)	1
Unverifiable	0

Unresolved references

These identifiers did not resolve to a record and may be fabricated. A lookup that failed for transport reasons is indistinguishable from one that failed because the record does not exist, so spot-check before acting on them:

DOI:10.3390/jcm14238442](https://doi.org/10.3390/jcm14238442 (1 mention) - Identifier did not resolve to a record

Ask OpenScientist

OpenScientist Report

Classifications

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Differential Diagnoses

Source YAML

References & Deep Research

References

Deep Research

Neurodevelopmental Disorder with Hearing Loss and Spasticity: Research Report

Executive summary

1. Disease information

Definition and identifiers

2. Etiology, risk, and protective factors

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Upstream molecular defect

Replisome proteostasis

Downstream causal chain

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical workup

Molecular diagnosis

Differential diagnosis

11. Outcome and prognosis

12. Treatment and current implementation

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Evidence appraisal and principal knowledge gaps

Key abstract-supported statements

Artifacts

Reference Validation

Unresolved references