Basel-Vanagaite-Smirin-Yosef Syndrome

Mendelian MONDO:0014643 Pathograph 110 Show in embeddings browser Autosomal recessive intellectual disability Neurodevelopmental disorder Mediator complex-associated disorder

Basel-Vanagaite-Smirin-Yosef syndrome is an autosomal recessive neurodevelopmental disorder associated with biallelic MED25 variants. MED25 encodes a subunit of the Mediator transcriptional coactivator complex. Intellectual and speech impairment accompany variable ocular, brain, cardiac, palatal, skeletal, and growth abnormalities; epilepsy and hypotonia are also reported. The allelic spectrum includes missense, truncating, and splice-altering variants. Tyr39Cys impairs MED25 association with Mediator in a cell-based assay, while specific splice variants alter RNA processing. These results do not establish a single molecular defect for all alleles or a resolved cellular pathway to every clinical manifestation.

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4
Pathophys.
80
Phenotypes
1
Hypotheses
110
Pathograph
1
Genes
14
Variants
7
Medical Actions
6
Models
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Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE NEUROLOGIC
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Mechanistic Hypotheses

1
MED25-dependent SOX9 transcription and palatal development
MED25_SOX9_PALATE EMERGING
Evidence balance 3 support
A model-supported hypothesis for a subset of palatal manifestations. Human variant effects on the SOX9–WWP2–MED25 transcriptional complex and cartilage matrix production have not been established.
Pathograph links
Biallelic MED25 dysfunction -> Reduced SOX9-dependent cartilage matrix transcription INDIRECT UNKNOWN INTERMEDIATES Med25 knockdown motivates this candidate pathway; no patient variant has been shown to disrupt Sox9-dependent transcription in the cited experiments.
Reduced SOX9-dependent cartilage matrix transcription -> Cleft palate INDIRECT UNKNOWN INTERMEDIATES The cellular and zebrafish findings motivate a possible palatal developmental mechanism, but the route from human variants to cleft palate remains untested.
Show evidence (3 references)
PMID:21427722 SUPPORT PRIMARY RESULT In Vitro
"Knockdown of either Wwp2 or Med25 in C3H10T1/2 cells resulted in significant downregulation of Col2a1 transcripts (Fig. 5b,c)."
Med25 depletion reduces a cartilage matrix transcript in mouse mesenchymal cells; this is not a patient-allele experiment.
PMID:21427722 SUPPORT PRIMARY RESULT In Vitro
"Importantly, knockdown of Wwp2 in ATDC5 cells attenuated the physical interaction between endogenous Sox9 and HA-tagged Med25 (Fig. 5g)."
The chondrogenic cell assay supports Wwp2-dependent Sox9–Med25 association.
PMID:21427722 SUPPORT PRIMARY RESULT Model Organism
"Intriguingly, morpholino-mediated knockdown of med25 in zebrafish resulted in palatal malformation (Fig. 4d), which closely resembled the palatal phenotype of wwp2 or sox9 mutants23 (Fig. 2f)."
Transient zebrafish med25 depletion affects palatal cartilage; neither a stable mutation nor a human disease allele was tested.
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Pathophysiology

4
Biallelic MED25 dysfunction
Homozygous and compound heterozygous MED25 variants are associated with a variable developmental syndrome. Both missense and truncating alleles have been described, and splice defects have been demonstrated for particular intronic variants. Functional consequences and the strength of pathogenicity evidence differ between alleles.
MED25-dependent SOX9 transcription and palatal development
MED25 hgnc:28845 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MED25 (hgnc:28845). hgnc:28845 is a gene from the HUGO Gene Nomenclature Committee.
Animal models
Med25-null mouse Mus musculus perturbs Removes Med25 and tests consequences for embryonic development and viability.
Downstream
MED25 Mediator incorporation failure The Tyr39Cys allele reduces association with Mediator in the tested overexpression system.
Abnormal MED25 pre-mRNA splicing Specific splice-region alleles alter MED25 RNA processing; this is not a demonstrated consequence of all missense alleles.
Severe intellectual disability Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Microcephaly Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Global developmental delay Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Absent speech Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Delayed speech and language development Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Loss of speech Loss of acquired verbal expression was reported in one affected child; the intervening mechanism is unresolved.
Short stature Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Hypotonia Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Spasticity Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Hyporeflexia Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Seizure Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Thin corpus callosum Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Agenesis of corpus callosum Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Ventriculomegaly Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Cerebral atrophy Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Cavum septum pellucidum Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Developmental cataract Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Microcornea Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Microphthalmia Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Hypermetropia Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Ptosis Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Amblyopia Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Strabismus Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Cleft palate Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
High palate Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Narrow palate Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Retrognathia Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Hypertelorism Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Downslanted palpebral fissures Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Low-set ears Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Short philtrum Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Exaggerated cupid's bow Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Sparse hair Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Sparse eyebrow Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Nevus flammeus of the forehead Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Atrial septal defect Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Ventricular septal defect Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Elevated pulmonary artery pressure Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Hypospadias Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Hydronephrosis Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Increased size of the clitoris Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Inguinal hernia Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Male urethral meatus stenosis Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Scoliosis Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Kyphosis Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Broad distal phalanx of the toes Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
2-3 toe syndactyly Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Camptodactyly of finger Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Single transverse palmar crease Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Pes cavus Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Adducted thumb Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Overlapping fingers Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Clinodactyly Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Pectus carinatum Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Overlapping toe Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Constipation Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Gastroesophageal reflux Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Cholelithiasis Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Wide anterior fontanel Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
High forehead Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Depressed nasal bridge Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Broad nasal tip Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Wide mouth Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Thin upper lip vermilion Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Coarctation of aorta Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Bilateral perisylvian polymicrogyria Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Hippocampal atrophy Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Periventricular white matter hyperintensities Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Duane anomaly Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Retinal detachment Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Glaucoma Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Metatarsus adductus Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Focal-onset seizure Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Myoclonic seizure Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Bilateral tonic-clonic seizure with generalized onset Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
Reduced SOX9-dependent cartilage matrix transcription Med25 knockdown motivates this candidate pathway; no patient variant has been shown to disrupt Sox9-dependent transcription in the cited experiments. MED25-dependent SOX9 transcription and palatal development
Cleft lip Clinical association with the MED25 developmental disorder; the tissue pathway is unresolved.
Failure to thrive Clinical association with the MED25 developmental disorder; the tissue pathway is unresolved.
Show evidence (2 references)
PMID:25792360 SUPPORT PRIMARY RESULT Human Clinical
"Using exome sequencing, we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four..."
The defining clinical series establishes the association between biallelic MED25 variation and a multisystem developmental syndrome; it does not measure the cellular pathway to each manifestation.
PMID:32816121 SUPPORT PRIMARY RESULT Human Clinical
"Whole exome sequencing detected a homozygous frameshift variant in the MED25 gene: NM_030973.3:c.1778_1779delAG, p.(Gln593Argfs)."
The reported homozygous frameshift extends the allelic spectrum beyond VWA-domain missense variants.
MED25 Mediator incorporation failure
The VWA-domain Tyr39Cys substitution impairs association of MED25 with Mediator. The experiment compared tagged wild-type and mutant MED25 expressed in 293-HEK cells, with comparable production and immunoprecipitation efficiency. It does not demonstrate loss of the entire Mediator complex or a shared incorporation defect for all disease-associated alleles.
MED25 hgnc:28845 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MED25 (hgnc:28845). hgnc:28845 is a gene from the HUGO Gene Nomenclature Committee.
Experimental models
Tyr39Cys MED25 expression in 293-HEK cells CELL LINE Tests variant-specific MED25 association with Mediator.
Show evidence (3 references)
PMID:25792360 SUPPORT PRIMARY RESULT In Vitro
"The MED25 point mutation is located in the von Willebrand factor type A (MED25 VWA) domain which is responsible for MED25 recruitment into the Mediator complex; co-immunoprecipitation experiment demonstrated that this mutation dramatically impairs MED25 interaction with the Mediator complex in..."
The recruitment defect was demonstrated for Tyr39Cys; it has not been established experimentally for every reported MED25 allele.
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/figures/4 SUPPORT PRIMARY RESULT In Vitro
"mutation impaired Mediator recruitment. WT or YC mutated Flag-NLS-MED25 was expressed in 293-HEK cells."
The figure caption identifies this as the Y39C MED25 experiment and specifies the tested cell system.
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/figures/4 SUPPORT PRIMARY RESULT In Vitro
"Anti-Flag detection was also performed to assess precipitation efficiency and comparable WT and YC MED25 production levels"
Comparable tagged-protein production and precipitation controls support an incorporation defect rather than simply absent expression.
Abnormal MED25 pre-mRNA splicing
The c.1965+1dup allele generates intron-16 one-base retention and exon-16 skipping in minigene assays. Carrier-mother blood RNA contains the one-base-retention product alongside normally spliced transcript; exon skipping was not demonstrated in that blood experiment. Altered protein products are predicted consequences, whereas neuronal protein abundance and Mediator assembly were not measured. Arg224Gly did not alter splicing in the tested constructs. A separate 2026 report describes intron-2 retention associated with c.180+5G>C.
MED25 hgnc:28845 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MED25 (hgnc:28845). hgnc:28845 is a gene from the HUGO Gene Nomenclature Committee.
Experimental models
MED25 minigene splice assays in HEK293T and HeLa cells CELL LINE Directly assays RNA-processing consequences of the two reported variants.
Show evidence (3 references)
PMID:40909439 SUPPORT PRIMARY RESULT In Vitro
"In vitro MSA results indicated that the variant c.670C > G (p.R224G) did not disrupt the normal splicing of the MED25 gene (Supplementary Figure S3). In contrast, the variant c.1965 + 1dup affected normal splicing, resulting in two abnormal transcripts: retention of 1 bp in intron 16; skipping..."
Minigenes in HEK293T and HeLa cells distinguish an experimentally demonstrated splice defect from the normal splicing of the missense allele.
PMID:40909439 SUPPORT PRIMARY RESULT Human Clinical
"Using the proband’s father’s sample as a control, we assessed the impact of the mutation on MED25 mRNA splicing in the mother’s blood sample. The results indicated that the mutation c.1965 + 1dup affects the splicing of the MED25 gene in vivo, producing only one abnormal splicing product, a 1 bp..."
Carrier-parent blood RNA supports intron retention, but not the exon-skipping product observed in minigenes. These are blood assays, not neuronal or whole-animal experiments.
PMID:42663018 SUPPORT PRIMARY RESULT Human Clinical
"Transcriptome sequencing confirmed that the c.180+5G>C variant may cause aberrant splicing with retention of intron 2."
The abstract reports RNA evidence of intron retention; the tissue and detailed assay performance cannot be established from this abstract.
Reduced SOX9-dependent cartilage matrix transcription
Mechanism confidence: Provisional
Med25 supports Sox9-dependent cartilage matrix transcription in mouse cell systems. Wwp2 facilitates Sox9–Med25 association, and Med25 depletion reduces Col2a1 expression. Together with zebrafish palatal abnormalities after med25 knockdown, these experiments suggest a possible route to human palatal anomalies. A defect in this pathway has not been demonstrated for BVSYS patient variants or patient palatal tissue.
MED25-dependent SOX9 transcription and palatal development
MED25 hgnc:28845 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MED25 (hgnc:28845). hgnc:28845 is a gene from the HUGO Gene Nomenclature Committee.
Experimental models
Med25 siRNA in C3H10T1/2 mesenchymal cells CELL LINE Perturbs the candidate transcriptional mechanism by depleting Med25.
Sox9–Med25 association in ATDC5 cells CELL LINE Measures association of components of the candidate transcriptional complex.
Animal models
med25 morpholino zebrafish Danio rerio perturbs Tests a developmental consequence of med25 depletion consistent with the Sox9-associated palatal hypothesis.
Downstream
Cleft palate The cellular and zebrafish findings motivate a possible palatal developmental mechanism, but the route from human variants to cleft palate remains untested. MED25-dependent SOX9 transcription and palatal development
Show evidence (3 references)
PMID:21427722 SUPPORT PRIMARY RESULT In Vitro
"Knockdown of either Wwp2 or Med25 in C3H10T1/2 cells resulted in significant downregulation of Col2a1 transcripts (Fig. 5b,c)."
Med25 depletion reduces a cartilage matrix transcript in mouse mesenchymal cells; this is not a patient-allele experiment.
PMID:21427722 SUPPORT PRIMARY RESULT In Vitro
"Importantly, knockdown of Wwp2 in ATDC5 cells attenuated the physical interaction between endogenous Sox9 and HA-tagged Med25 (Fig. 5g)."
The chondrogenic cell assay supports Wwp2-dependent Sox9–Med25 association.
PMID:21427722 SUPPORT PRIMARY RESULT Model Organism
"Intriguingly, morpholino-mediated knockdown of med25 in zebrafish resulted in palatal malformation (Fig. 4d), which closely resembled the palatal phenotype of wwp2 or sox9 mutants23 (Fig. 2f)."
Transient zebrafish med25 depletion affects palatal cartilage; neither a stable mutation nor a human disease allele was tested.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Basel-Vanagaite-Smirin-Yosef Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

80
Cardiovascular 4
Atrial septal defect HP:0001631 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Atrial septal defect, pulmonary hypertension"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Ventricular septal defect HP:0001629 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular septal defect (HP:0001629). HP:0001629 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31602195 SUPPORT PRIMARY RESULT Human Clinical
"Cardiac evaluation revealed coarctation of the aorta and a ventricular septal defect."
The primary clinical evaluation of the affected boy confirms a ventricular septal defect.
Elevated pulmonary artery pressure HP:0004890 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated pulmonary artery pressure (HP:0004890). HP:0004890 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Atrial septal defect, pulmonary hypertension"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Coarctation of aorta HP:0001680 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coarctation of aorta (HP:0001680). HP:0001680 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31602195 SUPPORT PRIMARY RESULT Human Clinical
"Cardiac evaluation revealed coarctation of the aorta and a ventricular septal defect."
Cardiac assessment of the affected boy established both defects.
Digestive 4
Inguinal hernia HP:0000023 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inguinal hernia (HP:0000023). HP:0000023 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Hydronephrosis, bilateral inguinal hernia hypospadias,meatal stenosis"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Constipation HP:0002019 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Constipation (HP:0002019). HP:0002019 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Gallbladder calculi, gastrointestinal reflux, constipation"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Gastroesophageal reflux HP:0002020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastroesophageal reflux (HP:0002020). HP:0002020 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Gallbladder calculi, gastrointestinal reflux, constipation"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Cholelithiasis HP:0001081 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cholelithiasis (HP:0001081). HP:0001081 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Gallbladder calculi, gastrointestinal reflux, constipation"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Ear 1
Low-set ears HP:0000369 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low-set ears (HP:0000369). HP:0000369 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Ears ... Low set ears"
Table 1 records low-set ears in patient 5; the caption and row heading supply the clinical-table context.
Eye 11
Developmental cataract HP:0000519 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental cataract (HP:0000519). HP:0000519 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Eyes ... Ptosis, congenital cataract, amblyopia"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Microcornea HP:0000482 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcornea (HP:0000482). HP:0000482 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Downslanting palpebral fissures, ptosis, bilateral microcornea"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Microphthalmia HP:0000568 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microphthalmia (HP:0000568). HP:0000568 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Hypertelorism, downslanting palpebral fissures, microphthlmia, microcornea, high hypermetropia, ptosis, congenital cataract"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Hypermetropia HP:0000540 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypermetropia (HP:0000540). HP:0000540 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Hypertelorism, downslanting palpebral fissures, microphthlmia, microcornea, high hypermetropia, ptosis, congenital cataract"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Ptosis HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Eyes ... Ptosis, congenital cataract, amblyopia"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Amblyopia HP:0000646 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Amblyopia (HP:0000646). HP:0000646 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Eyes ... Ptosis, congenital cataract, amblyopia"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Strabismus HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Eyes ... Strabismus"
Table 1 records strabismus in patient 6; the caption and row heading supply the clinical-table context.
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Hypertelorism, downslanting palpebral fissures, ptosis? Congenital cataract"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Duane anomaly HP:0009921 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Duane anomaly (HP:0009921). HP:0009921 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40990994 SUPPORT PRIMARY RESULT Human Clinical
"Other medical conditions include bilateral Duane syndrome, sleep-disordered breathing, systemic hypertension, nephrocalcinosis, hypocalcemia, and gastroesophageal reflux."
This case directly documents Duane syndrome; coexisting renal and metabolic findings have potentially confounding SLC34A1 variation.
Retinal detachment HP:0000541 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retinal detachment (HP:0000541). HP:0000541 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40990994 SUPPORT PRIMARY RESULT Human Clinical
"Her medical diagnoses included closed ventricular septal defect, short stature, clubfeet, hypercalcinuria, nephrocalcinosis congenital cataracts, retinal detachments, and glaucoma."
The primary patient description records this ocular finding; the list does not demonstrate its independent molecular mechanism.
Glaucoma HP:0000501 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Glaucoma (HP:0000501). HP:0000501 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40990994 SUPPORT PRIMARY RESULT Human Clinical
"Her medical diagnoses included closed ventricular septal defect, short stature, clubfeet, hypercalcinuria, nephrocalcinosis congenital cataracts, retinal detachments, and glaucoma."
The primary patient description records this ocular finding; the list does not demonstrate its independent molecular mechanism.
Genitourinary 4
Hypospadias HP:0000047 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypospadias (HP:0000047). HP:0000047 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Hydronephrosis, bilateral inguinal hernia hypospadias,meatal stenosis"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Hydronephrosis HP:0000126 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydronephrosis (HP:0000126). HP:0000126 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Hydronephrosis, bilateral inguinal hernia hypospadias,meatal stenosis"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Increased size of the clitoris HP:0040253 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased size of the clitoris (HP:0040253). HP:0040253 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Urogenital system ... Clitoromegaly"
Table 1 records clitoromegaly in patient 4; the caption and row heading supply the clinical-table context.
Male urethral meatus stenosis HP:0032077 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Male urethral meatus stenosis (HP:0032077). HP:0032077 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Hydronephrosis, bilateral inguinal hernia hypospadias,meatal stenosis"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Head and Neck 16
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25792360 SUPPORT PRIMARY RESULT Human Clinical
"a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability"
The defining report documents microcephaly; the later Ile173Thr siblings had normal head growth.
PMID:31602195 REFUTE PRIMARY RESULT Human Clinical
"Her OFC was 45.5 cm, length 76 cm, and her weight was 9.5 kg (all at the 50th percentile)."
Normal head circumference in the affected one-year-old sister refutes universal microcephaly, while leaving its occurrence in other affected individuals intact.
Cleft palate HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Paranasal widening, anteverted nasal tip, short philtrum, cleft palate, retrognathia"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
High palate HP:0000218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High palate (HP:0000218). HP:0000218 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Paranasal widening, anteverted nasal tip, high and narrow palate, wide cupid bow, grooved tongue"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Narrow palate HP:0000189 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Narrow palate (HP:0000189). HP:0000189 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Paranasal widening, anteverted nasal tip, high and narrow palate, wide cupid bow, grooved tongue"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Retrognathia HP:0000278 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retrognathia (HP:0000278). HP:0000278 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Paranasal widening, anteverted nasal tip, short philtrum, cleft palate, retrognathia"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Downslanted palpebral fissures HP:0000494 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downslanted palpebral fissures (HP:0000494). HP:0000494 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Downslanting palpebral fissures, ptosis, bilateral microcornea"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Short philtrum HP:0000322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short philtrum (HP:0000322). HP:0000322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Cleft palate, short philtrum, wide cupid bow"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Exaggerated cupid's bow HP:0002263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exaggerated cupid's bow (HP:0002263). HP:0002263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Cleft palate, short philtrum, wide cupid bow"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Sparse eyebrow HP:0045075 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sparse eyebrow (HP:0045075). HP:0045075 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Nevus flammeus simplex on the forehead, sparse lateral part of the eyebrows"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Wide anterior fontanel HP:0000260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wide anterior fontanel (HP:0000260). HP:0000260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31602195 SUPPORT PRIMARY RESULT Human Clinical
"Upon examination, he had several craniofacial anomalies, including large anterior fontanel, high forehead, sparse scalp hair and eyebrows, flat nasal bridge with a broad nasal tip, hypertelorism, short philtrum, a large mouth with a thin upper lip, and a cleft palate (Fig. 1a)."
The primary clinical examination of the affected three-year-old boy documents this finding.
High forehead HP:0000348 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High forehead (HP:0000348). HP:0000348 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31602195 SUPPORT PRIMARY RESULT Human Clinical
"Upon examination, he had several craniofacial anomalies, including large anterior fontanel, high forehead, sparse scalp hair and eyebrows, flat nasal bridge with a broad nasal tip, hypertelorism, short philtrum, a large mouth with a thin upper lip, and a cleft palate (Fig. 1a)."
The primary clinical examination of the affected three-year-old boy documents this finding.
Depressed nasal bridge HP:0005280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Depressed nasal bridge (HP:0005280). HP:0005280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31602195 SUPPORT PRIMARY RESULT Human Clinical
"Upon examination, he had several craniofacial anomalies, including large anterior fontanel, high forehead, sparse scalp hair and eyebrows, flat nasal bridge with a broad nasal tip, hypertelorism, short philtrum, a large mouth with a thin upper lip, and a cleft palate (Fig. 1a)."
The primary clinical examination of the affected three-year-old boy documents this finding.
Broad nasal tip HP:0000455 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad nasal tip (HP:0000455). HP:0000455 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31602195 SUPPORT PRIMARY RESULT Human Clinical
"Upon examination, he had several craniofacial anomalies, including large anterior fontanel, high forehead, sparse scalp hair and eyebrows, flat nasal bridge with a broad nasal tip, hypertelorism, short philtrum, a large mouth with a thin upper lip, and a cleft palate (Fig. 1a)."
The primary clinical examination of the affected three-year-old boy documents this finding.
Wide mouth HP:0000154 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wide mouth (HP:0000154). HP:0000154 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31602195 SUPPORT PRIMARY RESULT Human Clinical
"Upon examination, he had several craniofacial anomalies, including large anterior fontanel, high forehead, sparse scalp hair and eyebrows, flat nasal bridge with a broad nasal tip, hypertelorism, short philtrum, a large mouth with a thin upper lip, and a cleft palate (Fig. 1a)."
The primary clinical examination of the affected three-year-old boy documents this finding.
Thin upper lip vermilion HP:0000219 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin upper lip vermilion (HP:0000219). HP:0000219 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31602195 SUPPORT PRIMARY RESULT Human Clinical
"Upon examination, he had several craniofacial anomalies, including large anterior fontanel, high forehead, sparse scalp hair and eyebrows, flat nasal bridge with a broad nasal tip, hypertelorism, short philtrum, a large mouth with a thin upper lip, and a cleft palate (Fig. 1a)."
The primary clinical examination of the affected three-year-old boy documents this finding.
Cleft lip HP:0410030 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft lip (HP:0410030). HP:0410030 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32324310 SUPPORT PRIMARY RESULT Human Clinical
"The major features determined by "reverse phenotyping" include significant to profound developmental delays/intellectual disability with absent or delayed speech, epilepsy, ocular abnormalities, cleft lip and/or palate, congenital heart disease, urogenital anomalies, skeletal abnormalities,..."
The primary three-patient series expands the clinical spectrum; this abstract does not provide individual denominators for each finding.
Integument 3
Sparse hair HP:0008070 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sparse hair (HP:0008070). HP:0008070 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Nevus flammeus simplex on the forehead, sparse hair, receding frontal hairline"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Nevus flammeus of the forehead HP:0007413 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nevus flammeus of the forehead (HP:0007413). HP:0007413 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Nevus flammeus simplex on the forehead, sparse hair, receding frontal hairline"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Single transverse palmar crease HP:0000954 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Single transverse palmar crease (HP:0000954). HP:0000954 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"2nd finger deviation, bilateral single transverse palmar crease, clinodactyly"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Limbs 9
Broad distal phalanx of the toes HP:0010186 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad distal phalanx of the toes (HP:0010186). HP:0010186 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Kyphosis, scoliosis, mild interdigital webbing, broad distal phalanges of toes, syndactyly of 2–3 toes"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
2-3 toe syndactyly HP:0004691 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is 2-3 toe syndactyly (HP:0004691). HP:0004691 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Syndactyly of 2–3 toes, 3rd finger camptodactyly, overlapping fingers, adducted thumbs"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Camptodactyly of finger HP:0100490 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Camptodactyly of finger (HP:0100490). HP:0100490 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Syndactyly of 2–3 toes, 3rd finger camptodactyly, overlapping fingers, adducted thumbs"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Pes cavus HP:0001761 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pes cavus (HP:0001761). HP:0001761 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Syndactyly of 2–3 toes, 3rd finger camptodactyly, partial single transverse palmar crease, pes cavus"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Adducted thumb HP:0001181 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Adducted thumb (HP:0001181). HP:0001181 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Syndactyly of 2–3 toes, 3rd finger camptodactyly, overlapping fingers, adducted thumbs"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Overlapping fingers HP:0010557 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Overlapping fingers (HP:0010557). HP:0010557 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Syndactyly of 2–3 toes, 3rd finger camptodactyly, overlapping fingers, adducted thumbs"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Clinodactyly HP:0030084 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Clinodactyly (HP:0030084). HP:0030084 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"2nd finger deviation, bilateral single transverse palmar crease, clinodactyly"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Overlapping toe HP:0001845 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Overlapping toe (HP:0001845). HP:0001845 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Skeletal system ... Pectus carinatum, overlapping toes"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Metatarsus adductus HP:0001840 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metatarsus adductus (HP:0001840). HP:0001840 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40990994 SUPPORT PRIMARY RESULT Human Clinical
"She had a moderate atrial septal defect and bilateral metatarsus adductus type 1, which were managed conservatively."
The primary clinical description documents the foot malformation.
Musculoskeletal 5
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Neurological abnormalities ... Hypotonia, later spasticity, seizures"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Spasticity HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Neurological abnormalities ... Hypotonia, later spasticity, seizures"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Kyphosis, scoliosis, mild interdigital webbing, broad distal phalanges of toes, syndactyly of 2–3 toes"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Kyphosis HP:0002808 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Kyphosis (HP:0002808). HP:0002808 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Kyphosis, scoliosis, mild interdigital webbing, broad distal phalanges of toes, syndactyly of 2–3 toes"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Pectus carinatum HP:0000768 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pectus carinatum (HP:0000768). HP:0000768 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Skeletal system ... Pectus carinatum, overlapping toes"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Nervous System 21
Severe intellectual disability HP:0010864 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe intellectual disability (HP:0010864). HP:0010864 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25792360 SUPPORT PRIMARY RESULT Human Clinical
"a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability"
The original series explicitly describes severe intellectual disability.
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31602195 SUPPORT PRIMARY RESULT Human Clinical
"Here, we report an additional Lebanese family with 2 affected siblings presenting with severely delayed psychomotor and language development as well as craniofacial anomalies."
Both siblings had substantial developmental impairment.
Absent speech HP:0001344 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent speech (HP:0001344). HP:0001344 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40990994 SUPPORT PRIMARY RESULT Human Clinical
"Developmentally, she did not speak any words and was nonambulatory."
Patient N1 had no spoken words at the reported assessment.
Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31602195 SUPPORT PRIMARY RESULT Human Clinical
"At 3 years of age, he presented with severely impaired psychomotor and language development."
The affected boy had severely impaired language development at age three.
Loss of speech HP:0002371 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Loss of speech (HP:0002371). HP:0002371 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40909439 SUPPORT PRIMARY RESULT Human Clinical
"The patient’s language comprehension remains intact; however, verbal expression has been completely lost."
The later case documents expressive language loss, without establishing a uniform progressive course.
Hyporeflexia HP:0001265 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyporeflexia (HP:0001265). HP:0001265 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Hypotonia decreased deep tendon reflexes, seizures"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Neurological abnormalities ... Hypotonia, later spasticity, seizures"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Thin corpus callosum HP:0033725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin corpus callosum (HP:0033725). HP:0033725 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Thin corpus callosum, cavum septum pellucidum and vergae"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Agenesis of corpus callosum HP:0001274 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Agenesis of corpus callosum (HP:0001274). HP:0001274 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Absent corpus callosum, dilated lateral and third brain ventricles, cerebral parenchymal atrophy"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Ventriculomegaly HP:0002119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventriculomegaly (HP:0002119). HP:0002119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Absent corpus callosum, dilated lateral and third brain ventricles, cerebral parenchymal atrophy"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Cerebral atrophy HP:0002059 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral atrophy (HP:0002059). HP:0002059 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Absent corpus callosum, dilated lateral and third brain ventricles, cerebral parenchymal atrophy"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Cavum septum pellucidum HP:0002389 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cavum septum pellucidum (HP:0002389). HP:0002389 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1 SUPPORT PRIMARY RESULT Human Clinical
"Thin corpus callosum, cavum septum pellucidum and vergae"
The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
Bilateral perisylvian polymicrogyria HP:0032407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral perisylvian polymicrogyria (HP:0032407). HP:0032407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s10048-020-00625-2/figures/2 SUPPORT PRIMARY RESULT Human Clinical
"T2 coronal view: bilateral perisylvian polymicrogyria."
The MRI caption specifies bilateral perisylvian involvement, supporting a more precise binding than generic polymicrogyria.
Hippocampal atrophy HP:0410170 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hippocampal atrophy (HP:0410170). HP:0410170 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40909439 SUPPORT PRIMARY RESULT Human Clinical
"Additionally, there was bilateral hippocampal volume loss with widening of the temporal horns, and the cavum septum pellucidum was present (Figure 1C)."
The clinical MRI description documents hippocampal volume loss.
Periventricular white matter hyperintensities HP:0030891 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Periventricular white matter hyperintensities (HP:0030891). HP:0030891 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40990994 SUPPORT PRIMARY RESULT Human Clinical
"Brain MRI at 12 years of age demonstrated patchy periventricular T2 hyperintensities and mild ventricular dilatation (Figure 1A)."
Patient N2 had this MRI finding; it is not established as universal or as a specific demyelinating process.
Focal-onset seizure HP:0007359 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Focal-onset seizure (HP:0007359). HP:0007359 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40990994 SUPPORT PRIMARY RESULT Human Clinical
"Four months after her first seizure, she had an unprovoked focal impaired consciousness seizure."
Patient N3 had an unprovoked focal seizure following an earlier infection-associated bilateral convulsion.
Myoclonic seizure HP:0032794 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myoclonic seizure (HP:0032794). HP:0032794 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40990994 SUPPORT PRIMARY RESULT Human Clinical
"She later developed frequent generalized myoclonic seizures."
The primary clinical account documents this seizure type.
Bilateral tonic-clonic seizure with generalized onset HP:0025190 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral tonic-clonic seizure with generalized onset (HP:0025190). HP:0025190 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40990994 SUPPORT PRIMARY RESULT Human Clinical
"Prolonged focal impaired consciousness seizures and generalized tonic-clonic seizures were documented."
The primary N2 description specifies generalized tonic-clonic seizures.
EEG with photoparoxysmal response HP:0010852 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is EEG with photoparoxysmal response (HP:0010852). HP:0010852 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40990994 SUPPORT PRIMARY RESULT Human Clinical
"EEG showed frequent generalized epileptiform discharges and independent multifocal epileptiform discharges as well as photoparoxysmal response elicited between 9 and 30 Hz that was blocked by blue, red, and green filters."
Patient N3 provides a direct EEG example; the report describes analogous abnormalities in the other two epilepsy-ascertained patients.
Multifocal epileptiform discharges HP:0010841 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Multifocal epileptiform discharges (HP:0010841). HP:0010841 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40990994 SUPPORT PRIMARY RESULT Human Clinical
"EEG showed frequent generalized epileptiform discharges and independent multifocal epileptiform discharges as well as photoparoxysmal response elicited between 9 and 30 Hz that was blocked by blue, red, and green filters."
Patient N3 provides a direct EEG example; the report describes analogous abnormalities in the other two epilepsy-ascertained patients.
EEG with generalized epileptiform discharges HP:0011198 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is EEG with generalized epileptiform discharges (HP:0011198). HP:0011198 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40990994 SUPPORT PRIMARY RESULT Human Clinical
"EEG showed frequent generalized epileptiform discharges and independent multifocal epileptiform discharges as well as photoparoxysmal response elicited between 9 and 30 Hz that was blocked by blue, red, and green filters."
Patient N3 provides a direct EEG example; the report describes analogous abnormalities in the other two epilepsy-ascertained patients.
Growth 2
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40909439 SUPPORT PRIMARY RESULT Human Clinical
"Now, at the age of 6.5 years, the proband exhibits persistent growth retardation according to WHO growth standards, with a height of 1.0 m (−2.3 SD) and a weight of 15 kg (−1.8 SD)."
Height was below two standard deviations in this case; population frequency cannot be inferred.
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32324310 SUPPORT PRIMARY RESULT Human Clinical
"The major features determined by "reverse phenotyping" include significant to profound developmental delays/intellectual disability with absent or delayed speech, epilepsy, ocular abnormalities, cleft lip and/or palate, congenital heart disease, urogenital anomalies, skeletal abnormalities,..."
The primary three-patient series expands the clinical spectrum; this abstract does not provide individual denominators for each finding.
🧬

Genetic Associations

1
Biallelic MED25 variants (Causative)
Gene: MED25 hgnc:28845 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MED25 (hgnc:28845). hgnc:28845 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal Recessive
Show evidence (4 references)
PMID:25792360 SUPPORT PRIMARY RESULT Human Clinical
"Using exome sequencing, we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four..."
The defining clinical series establishes the association between biallelic MED25 variation and a multisystem developmental syndrome; it does not measure the cellular pathway to each manifestation.
PMID:32816121 SUPPORT PRIMARY RESULT Human Clinical
"Whole exome sequencing detected a homozygous frameshift variant in the MED25 gene: NM_030973.3:c.1778_1779delAG, p.(Gln593Argfs)."
The reported homozygous frameshift extends the allelic spectrum beyond VWA-domain missense variants.
PMID:31602195 SUPPORT PRIMARY RESULT Human Clinical
"In addition, haplotype analysis around the variant in both the families revealed that although the variant occurs within a run of homozygosity in the previously reported patients from the consanguineous family, this is not so in the case of the probands reported here: the variant seems to have..."
The full-text haplotype result argues against treating Ile173Thr as an established shared founder allele in these families.
+ 1 more reference
Variants (14)
p.Tyr39Cys
Gene: MED25 hgnc:28845 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MED25 (hgnc:28845). hgnc:28845 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Variant detail: Missense
Genomic context: coding sequence
Homozygous variant reported in seven patients from four families in the same Israeli village. Co-immunoprecipitation demonstrates impaired Mediator association; this result should not be generalized to all MED25 missense alleles.
Show evidence (2 references)
PMID:25792360 SUPPORT PRIMARY RESULT Human Clinical
"Using exome sequencing, we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four..."
The defining clinical series establishes the association between biallelic MED25 variation and a multisystem developmental syndrome; it does not measure the cellular pathway to each manifestation.
PMID:25792360 SUPPORT PRIMARY RESULT In Vitro
"The MED25 point mutation is located in the von Willebrand factor type A (MED25 VWA) domain which is responsible for MED25 recruitment into the Mediator complex; co-immunoprecipitation experiment demonstrated that this mutation dramatically impairs MED25 interaction with the Mediator complex in..."
The recruitment defect was demonstrated for Tyr39Cys; it has not been established experimentally for every reported MED25 allele.
c.518T>C (p.Ile173Thr)
Gene: MED25 hgnc:28845 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MED25 (hgnc:28845). hgnc:28845 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Variant detail: Missense
Genomic context: coding sequence
Homozygous in two affected siblings born to nonconsanguineous Lebanese parents. An earlier patient also carried a COQ8A variant, complicating phenotype attribution. Haplotype analysis did not support a shared founder origin between the families.
Show evidence (3 references)
PMID:31602195 SUPPORT PRIMARY RESULT Human Clinical
"This NM_030973.3:c.518T>C variant is predicted to result in a p.Ile173Thr change in the MED25 protein"
The primary report specifies the transcript-level and protein-level variant.
PMID:31602195 SUPPORT PRIMARY RESULT Human Clinical
"In addition, haplotype analysis around the variant in both the families revealed that although the variant occurs within a run of homozygosity in the previously reported patients from the consanguineous family, this is not so in the case of the probands reported here: the variant seems to have..."
The full-text haplotype result argues against treating Ile173Thr as an established shared founder allele in these families.
PMID:30800049 SUPPORT PRIMARY RESULT Human Clinical
"Potentially causal homozygous variants in the MED25 (p.Ile173Thr) and COQ8A (p.Arg512Trp) genes were found."
The earlier patient carried variants in two genes; the proposed synergistic contribution was not functionally demonstrated. This complicates assigning the ataxia and elevated lactate exclusively to MED25.
c.377A>T (p.Asp126Val) Likely Pathogenic
Gene: MED25 hgnc:28845 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MED25 (hgnc:28845). hgnc:28845 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Variant detail: Missense
Genomic context: coding sequence
Recurrent homozygous allele in the three epilepsy-ascertained Calgary patients from two Lebanese families. The authors describe it as likely pathogenic in their discussion and as a founder allele in their cohort. This does not establish the same founder history for Ile173Thr.
Show evidence (1 reference)
PMID:40990994 SUPPORT PRIMARY RESULT Human Clinical
"In this case series, we described 3 patients from 2 unrelated Lebanese families in Calgary, Alberta, with the same MED25 c.377A>T p.Asp126Val likely pathogenic variant."
Reported classification and clinical recurrence; no variant-specific molecular assay is presented.
c.418C>T (p.Arg140Trp)
Gene: MED25 hgnc:28845 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MED25 (hgnc:28845). hgnc:28845 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Variant detail: Missense
Genomic context: coding sequence
Homozygous variant segregating with syndromic intellectual disability in a Brazilian kindred with seven affected adults. The report identifies two linked regions and computational deleteriousness predictions; those data alone are not an experimentally demonstrated functional defect or an independent ACMG classification.
Show evidence (1 reference)
PMID:25527630 SUPPORT PRIMARY RESULT Human Clinical
"WES disclosed in the critical region of chromosome 19 a homozygous variant (c.418C>T, p.Arg140Trp) in Mediator complex subunit 25 (MED25), predicted as deleterious by PolyPhen-2, Provean, Mutation Taster and Sorting Intolerant From Tolerant (SIFT)."
The family report provides segregation and computational support, without a functional assay in the accessible abstract.
c.1778_1779delAG (p.Gln593Argfs)
Gene: MED25 hgnc:28845 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MED25 (hgnc:28845). hgnc:28845 is a gene from the HUGO Gene Nomenclature Committee. deletion
Variant detail: Frameshift
Genomic context: coding sequence
Homozygous two-base deletion in two sisters with perisylvian polymicrogyria. The reported protein notation does not specify a termination distance, which is not inferred here.
Show evidence (1 reference)
PMID:32816121 SUPPORT PRIMARY RESULT Human Clinical
"Whole exome sequencing detected a homozygous frameshift variant in the MED25 gene: NM_030973.3:c.1778_1779delAG, p.(Gln593Argfs)."
The reported homozygous frameshift extends the allelic spectrum beyond VWA-domain missense variants.
c.1965+1dup Pathogenic
Gene: MED25 hgnc:28845 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MED25 (hgnc:28845). hgnc:28845 is a gene from the HUGO Gene Nomenclature Committee. duplication
Variant detail: Splice-altering intronic duplication
Genomic context: intron
Maternally inherited NM_030973.4 allele in trans with Arg224Gly. Minigenes show intron-16 one-base retention and exon-16 skipping, whereas carrier-mother blood RNA confirms only the retention product. The authors classify the allele as pathogenic after functional assessment; neuronal protein expression was not measured.
Show evidence (2 references)
PMID:40909439 SUPPORT PRIMARY RESULT In Vitro
"In vitro MSA results indicated that the variant c.670C > G (p.R224G) did not disrupt the normal splicing of the MED25 gene (Supplementary Figure S3). In contrast, the variant c.1965 + 1dup affected normal splicing, resulting in two abnormal transcripts: retention of 1 bp in intron 16; skipping..."
Minigenes in HEK293T and HeLa cells distinguish an experimentally demonstrated splice defect from the normal splicing of the missense allele.
PMID:40909439 SUPPORT PRIMARY RESULT Human Clinical
"Using the proband’s father’s sample as a control, we assessed the impact of the mutation on MED25 mRNA splicing in the mother’s blood sample. The results indicated that the mutation c.1965 + 1dup affects the splicing of the MED25 gene in vivo, producing only one abnormal splicing product, a 1 bp..."
Carrier-parent blood RNA supports intron retention, but not the exon-skipping product observed in minigenes. These are blood assays, not neuronal or whole-animal experiments.
c.670C>G (p.Arg224Gly) Likely Pathogenic
Gene: MED25 hgnc:28845 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MED25 (hgnc:28845). hgnc:28845 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Variant detail: Missense
Genomic context: coding sequence
Paternally inherited NM_030973.4 allele in trans with c.1965+1dup. Minigene assays found normal splicing. The authors classify it as likely pathogenic using clinical and computational evidence; a damaging protein-structure effect is predicted, not experimentally demonstrated.
Show evidence (2 references)
PMID:40909439 SUPPORT PRIMARY RESULT In Vitro
"In vitro MSA results indicated that the variant c.670C > G (p.R224G) did not disrupt the normal splicing of the MED25 gene (Supplementary Figure S3). In contrast, the variant c.1965 + 1dup affected normal splicing, resulting in two abnormal transcripts: retention of 1 bp in intron 16; skipping..."
Minigenes in HEK293T and HeLa cells distinguish an experimentally demonstrated splice defect from the normal splicing of the missense allele.
PMID:40909439 SUPPORT PRIMARY RESULT Human Clinical
"and was classified as a likely pathogenic variant (PM2 + PP3 + PM1 + PP4)."
The authors’ final classification concerns Arg224Gly. Their protein effect evidence is computational, not a direct biochemical assay.
c.180+5G>C Likely Pathogenic
Gene: MED25 hgnc:28845 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MED25 (hgnc:28845). hgnc:28845 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Variant detail: Splice-region substitution
Genomic context: intron
Maternal NM_030973.3 allele reported in trans with paternal Arg132Gly. RNA sequencing supports intron-2 retention. The authors classify this allele as likely pathogenic; the second allele remains a VUS, so the pair is not recorded as two established pathogenic alleles.
Show evidence (2 references)
PMID:42663018 SUPPORT PRIMARY RESULT Human Clinical
"Transcriptome sequencing confirmed that the c.180+5G>C variant may cause aberrant splicing with retention of intron 2."
The abstract reports RNA evidence of intron retention; the tissue and detailed assay performance cannot be established from this abstract.
PMID:42663018 SUPPORT PRIMARY RESULT Human Clinical
"Based on the ACMG guidelines, this variant met the criteria PS3+PM2_Supporting+PP3 and was classified as likely pathogenic."
This is the authors’ classification for c.180+5G>C.
c.394C>G (p.Arg132Gly) Uncertain Significance
Gene: MED25 hgnc:28845 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MED25 (hgnc:28845). hgnc:28845 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Variant detail: Missense
Genomic context: coding sequence
Paternally inherited allele in the 2026 child with maternal c.180+5G>C. It remains of uncertain significance despite computational deleteriousness predictions; it is distinct from the previously reported Arg132Cys allele.
Show evidence (1 reference)
PMID:42663018 SUPPORT PRIMARY RESULT Human Clinical
"The c.394C>G (p.Arg132Gly) variant resulted in an amino acid substitution and was predicted to be deleterious by in silico analysis. Based on the ACMG criteria (PM2_Supporting+PMS+PP3), it was classified as a variant of uncertain significance."
The abstract explicitly retains VUS status. The printed criterion string is quoted as reported, not endorsed as an independent ACMG reassessment.
c.1366C>T (p.Gln456Ter)
Gene: MED25 hgnc:28845 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MED25 (hgnc:28845). hgnc:28845 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Variant detail: Nonsense
Genomic context: coding sequence
Maternal truncating allele reported in trans with paternal Leu144Phe in a nine-year-old girl. Functional protein abundance and Mediator incorporation were not measured in the accessible abstract.
Show evidence (1 reference)
PMID:42714655 SUPPORT PRIMARY RESULT Human Clinical
"Trio-based whole-exome sequencing revealed compound heterozygous variants in MED25: a maternally transmitted truncating variant (c.1366 C > T; p.Gln456*) and a paternally inherited missense variant (c.430 C > T; p.Leu144Phe)."
Trio sequencing establishes the reported compound-heterozygous pair and parental origins; the abstract does not provide a directly measured functional effect.
c.430C>T (p.Leu144Phe)
Gene: MED25 hgnc:28845 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MED25 (hgnc:28845). hgnc:28845 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Variant detail: Missense
Genomic context: coding sequence
Paternal allele reported in trans with Gln456Ter. The abstract calls it potentially pathogenic on segregation, phenotype, and computational grounds. No standardized classification is inferred from that wording. Its claimed ACID localization is not used as mechanistic evidence.
Show evidence (1 reference)
PMID:42714655 SUPPORT PRIMARY RESULT Human Clinical
"Trio-based whole-exome sequencing revealed compound heterozygous variants in MED25: a maternally transmitted truncating variant (c.1366 C > T; p.Gln456*) and a paternally inherited missense variant (c.430 C > T; p.Leu144Phe)."
Trio sequencing establishes the reported compound-heterozygous pair and parental origins; the abstract does not provide a directly measured functional effect.
c.316G>A (p.Gly106Arg)
Gene: MED25 hgnc:28845 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MED25 (hgnc:28845). hgnc:28845 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Variant detail: Missense
Genomic context: coding sequence
Reported with c.1165del (p.Leu389SerfsTer35) in a 2020 patient, as summarized in the later epilepsy review. No variant-specific functional assay is established by this table.
Show evidence (1 reference)
PMID:40990994 SUPPORT BACKGROUND Human Clinical
"| MED25 variant | c.377A>T p.D126V homozygous | c.377A>T p.D126V homozygous | c.377A>T p.D126V homozygous | c.418C > T p.R140W homozygous | c.116A > G p.Y39C homozygous | c. 518T>C p.I173T homozygous | c. 518T>C p.I173T homozygous | c.316G > A p.G106R and c.1165delp.L389Sfs*35 | c.394C > T..."
The comparative table summarizes Haynes et al. 2020 variants; this is secondary evidence for those earlier patients.
c.1165del (p.Leu389SerfsTer35)
Gene: MED25 hgnc:28845 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MED25 (hgnc:28845). hgnc:28845 is a gene from the HUGO Gene Nomenclature Committee. deletion
Variant detail: Frameshift
Genomic context: coding sequence
Reported with Gly106Arg in a 2020 patient in the later comparative table. Protein notation is retained as reported, without inferring an unprovided transcript accession.
Show evidence (1 reference)
PMID:40990994 SUPPORT BACKGROUND Human Clinical
"| MED25 variant | c.377A>T p.D126V homozygous | c.377A>T p.D126V homozygous | c.377A>T p.D126V homozygous | c.418C > T p.R140W homozygous | c.116A > G p.Y39C homozygous | c. 518T>C p.I173T homozygous | c. 518T>C p.I173T homozygous | c.316G > A p.G106R and c.1165delp.L389Sfs*35 | c.394C > T..."
The comparative table summarizes Haynes et al. 2020 variants; this is secondary evidence for those earlier patients.
c.394C>T (p.Arg132Cys)
Gene: MED25 hgnc:28845 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MED25 (hgnc:28845). hgnc:28845 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Variant detail: Missense
Genomic context: coding sequence
Homozygous in a 2020 patient, as summarized in the later review. This allele differs from c.394C>G (Arg132Gly), whose 2026 report retains uncertain significance.
Show evidence (1 reference)
PMID:40990994 SUPPORT BACKGROUND Human Clinical
"| MED25 variant | c.377A>T p.D126V homozygous | c.377A>T p.D126V homozygous | c.377A>T p.D126V homozygous | c.418C > T p.R140W homozygous | c.116A > G p.Y39C homozygous | c. 518T>C p.I173T homozygous | c. 518T>C p.I173T homozygous | c.316G > A p.G106R and c.1165delp.L389Sfs*35 | c.394C > T..."
The comparative table summarizes Haynes et al. 2020 variants; this is secondary evidence for those earlier patients.
💊

Medical Actions

7
Supportive Care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Supportive care is tailored to developmental and organ-specific needs. Reported accommodations include ankle-foot orthoses, a walker, and an eye-gaze communication device. These observations do not establish comparative efficacy of a rehabilitation program.
Show evidence (3 references)
PMID:40990994 SUPPORT PRIMARY RESULT Human Clinical
"Developmentally, she is able to ambulate independently with bilateral ankle foot orthoses at 2.5 years of age."
Orthoses were used for mobility support in N3; this is an individual care observation.
PMID:40990994 SUPPORT PRIMARY RESULT Human Clinical
"She uses an eye-gaze, “yes-no” communication device."
Patient N2 used an assistive communication device.
PMID:40990994 SUPPORT PRIMARY RESULT Human Clinical
"At 17 years of age, she sits independently and requires a walker to ambulate."
Patient N2 used a walker for mobility.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Genetic counseling addresses autosomal recessive inheritance, parental carrier testing, and reproductive options after the familial variants have been interpreted. Recurrence counseling should not depend on assuming a founder origin for every recurrent allele.
Show evidence (1 reference)
PMID:25792360 SUPPORT Human Clinical
"we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four unrelated families"
A homozygous MED25 variant in affected individuals provides the genetic basis for counseling; this clinical series is not a trial of a counseling intervention.
Levetiracetam
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: levetiracetam CHEBI:6437 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses levetiracetam (CHEBI:6437). CHEBI:6437 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Seizure freedom was reported in N3, while N2 initially responded and later had recurrence after discontinuation for adverse effects. N1 had behavioral adverse effects. These small uncontrolled observations do not establish a syndrome-specific first-line regimen.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:40990994 SUPPORT PRIMARY RESULT Human Clinical
"She was seizure-free since levetiracetam was started."
The primary report documents seizure freedom in N3.
PMID:40990994 SUPPORT PRIMARY RESULT Human Clinical
"Although the seizures were initially controlled on levetiracetam, the family declined to continue antiseizure medications after the age of 17 years because of adverse effects. This led to a recurrence of monthly generalized tonic-clonic seizures."
N2 initially responded, then relapsed after medication withdrawal.
PMID:40990994 SUPPORT PRIMARY RESULT Human Clinical
"The patient eventually developed side effects to both levetiracetam (withdrawn, hallucination) and clonazepam (sedation), and the family declined to continue antiseizure medication."
N1 stopped both agents because of adverse effects; this cannot be equated with pharmacologic nonresponse.
Clonazepam
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: clonazepam CHEBI:3756 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses clonazepam (CHEBI:3756). CHEBI:3756 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Used with levetiracetam in N1, but sedation contributed to discontinuation. The report does not establish independent clonazepam efficacy.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40990994 SUPPORT PRIMARY RESULT Human Clinical
"The patient eventually developed side effects to both levetiracetam (withdrawn, hallucination) and clonazepam (sedation), and the family declined to continue antiseizure medication."
N1 stopped both agents because of adverse effects; this cannot be equated with pharmacologic nonresponse.
Valproate
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: valproic acid CHEBI:39867 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses valproic acid (CHEBI:39867). CHEBI:39867 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
The later review lists valproate use in the founding cohort. Patient-level dosing, response, and tolerability cannot be determined from this comparative table.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40990994 SUPPORT BACKGROUND Human Clinical
"| Antiseizure medication | Levetiracetam, clonazepam | Levetiracetam | Levetiracetam | NA | Valproate | NA, seizures well controlled | - | NA | NA | NA | Topiramate, oxcarbazepine, levetiracetam |"
The comparative table reports medication exposure in earlier publications, not a comparative trial or agent-specific efficacy estimate.
Topiramate
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: topiramate CHEBI:63631 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses topiramate (CHEBI:63631). CHEBI:63631 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Listed among antiseizure medications used in the Maini sisters in a later review. The table does not establish an independent response to topiramate.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40990994 SUPPORT BACKGROUND Human Clinical
"| Antiseizure medication | Levetiracetam, clonazepam | Levetiracetam | Levetiracetam | NA | Valproate | NA, seizures well controlled | - | NA | NA | NA | Topiramate, oxcarbazepine, levetiracetam |"
The comparative table reports medication exposure in earlier publications, not a comparative trial or agent-specific efficacy estimate.
Oxcarbazepine
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: oxcarbazepine CHEBI:7824 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses oxcarbazepine (CHEBI:7824). CHEBI:7824 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Listed among antiseizure medications used in the Maini sisters in a later review. The table does not establish an independent response to oxcarbazepine.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40990994 SUPPORT BACKGROUND Human Clinical
"| Antiseizure medication | Levetiracetam, clonazepam | Levetiracetam | Levetiracetam | NA | Valproate | NA, seizures well controlled | - | NA | NA | NA | Topiramate, oxcarbazepine, levetiracetam |"
The comparative table reports medication exposure in earlier publications, not a comparative trial or agent-specific efficacy estimate.
🔬

Diagnosis

4
Molecular diagnosis and parental segregation
Exome or genome sequencing can identify biallelic MED25 candidates, followed by confirmation and parental segregation. Variant interpretation must distinguish uncertain missense alleles from functionally supported variants; a VUS is not independently diagnostic.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:31602195 SUPPORT PRIMARY RESULT Human Clinical
"Direct sequencing of the MED25 gene in both affected sibs confirmed the presence of the variant in a homozygous state (Fig. 2)."
Molecular confirmation was used in the affected siblings.
PMID:42663018 SUPPORT PRIMARY RESULT Human Clinical
"The c.394C>G (p.Arg132Gly) variant resulted in an amino acid substitution and was predicted to be deleterious by in silico analysis. Based on the ACMG criteria (PM2_Supporting+PMS+PP3), it was classified as a variant of uncertain significance."
The abstract explicitly retains VUS status. The printed criterion string is quoted as reported, not endorsed as an independent ACMG reassessment.
EEG characterization of suspected seizures
EEG can characterize focal, generalized, and photosensitive discharges and help distinguish epileptic events from behavioral episodes. Laughter or staring alone does not establish a seizure diagnosis.
Electroencephalography NCIT:C38054 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:40990994 SUPPORT PRIMARY RESULT Human Clinical
"Other event types included staring spells and laughing spells that were deemed nonepileptic (behavioral) because of lack of ictal correlate on the EEG."
The N1 evaluation explicitly distinguishes nonepileptic spells from seizures.
Brain MRI assessment
Brain MRI documents variable cortical, callosal, ventricular, and white matter findings. A normal scan does not exclude the disorder.
Magnetic Resonance Imaging NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:40990994 SUPPORT PRIMARY RESULT Human Clinical
"Magnetic response imaging (MRI) of the brain performed at 2 months of age was normal."
Patient N1 had a normal early brain MRI despite the clinical and molecular diagnosis.
PMID:40909439 SUPPORT PRIMARY RESULT Human Clinical
"Additionally, there was bilateral hippocampal volume loss with widening of the temporal horns, and the cavum septum pellucidum was present (Figure 1C)."
The later case illustrates an abnormal MRI phenotype.
Ophthalmological assessment
Assessment characterizes cataracts and other ocular findings. Normal ophthalmological examination has been documented in affected individuals.
Eye Examination NCIT:C38060 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:31602195 SUPPORT PRIMARY RESULT Human Clinical
"Ophthalmological examination, brainstem auditory evoked response, and brain MRI were normal (Table 1)."
The affected boy had a normal eye examination, illustrating variable ocular involvement.
📊

Prevalence

1
Worldwide
Cases In Literature
Population prevalence is unknown. Published reports describe small, sometimes overlapping families and case series. Their patient counts should not be treated as population prevalence estimates or pooled without checking overlap.
Show evidence (1 reference)
PMID:25792360 SUPPORT PRIMARY RESULT Human Clinical
"Using exome sequencing, we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four..."
The defining clinical series establishes the association between biallelic MED25 variation and a multisystem developmental syndrome; it does not measure the cellular pathway to each manifestation.
🧫

Experimental Models

4
Tyr39Cys MED25 expression in 293-HEK cells CELL_LINE
Tagged MED25 proteins were compared by anti-Flag immunoprecipitation and detection of associated Mediator subunits.
Organism
Homo sapiens NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Established 293-HEK cell line
Culture
Transient expression of wild-type or Tyr39Cys Flag-NLS-MED25
Publication
PMID:25792360
Pathograph links
MED25 Mediator incorporation failure measures fidelity: unknown observes: molecular Tests variant-specific MED25 association with Mediator.
Limitations: Overexpression in an established cell line does not establish the magnitude of the defect in patient neurons or palatal tissues. Only Tyr39Cys was compared with wild type.
Readouts
Mediator co-immunoprecipitation
Mediator recruitment was impaired by Tyr39Cys.
Direction: DECREASED
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/figures/4 SUPPORT PRIMARY RESULT In Vitro
"mutation impaired Mediator recruitment. WT or YC mutated Flag-NLS-MED25 was expressed in 293-HEK cells."
The figure caption identifies this as the Y39C MED25 experiment and specifies the tested cell system.
Tagged MED25 production
Wild-type and mutant production was comparable.
Direction: UNCHANGED
Show evidence (1 reference)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/figures/4 SUPPORT PRIMARY RESULT In Vitro
"Anti-Flag detection was also performed to assess precipitation efficiency and comparable WT and YC MED25 production levels"
Comparable tagged-protein production and precipitation controls support an incorporation defect rather than simply absent expression.
Show evidence (2 references)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/figures/4 SUPPORT PRIMARY RESULT In Vitro
"mutation impaired Mediator recruitment. WT or YC mutated Flag-NLS-MED25 was expressed in 293-HEK cells."
The figure caption identifies this as the Y39C MED25 experiment and specifies the tested cell system.
+ 1 more reference
Show evidence (2 references)
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/figures/4 SUPPORT PRIMARY RESULT In Vitro
"mutation impaired Mediator recruitment. WT or YC mutated Flag-NLS-MED25 was expressed in 293-HEK cells."
The figure caption identifies this as the Y39C MED25 experiment and specifies the tested cell system.
url:https://link.springer.com/article/10.1007/s00439-015-1541-x/figures/4 SUPPORT PRIMARY RESULT In Vitro
"Anti-Flag detection was also performed to assess precipitation efficiency and comparable WT and YC MED25 production levels"
Comparable tagged-protein production and precipitation controls support an incorporation defect rather than simply absent expression.
MED25 minigene splice assays in HEK293T and HeLa cells CELL_LINE
The c.1965+1dup construct produces intron retention and exon skipping, whereas c.670C>G does not disrupt splicing in the tested constructs.
Organism
Homo sapiens NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Established HEK293T and HeLa cell lines
Culture
Wild-type and mutant minigene transfection followed by RT-PCR and sequencing
Publication
PMID:40909439
Pathograph links
Abnormal MED25 pre-mRNA splicing measures fidelity: unknown observes: molecular Directly assays RNA-processing consequences of the two reported variants.
Limitations: Minigenes incompletely reproduce endogenous genomic and tissue context. Carrier-mother blood confirms one-base intron retention but not the exon-skipping product; neither experiment measures neuronal protein function.
Readouts
c.1965+1dup transcript products
One-base intron-16 retention and exon-16 skipping occurred in minigenes.
Direction: ALTERED
Show evidence (1 reference)
PMID:40909439 SUPPORT PRIMARY RESULT In Vitro
"In vitro MSA results indicated that the variant c.670C > G (p.R224G) did not disrupt the normal splicing of the MED25 gene (Supplementary Figure S3). In contrast, the variant c.1965 + 1dup affected normal splicing, resulting in two abnormal transcripts: retention of 1 bp in intron 16; skipping..."
Minigenes in HEK293T and HeLa cells distinguish an experimentally demonstrated splice defect from the normal splicing of the missense allele.
Arg224Gly transcript splicing
No splice disruption was observed for c.670C>G.
Direction: UNCHANGED
Show evidence (1 reference)
PMID:40909439 SUPPORT PRIMARY RESULT In Vitro
"In vitro MSA results indicated that the variant c.670C > G (p.R224G) did not disrupt the normal splicing of the MED25 gene (Supplementary Figure S3). In contrast, the variant c.1965 + 1dup affected normal splicing, resulting in two abnormal transcripts: retention of 1 bp in intron 16; skipping..."
Minigenes in HEK293T and HeLa cells distinguish an experimentally demonstrated splice defect from the normal splicing of the missense allele.
Show evidence (2 references)
PMID:40909439 SUPPORT PRIMARY RESULT In Vitro
"In vitro MSA results indicated that the variant c.670C > G (p.R224G) did not disrupt the normal splicing of the MED25 gene (Supplementary Figure S3). In contrast, the variant c.1965 + 1dup affected normal splicing, resulting in two abnormal transcripts: retention of 1 bp in intron 16; skipping..."
Minigenes in HEK293T and HeLa cells distinguish an experimentally demonstrated splice defect from the normal splicing of the missense allele.
+ 1 more reference
Show evidence (2 references)
PMID:40909439 SUPPORT PRIMARY RESULT In Vitro
"In vitro MSA results indicated that the variant c.670C > G (p.R224G) did not disrupt the normal splicing of the MED25 gene (Supplementary Figure S3). In contrast, the variant c.1965 + 1dup affected normal splicing, resulting in two abnormal transcripts: retention of 1 bp in intron 16; skipping..."
Minigenes in HEK293T and HeLa cells distinguish an experimentally demonstrated splice defect from the normal splicing of the missense allele.
PMID:40909439 SUPPORT PRIMARY RESULT In Vitro
"The successfully constructed wild-type/mutant recombinant minigene were transfected into Hela or HEK293T cells."
The assay uses transfected cell lines rather than patient-derived neurons.
Med25 siRNA in C3H10T1/2 mesenchymal cells CELL_LINE
Med25 depletion reduces Col2a1 transcripts in a cell system used to study Sox9-dependent chondrogenesis.
Organism
Mus musculus NCBITaxon:10090 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in Mus musculus (NCBITaxon:10090). NCBITaxon:10090 is an organism from the NCBI Taxonomy.
Cell source
Mouse C3H10T1/2 mesenchymal cell line
Culture
Med25 siRNA with cartilage matrix transcript and reporter assays
Publication
PMID:21427722
Pathograph links
Reduced SOX9-dependent cartilage matrix transcription perturbs fidelity: unknown observes: molecular Perturbs the candidate transcriptional mechanism by depleting Med25.
Limitations: Mouse cell depletion does not test human variants, palatal morphogenesis, or neurodevelopment. The result supports a hypothesis for human palatal disease.
Readouts
Col2a1 transcript abundance
Col2a1 mRNA decreased after Med25 knockdown.
Direction: DECREASED
Show evidence (1 reference)
PMID:21427722 SUPPORT PRIMARY RESULT In Vitro
"Knockdown of either Wwp2 or Med25 in C3H10T1/2 cells resulted in significant downregulation of Col2a1 transcripts (Fig. 5b,c)."
Med25 depletion reduces a cartilage matrix transcript in mouse mesenchymal cells; this is not a patient-allele experiment.
Show evidence (1 reference)
PMID:21427722 SUPPORT PRIMARY RESULT In Vitro
"Knockdown of either Wwp2 or Med25 in C3H10T1/2 cells resulted in significant downregulation of Col2a1 transcripts (Fig. 5b,c)."
Med25 depletion reduces a cartilage matrix transcript in mouse mesenchymal cells; this is not a patient-allele experiment.
Show evidence (1 reference)
PMID:21427722 SUPPORT PRIMARY RESULT In Vitro
"Knockdown of either Wwp2 or Med25 in C3H10T1/2 cells resulted in significant downregulation of Col2a1 transcripts (Fig. 5b,c)."
Med25 depletion reduces a cartilage matrix transcript in mouse mesenchymal cells; this is not a patient-allele experiment.
Sox9–Med25 association in ATDC5 cells CELL_LINE
Wwp2 knockdown attenuates interaction between endogenous Sox9 and HA-tagged Med25.
Organism
Mus musculus NCBITaxon:10090 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in Mus musculus (NCBITaxon:10090). NCBITaxon:10090 is an organism from the NCBI Taxonomy.
Cell source
Mouse ATDC5 chondrogenic cell line
Culture
Tagged Med25 expression and Wwp2 knockdown with co-immunoprecipitation
Publication
PMID:21427722
Pathograph links
Reduced SOX9-dependent cartilage matrix transcription measures fidelity: unknown observes: molecular Measures association of components of the candidate transcriptional complex.
Limitations: This assay perturbs Wwp2, not a BVSYS MED25 allele; physical association is not itself a measurement of human palatal development.
Readouts
Sox9–Med25 association after Wwp2 knockdown
The physical interaction was attenuated.
Direction: DECREASED
Show evidence (1 reference)
PMID:21427722 SUPPORT PRIMARY RESULT In Vitro
"Importantly, knockdown of Wwp2 in ATDC5 cells attenuated the physical interaction between endogenous Sox9 and HA-tagged Med25 (Fig. 5g)."
The chondrogenic cell assay supports Wwp2-dependent Sox9–Med25 association.
Show evidence (1 reference)
PMID:21427722 SUPPORT PRIMARY RESULT In Vitro
"Importantly, knockdown of Wwp2 in ATDC5 cells attenuated the physical interaction between endogenous Sox9 and HA-tagged Med25 (Fig. 5g)."
The chondrogenic cell assay supports Wwp2-dependent Sox9–Med25 association.
Show evidence (1 reference)
PMID:21427722 SUPPORT PRIMARY RESULT In Vitro
"Importantly, knockdown of Wwp2 in ATDC5 cells attenuated the physical interaction between endogenous Sox9 and HA-tagged Med25 (Fig. 5g)."
The chondrogenic cell assay supports Wwp2-dependent Sox9–Med25 association.
🐁

Animal Models

2
Med25-null mouse Knockout
Homozygous Med25-null embryos show variable craniofacial and brain abnormalities at E12.5–E15.5, including anophthalmia, telencephalon hypoplasia, facial clefts, cyclopia, and exencephaly. Perinatal lethality was observed in the E18.5 viability assessment.
Species
Mus musculus
Genotype
Med25−/−
Background
C57BL/6N
Genes
MED25 hgnc:28845 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns MED25 (hgnc:28845). hgnc:28845 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:36551904
Pathograph links
Biallelic MED25 dysfunction perturbs fidelity: unknown observes: tissue Removes Med25 and tests consequences for embryonic development and viability.
Limitations: A null allele is not equivalent to the patient missense alleles. Severe prenatal malformations and lethality limit extrapolation to surviving patients. The paper reports no adult Med25 behavioral results.
Readouts
Embryonic craniofacial and brain morphology
Anatomical abnormalities varied among 12 mutant embryos.
Direction: ALTERED
Show evidence (2 references)
PMID:36551904 SUPPORT PRIMARY RESULT Model Organism
"Gross morphological analysis of Med25−/− mutants at E12.5 and E15.5 revealed different ranges of abnormalities including anophthalmia"
The Med25-null embryos underwent direct anatomical assessment; the study’s adult behavioral findings from other lines cannot be assigned to Med25.
+ 1 more reference
Perinatal viability
Med25-null mice died during the E18.5 viability test.
Show evidence (1 reference)
PMID:36551904 SUPPORT PRIMARY RESULT Model Organism
"three lines displayed perinatal lethality and died during the viability test at E18.5 (Tubb3M388V/+, Kdm5c−/y, Med25−/−)"
Med25-null lethality limits transfer to surviving human patients with other alleles.
Show evidence (3 references)
PMID:36551904 SUPPORT PRIMARY RESULT Model Organism
"Gross morphological analysis of Med25−/− mutants at E12.5 and E15.5 revealed different ranges of abnormalities including anophthalmia"
The Med25-null embryos underwent direct anatomical assessment; the study’s adult behavioral findings from other lines cannot be assigned to Med25.
+ 2 more references
Show evidence (4 references)
PMID:36551904 SUPPORT PRIMARY RESULT Model Organism
"Gross morphological analysis of Med25−/− mutants at E12.5 and E15.5 revealed different ranges of abnormalities including anophthalmia"
The Med25-null embryos underwent direct anatomical assessment; the study’s adult behavioral findings from other lines cannot be assigned to Med25.
PMID:36551904 SUPPORT PRIMARY RESULT Model Organism
"hypoplasia of the telencephalon (three out of twelve mice) (Figure S4, panel D), rhinocephaly with cyclopia (one out of twelve mice) (Figure S4, panels K, H), proboscis (one out of twelve mice) (Figure S4, panel G), facial clefts (two out of twelve mice) (Figure S4, panel E) and exencephaly..."
The reported abnormalities are variable within the 12 Med25-null embryos; these proportions are model observations, not human phenotype frequencies.
PMID:36551904 SUPPORT PRIMARY RESULT Model Organism
"three lines displayed perinatal lethality and died during the viability test at E18.5 (Tubb3M388V/+, Kdm5c−/y, Med25−/−)"
Med25-null lethality limits transfer to surviving human patients with other alleles.
+ 1 more reference
med25 morpholino zebrafish Morpholino knockdown
Transient med25 translation blockade with 5–10 ng morpholino injected at the one- to two-cell stage produces palatal cartilage malformation.
Species
Danio rerio
Background
AB
Publication
PMID:21427722
Pathograph links
Reduced SOX9-dependent cartilage matrix transcription perturbs fidelity: unknown observes: tissue Tests a developmental consequence of med25 depletion consistent with the Sox9-associated palatal hypothesis.
Limitations: Transient knockdown in fish is not a stable genetic allele or a patient variant. Palatal cartilage morphology does not directly measure human cleft palate or neuronal impairment.
Readouts
Palatal cartilage morphology
med25 morphants had palatal malformation.
Direction: ALTERED
Show evidence (1 reference)
PMID:21427722 SUPPORT PRIMARY RESULT Model Organism
"Intriguingly, morpholino-mediated knockdown of med25 in zebrafish resulted in palatal malformation (Fig. 4d), which closely resembled the palatal phenotype of wwp2 or sox9 mutants23 (Fig. 2f)."
Transient zebrafish med25 depletion affects palatal cartilage; neither a stable mutation nor a human disease allele was tested.
Show evidence (2 references)
PMID:21427722 SUPPORT PRIMARY RESULT Model Organism
"Intriguingly, morpholino-mediated knockdown of med25 in zebrafish resulted in palatal malformation (Fig. 4d), which closely resembled the palatal phenotype of wwp2 or sox9 mutants23 (Fig. 2f)."
Transient zebrafish med25 depletion affects palatal cartilage; neither a stable mutation nor a human disease allele was tested.
+ 1 more reference
Co-injected sox9a/sox9b or wwp2 mRNA did not rescue the med25 morphant palate. This is a pathway experiment, not a therapeutic rescue of a human disease allele.
Show evidence (2 references)
PMID:21427722 SUPPORT PRIMARY RESULT Model Organism
"Intriguingly, morpholino-mediated knockdown of med25 in zebrafish resulted in palatal malformation (Fig. 4d), which closely resembled the palatal phenotype of wwp2 or sox9 mutants23 (Fig. 2f)."
Transient zebrafish med25 depletion affects palatal cartilage; neither a stable mutation nor a human disease allele was tested.
PMID:21427722 SUPPORT PRIMARY RESULT Model Organism
"We injected one- or two-cell stage zebrafish embryos with ~1–2 nl of morpholinos (20–25 ng for wwp2 splice blocker-MO and 5–10 ng for med25 ATG blocker)."
The med25 intervention was a translation-blocking morpholino at 5–10 ng; the larger dose applies to wwp2.
{ }

Source YAML

click to show 
name: Basel-Vanagaite-Smirin-Yosef Syndrome
creation_date: '2026-07-31T00:00:00Z'
category: Mendelian
synonyms:
- BVSYS
- MED25-related intellectual disability syndrome
- Eye-intellectual disability syndrome
- MED25-related multiple congenital anomalies-intellectual disability syndrome
- MED-DOCS
- MED25-related developmental disorder
description: Basel-Vanagaite-Smirin-Yosef syndrome is an autosomal recessive neurodevelopmental disorder associated with biallelic MED25 variants. MED25 encodes a subunit of the Mediator transcriptional coactivator complex. Intellectual and speech impairment accompany variable ocular, brain, cardiac, palatal, skeletal, and growth abnormalities; epilepsy and hypotonia are also reported. The allelic spectrum includes missense, truncating, and splice-altering variants. Tyr39Cys impairs MED25 association with Mediator in a cell-based assay, while specific splice variants alter RNA processing. These results do not establish a single molecular defect for all alleles or a resolved cellular pathway to every clinical manifestation.
disease_term:
  preferred_term: Basel-Vanagaite-Smirin-Yosef syndrome
  term:
    id: MONDO:0014643
    label: congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome
parents:
- Autosomal recessive intellectual disability
- Neurodevelopmental disorder
- Mediator complex-associated disorder
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:25792360
      reference_title: Homozygous MED25 mutation implicated in eye-intellectual disability syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four unrelated families
      explanation: Supports classification as a heritable autosomal recessive genetic disorder.
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:25792360
      reference_title: Homozygous MED25 mutation implicated in eye-intellectual disability syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four unrelated families
      explanation: Supports classification as a neurodevelopmental / neurologic disorder.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  notes: Population prevalence is unknown. Published reports describe small, sometimes overlapping families and case series. Their patient counts should not be treated as population prevalence estimates or pooled without checking overlap.
  evidence:
  - reference: PMID:25792360
    reference_title: Homozygous MED25 mutation implicated in eye-intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Using exome sequencing, we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four unrelated families, all originating from the same village.
    explanation: The defining clinical series establishes the association between biallelic MED25 variation and a multisystem developmental syndrome; it does not measure the cellular pathway to each manifestation.
pathophysiology:
- name: Biallelic MED25 dysfunction
  biological_scale: MOLECULAR
  genes:
  - preferred_term: MED25
    term:
      id: hgnc:28845
      label: MED25
  description: Homozygous and compound heterozygous MED25 variants are associated with a variable developmental syndrome. Both missense and truncating alleles have been described, and splice defects have been demonstrated for particular intronic variants. Functional consequences and the strength of pathogenicity evidence differ between alleles.
  evidence:
  - reference: PMID:25792360
    reference_title: Homozygous MED25 mutation implicated in eye-intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Using exome sequencing, we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four unrelated families, all originating from the same village.
    explanation: The defining clinical series establishes the association between biallelic MED25 variation and a multisystem developmental syndrome; it does not measure the cellular pathway to each manifestation.
  - reference: PMID:32816121
    reference_title: 'Improving the phenotype description of Basel-Vanagaite-Smirin-Yosef syndrome, MED25-related: polymicrogyria as a distinctive neuroradiological finding.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 'Whole exome sequencing detected a homozygous frameshift variant in the MED25 gene: NM_030973.3:c.1778_1779delAG, p.(Gln593Argfs).'
    explanation: The reported homozygous frameshift extends the allelic spectrum beyond VWA-domain missense variants.
  downstream:
  - target: MED25 Mediator incorporation failure
    causal_link_type: DIRECT
    description: The Tyr39Cys allele reduces association with Mediator in the tested overexpression system.
    evidence:
    - reference: PMID:25792360
      reference_title: Homozygous MED25 mutation implicated in eye-intellectual disability syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: The MED25 point mutation is located in the von Willebrand factor type A (MED25 VWA) domain which is responsible for MED25 recruitment into the Mediator complex; co-immunoprecipitation experiment demonstrated that this mutation dramatically impairs MED25 interaction with the Mediator complex in mammalian cells.
      explanation: The recruitment defect was demonstrated for Tyr39Cys; it has not been established experimentally for every reported MED25 allele.
  - target: Abnormal MED25 pre-mRNA splicing
    causal_link_type: DIRECT
    description: Specific splice-region alleles alter MED25 RNA processing; this is not a demonstrated consequence of all missense alleles.
    evidence:
    - reference: PMID:40909439
      reference_title: Unraveling the pathogenicity role of the novel compound heterozygous mutations of MED25 gene in a Chinese patient with BVSYS.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: 'In vitro MSA results indicated that the variant c.670C > G (p.R224G) did not disrupt the normal splicing of the MED25 gene (Supplementary Figure S3). In contrast, the variant c.1965 + 1dup affected normal splicing, resulting in two abnormal transcripts: retention of 1 bp in intron 16; skipping of exon 16 (Figure 2).'
      explanation: Minigenes in HEK293T and HeLa cells distinguish an experimentally demonstrated splice defect from the normal splicing of the missense allele.
  - target: Severe intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:25792360
      reference_title: Homozygous MED25 mutation implicated in eye-intellectual disability syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability
      explanation: The original series explicitly describes severe intellectual disability.
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:25792360
      reference_title: Homozygous MED25 mutation implicated in eye-intellectual disability syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability
      explanation: The defining report documents microcephaly; the later Ile173Thr siblings had normal head growth.
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:31602195
      reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Here, we report an additional Lebanese family with 2 affected siblings presenting with severely delayed psychomotor and language development as well as craniofacial anomalies.
      explanation: Both siblings had substantial developmental impairment.
  - target: Absent speech
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:40990994
      reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Developmentally, she did not speak any words and was nonambulatory.
      explanation: Patient N1 had no spoken words at the reported assessment.
  - target: Delayed speech and language development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:31602195
      reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: At 3 years of age, he presented with severely impaired psychomotor and language development.
      explanation: The affected boy had severely impaired language development at age three.
  - target: Loss of speech
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Loss of acquired verbal expression was reported in one affected child; the intervening mechanism is unresolved.
    evidence:
    - reference: PMID:40909439
      reference_title: Unraveling the pathogenicity role of the novel compound heterozygous mutations of MED25 gene in a Chinese patient with BVSYS.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: The patient’s language comprehension remains intact; however, verbal expression has been completely lost.
      explanation: The later case documents expressive language loss, without establishing a uniform progressive course.
  - target: Short stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:40909439
      reference_title: Unraveling the pathogenicity role of the novel compound heterozygous mutations of MED25 gene in a Chinese patient with BVSYS.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Now, at the age of 6.5 years, the proband exhibits persistent growth retardation according to WHO growth standards, with a height of 1.0 m (−2.3 SD) and a weight of 15 kg (−1.8 SD).
      explanation: Height was below two standard deviations in this case; population frequency cannot be inferred.
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Neurological abnormalities ... Hypotonia, later spasticity, seizures
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Spasticity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Neurological abnormalities ... Hypotonia, later spasticity, seizures
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Hyporeflexia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Hypotonia decreased deep tendon reflexes, seizures
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Neurological abnormalities ... Hypotonia, later spasticity, seizures
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Thin corpus callosum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Thin corpus callosum, cavum septum pellucidum and vergae
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Agenesis of corpus callosum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Absent corpus callosum, dilated lateral and third brain ventricles, cerebral parenchymal atrophy
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Ventriculomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Absent corpus callosum, dilated lateral and third brain ventricles, cerebral parenchymal atrophy
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Cerebral atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Absent corpus callosum, dilated lateral and third brain ventricles, cerebral parenchymal atrophy
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Cavum septum pellucidum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Thin corpus callosum, cavum septum pellucidum and vergae
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Developmental cataract
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Eyes ... Ptosis, congenital cataract, amblyopia
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Microcornea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Downslanting palpebral fissures, ptosis, bilateral microcornea
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Microphthalmia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Hypertelorism, downslanting palpebral fissures, microphthlmia, microcornea, high hypermetropia, ptosis, congenital cataract
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Hypermetropia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Hypertelorism, downslanting palpebral fissures, microphthlmia, microcornea, high hypermetropia, ptosis, congenital cataract
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Ptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Eyes ... Ptosis, congenital cataract, amblyopia
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Amblyopia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Eyes ... Ptosis, congenital cataract, amblyopia
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Strabismus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Eyes ... Strabismus
      explanation: Table 1 records strabismus in patient 6; the caption and row heading supply the clinical-table context.
  - target: Cleft palate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Paranasal widening, anteverted nasal tip, short philtrum, cleft palate, retrognathia
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: High palate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Paranasal widening, anteverted nasal tip, high and narrow palate, wide cupid bow, grooved tongue
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Narrow palate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Paranasal widening, anteverted nasal tip, high and narrow palate, wide cupid bow, grooved tongue
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Retrognathia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Paranasal widening, anteverted nasal tip, short philtrum, cleft palate, retrognathia
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Hypertelorism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Hypertelorism, downslanting palpebral fissures, ptosis? Congenital cataract
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Downslanted palpebral fissures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Downslanting palpebral fissures, ptosis, bilateral microcornea
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Low-set ears
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Ears ... Low set ears
      explanation: Table 1 records low-set ears in patient 5; the caption and row heading supply the clinical-table context.
  - target: Short philtrum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Cleft palate, short philtrum, wide cupid bow
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Exaggerated cupid's bow
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Cleft palate, short philtrum, wide cupid bow
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Sparse hair
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Nevus flammeus simplex on the forehead, sparse hair, receding frontal hairline
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Sparse eyebrow
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Nevus flammeus simplex on the forehead, sparse lateral part of the eyebrows
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Nevus flammeus of the forehead
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Nevus flammeus simplex on the forehead, sparse hair, receding frontal hairline
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Atrial septal defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Atrial septal defect, pulmonary hypertension
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Ventricular septal defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:31602195
      reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Cardiac evaluation revealed coarctation of the aorta and a ventricular septal defect.
      explanation: The primary clinical evaluation of the affected boy confirms a ventricular septal defect.
  - target: Elevated pulmonary artery pressure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Atrial septal defect, pulmonary hypertension
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Hypospadias
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Hydronephrosis, bilateral inguinal hernia hypospadias,meatal stenosis
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Hydronephrosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Hydronephrosis, bilateral inguinal hernia hypospadias,meatal stenosis
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Increased size of the clitoris
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Urogenital system ... Clitoromegaly
      explanation: Table 1 records clitoromegaly in patient 4; the caption and row heading supply the clinical-table context.
  - target: Inguinal hernia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Hydronephrosis, bilateral inguinal hernia hypospadias,meatal stenosis
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Male urethral meatus stenosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Hydronephrosis, bilateral inguinal hernia hypospadias,meatal stenosis
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Scoliosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Kyphosis, scoliosis, mild interdigital webbing, broad distal phalanges of toes, syndactyly of 2–3 toes
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Kyphosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Kyphosis, scoliosis, mild interdigital webbing, broad distal phalanges of toes, syndactyly of 2–3 toes
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Broad distal phalanx of the toes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Kyphosis, scoliosis, mild interdigital webbing, broad distal phalanges of toes, syndactyly of 2–3 toes
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: 2-3 toe syndactyly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Syndactyly of 2–3 toes, 3rd finger camptodactyly, overlapping fingers, adducted thumbs
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Camptodactyly of finger
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Syndactyly of 2–3 toes, 3rd finger camptodactyly, overlapping fingers, adducted thumbs
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Single transverse palmar crease
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: 2nd finger deviation, bilateral single transverse palmar crease, clinodactyly
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Pes cavus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Syndactyly of 2–3 toes, 3rd finger camptodactyly, partial single transverse palmar crease, pes cavus
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Adducted thumb
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Syndactyly of 2–3 toes, 3rd finger camptodactyly, overlapping fingers, adducted thumbs
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Overlapping fingers
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Syndactyly of 2–3 toes, 3rd finger camptodactyly, overlapping fingers, adducted thumbs
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Clinodactyly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: 2nd finger deviation, bilateral single transverse palmar crease, clinodactyly
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Pectus carinatum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Skeletal system ... Pectus carinatum, overlapping toes
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Overlapping toe
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Skeletal system ... Pectus carinatum, overlapping toes
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Constipation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Gallbladder calculi, gastrointestinal reflux, constipation
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Gastroesophageal reflux
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Gallbladder calculi, gastrointestinal reflux, constipation
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Cholelithiasis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
      reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Gallbladder calculi, gastrointestinal reflux, constipation
      explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
  - target: Wide anterior fontanel
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:31602195
      reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Upon examination, he had several craniofacial anomalies, including large anterior fontanel, high forehead, sparse scalp hair and eyebrows, flat nasal bridge with a broad nasal tip, hypertelorism, short philtrum, a large mouth with a thin upper lip, and a cleft palate (Fig. 1a).
      explanation: The primary clinical examination of the affected three-year-old boy documents this finding.
  - target: High forehead
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:31602195
      reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Upon examination, he had several craniofacial anomalies, including large anterior fontanel, high forehead, sparse scalp hair and eyebrows, flat nasal bridge with a broad nasal tip, hypertelorism, short philtrum, a large mouth with a thin upper lip, and a cleft palate (Fig. 1a).
      explanation: The primary clinical examination of the affected three-year-old boy documents this finding.
  - target: Depressed nasal bridge
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:31602195
      reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Upon examination, he had several craniofacial anomalies, including large anterior fontanel, high forehead, sparse scalp hair and eyebrows, flat nasal bridge with a broad nasal tip, hypertelorism, short philtrum, a large mouth with a thin upper lip, and a cleft palate (Fig. 1a).
      explanation: The primary clinical examination of the affected three-year-old boy documents this finding.
  - target: Broad nasal tip
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:31602195
      reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Upon examination, he had several craniofacial anomalies, including large anterior fontanel, high forehead, sparse scalp hair and eyebrows, flat nasal bridge with a broad nasal tip, hypertelorism, short philtrum, a large mouth with a thin upper lip, and a cleft palate (Fig. 1a).
      explanation: The primary clinical examination of the affected three-year-old boy documents this finding.
  - target: Wide mouth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:31602195
      reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Upon examination, he had several craniofacial anomalies, including large anterior fontanel, high forehead, sparse scalp hair and eyebrows, flat nasal bridge with a broad nasal tip, hypertelorism, short philtrum, a large mouth with a thin upper lip, and a cleft palate (Fig. 1a).
      explanation: The primary clinical examination of the affected three-year-old boy documents this finding.
  - target: Thin upper lip vermilion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:31602195
      reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Upon examination, he had several craniofacial anomalies, including large anterior fontanel, high forehead, sparse scalp hair and eyebrows, flat nasal bridge with a broad nasal tip, hypertelorism, short philtrum, a large mouth with a thin upper lip, and a cleft palate (Fig. 1a).
      explanation: The primary clinical examination of the affected three-year-old boy documents this finding.
  - target: Coarctation of aorta
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:31602195
      reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Cardiac evaluation revealed coarctation of the aorta and a ventricular septal defect.
      explanation: Cardiac assessment of the affected boy established both defects.
  - target: Bilateral perisylvian polymicrogyria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s10048-020-00625-2/figures/2
      reference_title: 'Figure 2 | Improving the phenotype description of Basel-Vanagaite-Smirin-Yosef syndrome, MED25-related: polymicrogyria as a distinctive neuroradiological finding | Neurogenetics | Springer Nature Link'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: 'T2 coronal view: bilateral perisylvian polymicrogyria.'
      explanation: The MRI caption specifies bilateral perisylvian involvement, supporting a more precise binding than generic polymicrogyria.
  - target: Hippocampal atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:40909439
      reference_title: Unraveling the pathogenicity role of the novel compound heterozygous mutations of MED25 gene in a Chinese patient with BVSYS.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Additionally, there was bilateral hippocampal volume loss with widening of the temporal horns, and the cavum septum pellucidum was present (Figure 1C).
      explanation: The clinical MRI description documents hippocampal volume loss.
  - target: Periventricular white matter hyperintensities
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:40990994
      reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Brain MRI at 12 years of age demonstrated patchy periventricular T2 hyperintensities and mild ventricular dilatation (Figure 1A).
      explanation: Patient N2 had this MRI finding; it is not established as universal or as a specific demyelinating process.
  - target: Duane anomaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:40990994
      reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Other medical conditions include bilateral Duane syndrome, sleep-disordered breathing, systemic hypertension, nephrocalcinosis, hypocalcemia, and gastroesophageal reflux.
      explanation: This case directly documents Duane syndrome; coexisting renal and metabolic findings have potentially confounding SLC34A1 variation.
  - target: Retinal detachment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:40990994
      reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Her medical diagnoses included closed ventricular septal defect, short stature, clubfeet, hypercalcinuria, nephrocalcinosis congenital cataracts, retinal detachments, and glaucoma.
      explanation: The primary patient description records this ocular finding; the list does not demonstrate its independent molecular mechanism.
  - target: Glaucoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:40990994
      reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Her medical diagnoses included closed ventricular septal defect, short stature, clubfeet, hypercalcinuria, nephrocalcinosis congenital cataracts, retinal detachments, and glaucoma.
      explanation: The primary patient description records this ocular finding; the list does not demonstrate its independent molecular mechanism.
  - target: Metatarsus adductus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:40990994
      reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: She had a moderate atrial septal defect and bilateral metatarsus adductus type 1, which were managed conservatively.
      explanation: The primary clinical description documents the foot malformation.
  - target: Focal-onset seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:40990994
      reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Four months after her first seizure, she had an unprovoked focal impaired consciousness seizure.
      explanation: Patient N3 had an unprovoked focal seizure following an earlier infection-associated bilateral convulsion.
  - target: Myoclonic seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:40990994
      reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: She later developed frequent generalized myoclonic seizures.
      explanation: The primary clinical account documents this seizure type.
  - target: Bilateral tonic-clonic seizure with generalized onset
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Observed in individuals with biallelic MED25 variants; the intervening tissue mechanism remains unresolved.
    evidence:
    - reference: PMID:40990994
      reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Prolonged focal impaired consciousness seizures and generalized tonic-clonic seizures were documented.
      explanation: The primary N2 description specifies generalized tonic-clonic seizures.
  - target: Reduced SOX9-dependent cartilage matrix transcription
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - MED25_SOX9_PALATE
    description: Med25 knockdown motivates this candidate pathway; no patient variant has been shown to disrupt Sox9-dependent transcription in the cited experiments.
    evidence:
    - reference: PMID:21427722
      reference_title: Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Knockdown of either Wwp2 or Med25 in C3H10T1/2 cells resulted in significant downregulation of Col2a1 transcripts (Fig. 5b,c).
      explanation: Med25 depletion reduces a cartilage matrix transcript in mouse mesenchymal cells; this is not a patient-allele experiment.
  - target: Cleft lip
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical association with the MED25 developmental disorder; the tissue pathway is unresolved.
    evidence:
    - reference: PMID:32324310
      reference_title: 'Further delineation of Basel-Vanagaite-Smirin-Yosef syndrome: Report of three patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: The major features determined by "reverse phenotyping" include significant to profound developmental delays/intellectual disability with absent or delayed speech, epilepsy, ocular abnormalities, cleft lip and/or palate, congenital heart disease, urogenital anomalies, skeletal abnormalities, brain malformations and/or microcephaly, failure to thrive, and dysmorphic features.
      explanation: The primary three-patient series expands the clinical spectrum; this abstract does not provide individual denominators for each finding.
  - target: Failure to thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Clinical association with the MED25 developmental disorder; the tissue pathway is unresolved.
    evidence:
    - reference: PMID:32324310
      reference_title: 'Further delineation of Basel-Vanagaite-Smirin-Yosef syndrome: Report of three patients.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: The major features determined by "reverse phenotyping" include significant to profound developmental delays/intellectual disability with absent or delayed speech, epilepsy, ocular abnormalities, cleft lip and/or palate, congenital heart disease, urogenital anomalies, skeletal abnormalities, brain malformations and/or microcephaly, failure to thrive, and dysmorphic features.
      explanation: The primary three-patient series expands the clinical spectrum; this abstract does not provide individual denominators for each finding.
- name: MED25 Mediator incorporation failure
  biological_scale: MOLECULAR
  genes:
  - preferred_term: MED25
    term:
      id: hgnc:28845
      label: MED25
  description: The VWA-domain Tyr39Cys substitution impairs association of MED25 with Mediator. The experiment compared tagged wild-type and mutant MED25 expressed in 293-HEK cells, with comparable production and immunoprecipitation efficiency. It does not demonstrate loss of the entire Mediator complex or a shared incorporation defect for all disease-associated alleles.
  evidence:
  - reference: PMID:25792360
    reference_title: Homozygous MED25 mutation implicated in eye-intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: The MED25 point mutation is located in the von Willebrand factor type A (MED25 VWA) domain which is responsible for MED25 recruitment into the Mediator complex; co-immunoprecipitation experiment demonstrated that this mutation dramatically impairs MED25 interaction with the Mediator complex in mammalian cells.
    explanation: The recruitment defect was demonstrated for Tyr39Cys; it has not been established experimentally for every reported MED25 allele.
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/figures/4
    reference_title: Figure 4 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: mutation impaired Mediator recruitment. WT or YC mutated Flag-NLS-MED25 was expressed in 293-HEK cells.
    explanation: The figure caption identifies this as the Y39C MED25 experiment and specifies the tested cell system.
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/figures/4
    reference_title: Figure 4 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Anti-Flag detection was also performed to assess precipitation efficiency and comparable WT and YC MED25 production levels
    explanation: Comparable tagged-protein production and precipitation controls support an incorporation defect rather than simply absent expression.
- name: Abnormal MED25 pre-mRNA splicing
  biological_scale: MOLECULAR
  genes:
  - preferred_term: MED25
    term:
      id: hgnc:28845
      label: MED25
  description: The c.1965+1dup allele generates intron-16 one-base retention and exon-16 skipping in minigene assays. Carrier-mother blood RNA contains the one-base-retention product alongside normally spliced transcript; exon skipping was not demonstrated in that blood experiment. Altered protein products are predicted consequences, whereas neuronal protein abundance and Mediator assembly were not measured. Arg224Gly did not alter splicing in the tested constructs. A separate 2026 report describes intron-2 retention associated with c.180+5G>C.
  evidence:
  - reference: PMID:40909439
    reference_title: Unraveling the pathogenicity role of the novel compound heterozygous mutations of MED25 gene in a Chinese patient with BVSYS.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: 'In vitro MSA results indicated that the variant c.670C > G (p.R224G) did not disrupt the normal splicing of the MED25 gene (Supplementary Figure S3). In contrast, the variant c.1965 + 1dup affected normal splicing, resulting in two abnormal transcripts: retention of 1 bp in intron 16; skipping of exon 16 (Figure 2).'
    explanation: Minigenes in HEK293T and HeLa cells distinguish an experimentally demonstrated splice defect from the normal splicing of the missense allele.
  - reference: PMID:40909439
    reference_title: Unraveling the pathogenicity role of the novel compound heterozygous mutations of MED25 gene in a Chinese patient with BVSYS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Using the proband’s father’s sample as a control, we assessed the impact of the mutation on MED25 mRNA splicing in the mother’s blood sample. The results indicated that the mutation c.1965 + 1dup affects the splicing of the MED25 gene in vivo, producing only one abnormal splicing product, a 1 bp retention at the left side of intron 16.
    explanation: Carrier-parent blood RNA supports intron retention, but not the exon-skipping product observed in minigenes. These are blood assays, not neuronal or whole-animal experiments.
  - reference: PMID:42663018
    reference_title: '[Clinical phenotype and genetic analysis of a child with Basel-Vanagaite-Smirin-Yosef syndrome due to variant of MED25 gene].'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Transcriptome sequencing confirmed that the c.180+5G>C variant may cause aberrant splicing with retention of intron 2.
    explanation: The abstract reports RNA evidence of intron retention; the tissue and detailed assay performance cannot be established from this abstract.
- name: Reduced SOX9-dependent cartilage matrix transcription
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  genes:
  - preferred_term: MED25
    term:
      id: hgnc:28845
      label: MED25
  description: Med25 supports Sox9-dependent cartilage matrix transcription in mouse cell systems. Wwp2 facilitates Sox9–Med25 association, and Med25 depletion reduces Col2a1 expression. Together with zebrafish palatal abnormalities after med25 knockdown, these experiments suggest a possible route to human palatal anomalies. A defect in this pathway has not been demonstrated for BVSYS patient variants or patient palatal tissue.
  evidence:
  - reference: PMID:21427722
    reference_title: Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Knockdown of either Wwp2 or Med25 in C3H10T1/2 cells resulted in significant downregulation of Col2a1 transcripts (Fig. 5b,c).
    explanation: Med25 depletion reduces a cartilage matrix transcript in mouse mesenchymal cells; this is not a patient-allele experiment.
  - reference: PMID:21427722
    reference_title: Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Importantly, knockdown of Wwp2 in ATDC5 cells attenuated the physical interaction between endogenous Sox9 and HA-tagged Med25 (Fig. 5g).
    explanation: The chondrogenic cell assay supports Wwp2-dependent Sox9–Med25 association.
  - reference: PMID:21427722
    reference_title: Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: Intriguingly, morpholino-mediated knockdown of med25 in zebrafish resulted in palatal malformation (Fig. 4d), which closely resembled the palatal phenotype of wwp2 or sox9 mutants23 (Fig. 2f).
    explanation: Transient zebrafish med25 depletion affects palatal cartilage; neither a stable mutation nor a human disease allele was tested.
  downstream:
  - target: Cleft palate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - MED25_SOX9_PALATE
    description: The cellular and zebrafish findings motivate a possible palatal developmental mechanism, but the route from human variants to cleft palate remains untested.
    evidence:
    - reference: PMID:21427722
      reference_title: Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: Intriguingly, morpholino-mediated knockdown of med25 in zebrafish resulted in palatal malformation (Fig. 4d), which closely resembled the palatal phenotype of wwp2 or sox9 mutants23 (Fig. 2f).
      explanation: Transient zebrafish med25 depletion affects palatal cartilage; neither a stable mutation nor a human disease allele was tested.
phenotypes:
- name: Severe intellectual disability
  category: Neurologic
  description: Severe intellectual disability characterizes the founding series. The degree of impairment varies across later reports.
  phenotype_term:
    preferred_term: Severe intellectual disability
    term:
      id: HP:0010864
      label: Severe intellectual disability
  evidence:
  - reference: PMID:25792360
    reference_title: Homozygous MED25 mutation implicated in eye-intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability
    explanation: The original series explicitly describes severe intellectual disability.
- name: Microcephaly
  category: Growth
  description: Microcephaly is reported in several families, but normal head size occurs in others and does not exclude the disorder.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:25792360
    reference_title: Homozygous MED25 mutation implicated in eye-intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability
    explanation: The defining report documents microcephaly; the later Ile173Thr siblings had normal head growth.
  - reference: PMID:31602195
    reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Her OFC was 45.5 cm, length 76 cm, and her weight was 9.5 kg (all at the 50th percentile).
    explanation: Normal head circumference in the affected one-year-old sister refutes universal microcephaly, while leaving its occurrence in other affected individuals intact.
- name: Global developmental delay
  category: Neurologic
  description: Motor and language development can be severely delayed, with variable acquisition of supported sitting and walking.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:31602195
    reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Here, we report an additional Lebanese family with 2 affected siblings presenting with severely delayed psychomotor and language development as well as craniofacial anomalies.
    explanation: Both siblings had substantial developmental impairment.
- name: Absent speech
  category: Neurologic
  description: Speech may remain absent; some individuals communicate through facial expression, sounds, or assistive devices.
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Developmentally, she did not speak any words and was nonambulatory.
    explanation: Patient N1 had no spoken words at the reported assessment.
- name: Delayed speech and language development
  category: Neurologic
  description: Marked language delay accompanies the developmental phenotype.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:31602195
    reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: At 3 years of age, he presented with severely impaired psychomotor and language development.
    explanation: The affected boy had severely impaired language development at age three.
- name: Loss of speech
  category: Neurologic
  description: Loss of verbal expression with preserved language comprehension was reported in one child; this does not establish a uniform progressive course.
  phenotype_term:
    preferred_term: Loss of speech
    term:
      id: HP:0002371
      label: Loss of speech
  evidence:
  - reference: PMID:40909439
    reference_title: Unraveling the pathogenicity role of the novel compound heterozygous mutations of MED25 gene in a Chinese patient with BVSYS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The patient’s language comprehension remains intact; however, verbal expression has been completely lost.
    explanation: The later case documents expressive language loss, without establishing a uniform progressive course.
- name: Short stature
  category: Growth
  description: Short stature occurs in some affected individuals; normal linear growth has also been documented.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:40909439
    reference_title: Unraveling the pathogenicity role of the novel compound heterozygous mutations of MED25 gene in a Chinese patient with BVSYS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Now, at the age of 6.5 years, the proband exhibits persistent growth retardation according to WHO growth standards, with a height of 1.0 m (−2.3 SD) and a weight of 15 kg (−1.8 SD).
    explanation: Height was below two standard deviations in this case; population frequency cannot be inferred.
- name: Hypotonia
  category: Neurologic
  description: Hypotonia can precede later spasticity.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Neurological abnormalities ... Hypotonia, later spasticity, seizures
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Spasticity
  category: Neurologic
  description: Later spasticity was recorded after hypotonia in two patients in the founding table.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Neurological abnormalities ... Hypotonia, later spasticity, seizures
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Hyporeflexia
  category: Neurologic
  description: Reduced deep tendon reflexes were reported in one founding patient.
  phenotype_term:
    preferred_term: Hyporeflexia
    term:
      id: HP:0001265
      label: Hyporeflexia
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Hypotonia decreased deep tendon reflexes, seizures
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Seizure
  category: Neurologic
  description: Epilepsy is variable and can include focal, myoclonic, or generalized tonic-clonic seizures. The founding series and later epilepsy-ascertained cases document this feature.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Neurological abnormalities ... Hypotonia, later spasticity, seizures
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Thin corpus callosum
  category: Neurologic
  description: A thin corpus callosum occurs in several reported patients.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Thin corpus callosum, cavum septum pellucidum and vergae
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Agenesis of corpus callosum
  category: Neurologic
  description: Absence of the corpus callosum was reported in a founding patient with ventriculomegaly and cerebral atrophy.
  phenotype_term:
    preferred_term: Agenesis of corpus callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Absent corpus callosum, dilated lateral and third brain ventricles, cerebral parenchymal atrophy
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Ventriculomegaly
  category: Neurologic
  description: Lateral and third ventricular dilation has been reported; it is not sufficient by itself to infer hydrocephalus.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Absent corpus callosum, dilated lateral and third brain ventricles, cerebral parenchymal atrophy
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Cerebral atrophy
  category: Neurologic
  description: Cerebral parenchymal atrophy was documented in one founding patient.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Absent corpus callosum, dilated lateral and third brain ventricles, cerebral parenchymal atrophy
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Cavum septum pellucidum
  category: Neurologic
  description: A persistent cavum septum pellucidum is among the reported brain imaging findings.
  phenotype_term:
    preferred_term: Cavum septum pellucidum
    term:
      id: HP:0002389
      label: Cavum septum pellucidum
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Thin corpus callosum, cavum septum pellucidum and vergae
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Developmental cataract
  category: Ophthalmologic
  description: Congenital cataracts, sometimes bilateral, are a prominent but non-universal ocular finding.
  phenotype_term:
    preferred_term: Developmental cataract
    term:
      id: HP:0000519
      label: Developmental cataract
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Eyes ... Ptosis, congenital cataract, amblyopia
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Microcornea
  category: Ophthalmologic
  description: Microcornea, including bilateral involvement, occurs in the founding series.
  phenotype_term:
    preferred_term: Microcornea
    term:
      id: HP:0000482
      label: Microcornea
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Downslanting palpebral fissures, ptosis, bilateral microcornea
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Microphthalmia
  category: Ophthalmologic
  description: Microphthalmia was reported together with microcornea and cataract in one founding patient.
  phenotype_term:
    preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Hypertelorism, downslanting palpebral fissures, microphthlmia, microcornea, high hypermetropia, ptosis, congenital cataract
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Hypermetropia
  category: Ophthalmologic
  description: Marked hypermetropia was reported with other structural eye abnormalities.
  phenotype_term:
    preferred_term: Hypermetropia
    term:
      id: HP:0000540
      label: Hypermetropia
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Hypertelorism, downslanting palpebral fissures, microphthlmia, microcornea, high hypermetropia, ptosis, congenital cataract
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Ptosis
  category: Ophthalmologic
  description: Ptosis is a variable ocular finding.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Eyes ... Ptosis, congenital cataract, amblyopia
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Amblyopia
  category: Ophthalmologic
  description: Amblyopia was reported in a patient with congenital cataract and ptosis.
  phenotype_term:
    preferred_term: Amblyopia
    term:
      id: HP:0000646
      label: Amblyopia
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Eyes ... Ptosis, congenital cataract, amblyopia
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Strabismus
  category: Ophthalmologic
  description: Strabismus was reported in one founding patient.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Eyes ... Strabismus
    explanation: Table 1 records strabismus in patient 6; the caption and row heading supply the clinical-table context.
- name: Cleft palate
  category: Craniofacial
  description: Cleft palate occurs in some families and is not obligatory.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Paranasal widening, anteverted nasal tip, short philtrum, cleft palate, retrognathia
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: High palate
  category: Craniofacial
  description: A high palate can occur without a reported cleft.
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Paranasal widening, anteverted nasal tip, high and narrow palate, wide cupid bow, grooved tongue
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Narrow palate
  category: Craniofacial
  description: A narrow palate was described with a high palatal arch.
  phenotype_term:
    preferred_term: Narrow palate
    term:
      id: HP:0000189
      label: Narrow palate
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Paranasal widening, anteverted nasal tip, high and narrow palate, wide cupid bow, grooved tongue
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Retrognathia
  category: Craniofacial
  description: Retrognathia was reported in a founding patient.
  phenotype_term:
    preferred_term: Retrognathia
    term:
      id: HP:0000278
      label: Retrognathia
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Paranasal widening, anteverted nasal tip, short philtrum, cleft palate, retrognathia
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Hypertelorism
  category: Craniofacial
  description: Hypertelorism is part of the variable facial phenotype.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Hypertelorism, downslanting palpebral fissures, ptosis? Congenital cataract
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Downslanted palpebral fissures
  category: Craniofacial
  description: Downslanted palpebral fissures occur in several founding patients.
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Downslanting palpebral fissures, ptosis, bilateral microcornea
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Low-set ears
  category: Craniofacial
  description: Low-set ears were recorded in one founding patient.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Ears ... Low set ears
    explanation: Table 1 records low-set ears in patient 5; the caption and row heading supply the clinical-table context.
- name: Short philtrum
  category: Craniofacial
  description: A short philtrum is reported across multiple families.
  phenotype_term:
    preferred_term: Short philtrum
    term:
      id: HP:0000322
      label: Short philtrum
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Cleft palate, short philtrum, wide cupid bow
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Exaggerated cupid's bow
  category: Craniofacial
  description: A wide Cupid’s bow was described in several founding patients.
  phenotype_term:
    preferred_term: Exaggerated cupid's bow
    term:
      id: HP:0002263
      label: Exaggerated cupid's bow
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Cleft palate, short philtrum, wide cupid bow
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Sparse hair
  category: Dermatologic
  description: Sparse scalp hair may accompany a receding frontal hairline.
  phenotype_term:
    preferred_term: Sparse hair
    term:
      id: HP:0008070
      label: Sparse hair
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Nevus flammeus simplex on the forehead, sparse hair, receding frontal hairline
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Sparse eyebrow
  category: Dermatologic
  description: Sparse eyebrows, including their lateral portions, have been described.
  phenotype_term:
    preferred_term: Sparse eyebrow
    term:
      id: HP:0045075
      label: Sparse eyebrow
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Nevus flammeus simplex on the forehead, sparse lateral part of the eyebrows
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Nevus flammeus of the forehead
  category: Dermatologic
  description: The founding series describes nevus flammeus simplex on the forehead.
  phenotype_term:
    preferred_term: Nevus flammeus of the forehead
    term:
      id: HP:0007413
      label: Nevus flammeus of the forehead
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Nevus flammeus simplex on the forehead, sparse hair, receding frontal hairline
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Atrial septal defect
  category: Cardiovascular
  description: Atrial septal defects occur in some affected individuals.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Atrial septal defect, pulmonary hypertension
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Ventricular septal defect
  category: Cardiovascular
  description: Ventricular septal defects are among the congenital cardiac findings.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:31602195
    reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Cardiac evaluation revealed coarctation of the aorta and a ventricular septal defect.
    explanation: The primary clinical evaluation of the affected boy confirms a ventricular septal defect.
- name: Elevated pulmonary artery pressure
  category: Cardiovascular
  description: Pulmonary hypertension was reported in one founding patient with an atrial septal defect. Its hemodynamic subtype was not specified.
  phenotype_term:
    preferred_term: Elevated pulmonary artery pressure
    term:
      id: HP:0004890
      label: Elevated pulmonary artery pressure
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Atrial septal defect, pulmonary hypertension
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Hypospadias
  category: Genitourinary
  description: Hypospadias was recorded in the male patients detailed in the founding table.
  phenotype_term:
    preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Hydronephrosis, bilateral inguinal hernia hypospadias,meatal stenosis
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Hydronephrosis
  category: Genitourinary
  description: Hydronephrosis was reported in one founding patient.
  phenotype_term:
    preferred_term: Hydronephrosis
    term:
      id: HP:0000126
      label: Hydronephrosis
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Hydronephrosis, bilateral inguinal hernia hypospadias,meatal stenosis
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Increased size of the clitoris
  category: Genitourinary
  description: Clitoromegaly was reported in one founding patient.
  phenotype_term:
    preferred_term: Increased size of the clitoris
    term:
      id: HP:0040253
      label: Increased size of the clitoris
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Urogenital system ... Clitoromegaly
    explanation: Table 1 records clitoromegaly in patient 4; the caption and row heading supply the clinical-table context.
- name: Inguinal hernia
  category: Genitourinary
  description: Bilateral inguinal hernia was reported in one founding patient.
  phenotype_term:
    preferred_term: Inguinal hernia
    term:
      id: HP:0000023
      label: Inguinal hernia
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Hydronephrosis, bilateral inguinal hernia hypospadias,meatal stenosis
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Male urethral meatus stenosis
  category: Genitourinary
  description: Meatal stenosis was reported with hypospadias in one male patient.
  phenotype_term:
    preferred_term: Male urethral meatus stenosis
    term:
      id: HP:0032077
      label: Male urethral meatus stenosis
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Hydronephrosis, bilateral inguinal hernia hypospadias,meatal stenosis
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Scoliosis
  category: Musculoskeletal
  description: Scoliosis was reported with kyphosis.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Kyphosis, scoliosis, mild interdigital webbing, broad distal phalanges of toes, syndactyly of 2–3 toes
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Kyphosis
  category: Musculoskeletal
  description: Kyphosis was reported with scoliosis.
  phenotype_term:
    preferred_term: Kyphosis
    term:
      id: HP:0002808
      label: Kyphosis
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Kyphosis, scoliosis, mild interdigital webbing, broad distal phalanges of toes, syndactyly of 2–3 toes
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Broad distal phalanx of the toes
  category: Musculoskeletal
  description: Broad distal toe phalanges were recorded in one founding patient.
  phenotype_term:
    preferred_term: Broad distal phalanx of the toes
    term:
      id: HP:0010186
      label: Broad distal phalanx of the toes
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Kyphosis, scoliosis, mild interdigital webbing, broad distal phalanges of toes, syndactyly of 2–3 toes
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: 2-3 toe syndactyly
  category: Musculoskeletal
  description: Syndactyly of the second and third toes was reported in several founding patients.
  phenotype_term:
    preferred_term: 2-3 toe syndactyly
    term:
      id: HP:0004691
      label: 2-3 toe syndactyly
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Syndactyly of 2–3 toes, 3rd finger camptodactyly, overlapping fingers, adducted thumbs
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Camptodactyly of finger
  category: Musculoskeletal
  description: Third-finger camptodactyly was described in two founding patients.
  phenotype_term:
    preferred_term: Camptodactyly of finger
    term:
      id: HP:0100490
      label: Camptodactyly of finger
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Syndactyly of 2–3 toes, 3rd finger camptodactyly, overlapping fingers, adducted thumbs
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Single transverse palmar crease
  category: Musculoskeletal
  description: Single transverse palmar creases may be partial or bilateral.
  phenotype_term:
    preferred_term: Single transverse palmar crease
    term:
      id: HP:0000954
      label: Single transverse palmar crease
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 2nd finger deviation, bilateral single transverse palmar crease, clinodactyly
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Pes cavus
  category: Musculoskeletal
  description: Pes cavus was reported in one founding patient.
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Syndactyly of 2–3 toes, 3rd finger camptodactyly, partial single transverse palmar crease, pes cavus
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Adducted thumb
  category: Musculoskeletal
  description: Adducted thumbs were reported with other finger abnormalities.
  phenotype_term:
    preferred_term: Adducted thumb
    term:
      id: HP:0001181
      label: Adducted thumb
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Syndactyly of 2–3 toes, 3rd finger camptodactyly, overlapping fingers, adducted thumbs
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Overlapping fingers
  category: Musculoskeletal
  description: Overlapping fingers were described in one founding patient.
  phenotype_term:
    preferred_term: Overlapping fingers
    term:
      id: HP:0010557
      label: Overlapping fingers
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Syndactyly of 2–3 toes, 3rd finger camptodactyly, overlapping fingers, adducted thumbs
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Clinodactyly
  category: Musculoskeletal
  description: Clinodactyly was reported in one founding patient.
  phenotype_term:
    preferred_term: Clinodactyly
    term:
      id: HP:0030084
      label: Clinodactyly
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 2nd finger deviation, bilateral single transverse palmar crease, clinodactyly
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Pectus carinatum
  category: Musculoskeletal
  description: Pectus carinatum was reported with overlapping toes.
  phenotype_term:
    preferred_term: Pectus carinatum
    term:
      id: HP:0000768
      label: Pectus carinatum
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Skeletal system ... Pectus carinatum, overlapping toes
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Overlapping toe
  category: Musculoskeletal
  description: Overlapping toes were reported in one founding patient.
  phenotype_term:
    preferred_term: Overlapping toe
    term:
      id: HP:0001845
      label: Overlapping toe
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Table 1 Summary of the Clinical Data of six Individuals with MED25 Mutation ... Skeletal system ... Pectus carinatum, overlapping toes
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Constipation
  category: Gastrointestinal
  description: Constipation is reported in several founding patients.
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Gallbladder calculi, gastrointestinal reflux, constipation
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Gastroesophageal reflux
  category: Gastrointestinal
  description: Reflux is reported in the clinical series and later case descriptions.
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Gallbladder calculi, gastrointestinal reflux, constipation
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Cholelithiasis
  category: Gastrointestinal
  description: Gallbladder calculi were recorded in one founding patient.
  phenotype_term:
    preferred_term: Cholelithiasis
    term:
      id: HP:0001081
      label: Cholelithiasis
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/tables/1
    reference_title: Table 1 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Gallbladder calculi, gastrointestinal reflux, constipation
    explanation: The primary clinical table records this finding in the affected individuals it describes; no population frequency is inferred.
- name: Wide anterior fontanel
  category: Craniofacial
  description: An enlarged anterior fontanel was reported at age three.
  phenotype_term:
    preferred_term: Wide anterior fontanel
    term:
      id: HP:0000260
      label: Wide anterior fontanel
  evidence:
  - reference: PMID:31602195
    reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Upon examination, he had several craniofacial anomalies, including large anterior fontanel, high forehead, sparse scalp hair and eyebrows, flat nasal bridge with a broad nasal tip, hypertelorism, short philtrum, a large mouth with a thin upper lip, and a cleft palate (Fig. 1a).
    explanation: The primary clinical examination of the affected three-year-old boy documents this finding.
- name: High forehead
  category: Craniofacial
  description: A high forehead is part of the reported facial phenotype.
  phenotype_term:
    preferred_term: High forehead
    term:
      id: HP:0000348
      label: High forehead
  evidence:
  - reference: PMID:31602195
    reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Upon examination, he had several craniofacial anomalies, including large anterior fontanel, high forehead, sparse scalp hair and eyebrows, flat nasal bridge with a broad nasal tip, hypertelorism, short philtrum, a large mouth with a thin upper lip, and a cleft palate (Fig. 1a).
    explanation: The primary clinical examination of the affected three-year-old boy documents this finding.
- name: Depressed nasal bridge
  category: Craniofacial
  description: A flat nasal bridge was described in the Ile173Thr family.
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - reference: PMID:31602195
    reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Upon examination, he had several craniofacial anomalies, including large anterior fontanel, high forehead, sparse scalp hair and eyebrows, flat nasal bridge with a broad nasal tip, hypertelorism, short philtrum, a large mouth with a thin upper lip, and a cleft palate (Fig. 1a).
    explanation: The primary clinical examination of the affected three-year-old boy documents this finding.
- name: Broad nasal tip
  category: Craniofacial
  description: A broad nasal tip was described in the Ile173Thr family.
  phenotype_term:
    preferred_term: Broad nasal tip
    term:
      id: HP:0000455
      label: Broad nasal tip
  evidence:
  - reference: PMID:31602195
    reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Upon examination, he had several craniofacial anomalies, including large anterior fontanel, high forehead, sparse scalp hair and eyebrows, flat nasal bridge with a broad nasal tip, hypertelorism, short philtrum, a large mouth with a thin upper lip, and a cleft palate (Fig. 1a).
    explanation: The primary clinical examination of the affected three-year-old boy documents this finding.
- name: Wide mouth
  category: Craniofacial
  description: A large mouth was recorded in the affected boy.
  phenotype_term:
    preferred_term: Wide mouth
    term:
      id: HP:0000154
      label: Wide mouth
  evidence:
  - reference: PMID:31602195
    reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Upon examination, he had several craniofacial anomalies, including large anterior fontanel, high forehead, sparse scalp hair and eyebrows, flat nasal bridge with a broad nasal tip, hypertelorism, short philtrum, a large mouth with a thin upper lip, and a cleft palate (Fig. 1a).
    explanation: The primary clinical examination of the affected three-year-old boy documents this finding.
- name: Thin upper lip vermilion
  category: Craniofacial
  description: A thin upper lip was described with a large mouth.
  phenotype_term:
    preferred_term: Thin upper lip vermilion
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  evidence:
  - reference: PMID:31602195
    reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Upon examination, he had several craniofacial anomalies, including large anterior fontanel, high forehead, sparse scalp hair and eyebrows, flat nasal bridge with a broad nasal tip, hypertelorism, short philtrum, a large mouth with a thin upper lip, and a cleft palate (Fig. 1a).
    explanation: The primary clinical examination of the affected three-year-old boy documents this finding.
- name: Coarctation of aorta
  category: Cardiovascular
  description: Coarctation of the aorta was reported in one affected boy with a ventricular septal defect.
  phenotype_term:
    preferred_term: Coarctation of aorta
    term:
      id: HP:0001680
      label: Coarctation of aorta
  evidence:
  - reference: PMID:31602195
    reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Cardiac evaluation revealed coarctation of the aorta and a ventricular septal defect.
    explanation: Cardiac assessment of the affected boy established both defects.
- name: Bilateral perisylvian polymicrogyria
  category: Neurologic
  description: Perisylvian polymicrogyria was reported in two sisters with a homozygous frameshift; bilateral involvement is explicitly shown for the older sister.
  phenotype_term:
    preferred_term: Bilateral perisylvian polymicrogyria
    term:
      id: HP:0032407
      label: Bilateral perisylvian polymicrogyria
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s10048-020-00625-2/figures/2
    reference_title: 'Figure 2 | Improving the phenotype description of Basel-Vanagaite-Smirin-Yosef syndrome, MED25-related: polymicrogyria as a distinctive neuroradiological finding | Neurogenetics | Springer Nature Link'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 'T2 coronal view: bilateral perisylvian polymicrogyria.'
    explanation: The MRI caption specifies bilateral perisylvian involvement, supporting a more precise binding than generic polymicrogyria.
- name: Hippocampal atrophy
  category: Neurologic
  description: Bilateral hippocampal volume loss was reported in the later compound-heterozygous case.
  phenotype_term:
    preferred_term: Hippocampal atrophy
    term:
      id: HP:0410170
      label: Hippocampal atrophy
  evidence:
  - reference: PMID:40909439
    reference_title: Unraveling the pathogenicity role of the novel compound heterozygous mutations of MED25 gene in a Chinese patient with BVSYS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Additionally, there was bilateral hippocampal volume loss with widening of the temporal horns, and the cavum septum pellucidum was present (Figure 1C).
    explanation: The clinical MRI description documents hippocampal volume loss.
- name: Periventricular white matter hyperintensities
  category: Neurologic
  description: Patchy periventricular T2 hyperintensities were reported in one Asp126Val patient.
  phenotype_term:
    preferred_term: Periventricular white matter hyperintensities
    term:
      id: HP:0030891
      label: Periventricular white matter hyperintensities
  evidence:
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Brain MRI at 12 years of age demonstrated patchy periventricular T2 hyperintensities and mild ventricular dilatation (Figure 1A).
    explanation: Patient N2 had this MRI finding; it is not established as universal or as a specific demyelinating process.
- name: Duane anomaly
  category: Ophthalmologic
  description: Bilateral Duane syndrome was documented in patient N1 of the Asp126Val epilepsy series.
  phenotype_term:
    preferred_term: Duane anomaly
    term:
      id: HP:0009921
      label: Duane anomaly
  evidence:
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Other medical conditions include bilateral Duane syndrome, sleep-disordered breathing, systemic hypertension, nephrocalcinosis, hypocalcemia, and gastroesophageal reflux.
    explanation: This case directly documents Duane syndrome; coexisting renal and metabolic findings have potentially confounding SLC34A1 variation.
- name: Retinal detachment
  category: Ophthalmologic
  description: Retinal detachment was reported in patient N2 with congenital cataracts.
  phenotype_term:
    preferred_term: Retinal detachment
    term:
      id: HP:0000541
      label: Retinal detachment
  evidence:
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Her medical diagnoses included closed ventricular septal defect, short stature, clubfeet, hypercalcinuria, nephrocalcinosis congenital cataracts, retinal detachments, and glaucoma.
    explanation: The primary patient description records this ocular finding; the list does not demonstrate its independent molecular mechanism.
- name: Glaucoma
  category: Ophthalmologic
  description: Glaucoma was reported in patient N2 with congenital cataracts.
  phenotype_term:
    preferred_term: Glaucoma
    term:
      id: HP:0000501
      label: Glaucoma
  evidence:
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Her medical diagnoses included closed ventricular septal defect, short stature, clubfeet, hypercalcinuria, nephrocalcinosis congenital cataracts, retinal detachments, and glaucoma.
    explanation: The primary patient description records this ocular finding; the list does not demonstrate its independent molecular mechanism.
- name: Metatarsus adductus
  category: Musculoskeletal
  description: Bilateral metatarsus adductus was documented in the third Asp126Val patient.
  phenotype_term:
    preferred_term: Metatarsus adductus
    term:
      id: HP:0001840
      label: Metatarsus adductus
  evidence:
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: She had a moderate atrial septal defect and bilateral metatarsus adductus type 1, which were managed conservatively.
    explanation: The primary clinical description documents the foot malformation.
- name: Focal-onset seizure
  category: Neurologic
  description: Focal seizures with preserved or impaired consciousness occur in the epilepsy series.
  phenotype_term:
    preferred_term: Focal-onset seizure
    term:
      id: HP:0007359
      label: Focal-onset seizure
  evidence:
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Four months after her first seizure, she had an unprovoked focal impaired consciousness seizure.
    explanation: Patient N3 had an unprovoked focal seizure following an earlier infection-associated bilateral convulsion.
- name: Myoclonic seizure
  category: Neurologic
  description: Generalized myoclonic seizures developed in patient N1.
  phenotype_term:
    preferred_term: Myoclonic seizure
    term:
      id: HP:0032794
      label: Myoclonic seizure
  evidence:
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: She later developed frequent generalized myoclonic seizures.
    explanation: The primary clinical account documents this seizure type.
- name: Bilateral tonic-clonic seizure with generalized onset
  category: Neurologic
  description: Generalized tonic-clonic seizures were documented in patient N2. The onset of the first bilateral convulsion in N3 was uncertain and is not used to establish generalized onset.
  phenotype_term:
    preferred_term: Bilateral tonic-clonic seizure with generalized onset
    term:
      id: HP:0025190
      label: Bilateral tonic-clonic seizure with generalized onset
  evidence:
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Prolonged focal impaired consciousness seizures and generalized tonic-clonic seizures were documented.
    explanation: The primary N2 description specifies generalized tonic-clonic seizures.
- name: EEG with photoparoxysmal response
  category: Neurologic
  description: Photoparoxysmal responses were recorded in all three epilepsy-ascertained Asp126Val cases. This small selected series does not establish a syndrome-wide frequency.
  phenotype_term:
    preferred_term: EEG with photoparoxysmal response
    term:
      id: HP:0010852
      label: EEG with photoparoxysmal response
  evidence:
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: EEG showed frequent generalized epileptiform discharges and independent multifocal epileptiform discharges as well as photoparoxysmal response elicited between 9 and 30 Hz that was blocked by blue, red, and green filters.
    explanation: Patient N3 provides a direct EEG example; the report describes analogous abnormalities in the other two epilepsy-ascertained patients.
  electrophysiology:
    electrophysiology_modality: EEG
  reports_on:
  - target: Seizure
    relationship: CORRELATES_WITH
    description: An EEG correlate of the epilepsy phenotype; a discharge is not by itself a clinical seizure.
    evidence:
    - reference: PMID:40990994
      reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: EEG showed frequent generalized epileptiform discharges and independent multifocal epileptiform discharges as well as photoparoxysmal response elicited between 9 and 30 Hz that was blocked by blue, red, and green filters.
      explanation: Patient N3 provides a direct EEG example; the report describes analogous abnormalities in the other two epilepsy-ascertained patients.
- name: Multifocal epileptiform discharges
  category: Neurologic
  description: Independent multifocal epileptiform discharges were documented in the Asp126Val epilepsy series.
  phenotype_term:
    preferred_term: Multifocal epileptiform discharges
    term:
      id: HP:0010841
      label: Multifocal epileptiform discharges
  evidence:
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: EEG showed frequent generalized epileptiform discharges and independent multifocal epileptiform discharges as well as photoparoxysmal response elicited between 9 and 30 Hz that was blocked by blue, red, and green filters.
    explanation: Patient N3 provides a direct EEG example; the report describes analogous abnormalities in the other two epilepsy-ascertained patients.
  electrophysiology:
    electrophysiology_modality: EEG
  reports_on:
  - target: Seizure
    relationship: CORRELATES_WITH
    description: An EEG correlate of the epilepsy phenotype; a discharge is not by itself a clinical seizure.
    evidence:
    - reference: PMID:40990994
      reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: EEG showed frequent generalized epileptiform discharges and independent multifocal epileptiform discharges as well as photoparoxysmal response elicited between 9 and 30 Hz that was blocked by blue, red, and green filters.
      explanation: Patient N3 provides a direct EEG example; the report describes analogous abnormalities in the other two epilepsy-ascertained patients.
- name: EEG with generalized epileptiform discharges
  category: Neurologic
  description: Generalized epileptiform discharges can coexist with focal or multifocal abnormalities.
  phenotype_term:
    preferred_term: EEG with generalized epileptiform discharges
    term:
      id: HP:0011198
      label: EEG with generalized epileptiform discharges
  evidence:
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: EEG showed frequent generalized epileptiform discharges and independent multifocal epileptiform discharges as well as photoparoxysmal response elicited between 9 and 30 Hz that was blocked by blue, red, and green filters.
    explanation: Patient N3 provides a direct EEG example; the report describes analogous abnormalities in the other two epilepsy-ascertained patients.
  electrophysiology:
    electrophysiology_modality: EEG
  reports_on:
  - target: Seizure
    relationship: CORRELATES_WITH
    description: An EEG correlate of the epilepsy phenotype; a discharge is not by itself a clinical seizure.
    evidence:
    - reference: PMID:40990994
      reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: EEG showed frequent generalized epileptiform discharges and independent multifocal epileptiform discharges as well as photoparoxysmal response elicited between 9 and 30 Hz that was blocked by blue, red, and green filters.
      explanation: Patient N3 provides a direct EEG example; the report describes analogous abnormalities in the other two epilepsy-ascertained patients.
- name: Cleft lip
  category: Craniofacial
  description: Cleft lip, with or without palatal clefting, is included in the later case-series phenotype.
  phenotype_term:
    preferred_term: Cleft lip
    term:
      id: HP:0410030
      label: Cleft lip
  evidence:
  - reference: PMID:32324310
    reference_title: 'Further delineation of Basel-Vanagaite-Smirin-Yosef syndrome: Report of three patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The major features determined by "reverse phenotyping" include significant to profound developmental delays/intellectual disability with absent or delayed speech, epilepsy, ocular abnormalities, cleft lip and/or palate, congenital heart disease, urogenital anomalies, skeletal abnormalities, brain malformations and/or microcephaly, failure to thrive, and dysmorphic features.
    explanation: The primary three-patient series expands the clinical spectrum; this abstract does not provide individual denominators for each finding.
- name: Failure to thrive
  category: Growth
  description: Failure to thrive occurs in the expanded clinical spectrum; normal growth in other families demonstrates variability.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:32324310
    reference_title: 'Further delineation of Basel-Vanagaite-Smirin-Yosef syndrome: Report of three patients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The major features determined by "reverse phenotyping" include significant to profound developmental delays/intellectual disability with absent or delayed speech, epilepsy, ocular abnormalities, cleft lip and/or palate, congenital heart disease, urogenital anomalies, skeletal abnormalities, brain malformations and/or microcephaly, failure to thrive, and dysmorphic features.
    explanation: The primary three-patient series expands the clinical spectrum; this abstract does not provide individual denominators for each finding.
genetic:
- name: Biallelic MED25 variants
  association: Causative
  gene_term:
    preferred_term: MED25
    term:
      id: hgnc:28845
      label: MED25
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:25792360
      reference_title: Homozygous MED25 mutation implicated in eye-intellectual disability syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four unrelated families
      explanation: Homozygous MED25 variants in affected individuals support autosomal recessive inheritance. Consanguinity is not required in every family.
  features: Homozygous and compound heterozygous missense, frameshift, nonsense, and splice-region variants have been reported. Tyr39Cys has functional evidence of impaired Mediator association. The recurrent Ile173Thr allele was initially reported with a COQ8A variant and subsequently in two affected siblings; haplotype analysis did not support a shared founder origin for those Lebanese families. Some recently reported missense alleles remain uncertain or have only computational functional support.
  evidence:
  - reference: PMID:25792360
    reference_title: Homozygous MED25 mutation implicated in eye-intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Using exome sequencing, we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four unrelated families, all originating from the same village.
    explanation: The defining clinical series establishes the association between biallelic MED25 variation and a multisystem developmental syndrome; it does not measure the cellular pathway to each manifestation.
  - reference: PMID:32816121
    reference_title: 'Improving the phenotype description of Basel-Vanagaite-Smirin-Yosef syndrome, MED25-related: polymicrogyria as a distinctive neuroradiological finding.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 'Whole exome sequencing detected a homozygous frameshift variant in the MED25 gene: NM_030973.3:c.1778_1779delAG, p.(Gln593Argfs).'
    explanation: The reported homozygous frameshift extends the allelic spectrum beyond VWA-domain missense variants.
  - reference: PMID:31602195
    reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 'In addition, haplotype analysis around the variant in both the families revealed that although the variant occurs within a run of homozygosity in the previously reported patients from the consanguineous family, this is not so in the case of the probands reported here: the variant seems to have an independent origin in the 2 alleles, ruling out the presence of a founder mutation.'
    explanation: The full-text haplotype result argues against treating Ile173Thr as an established shared founder allele in these families.
  - reference: PMID:30039206
    reference_title: The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: In conclusion, we provide evidence that PNKP is the main gene related to CMT2B2 instead of MED25, and that it should be considered as a gene involved in an axonal peripheral neuropathy with late age onset, cerebellar atrophy, and with or without oculomotor apraxia.
    explanation: The reassessment prevents importing the superseded MED25 neuropathy attribution into this developmental syndrome.
  variants:
  - name: p.Tyr39Cys
    gene:
      preferred_term: MED25
      term:
        id: hgnc:28845
        label: MED25
    type: Missense
    variant_type: single nucleotide variant
    genomic_contexts:
    - coding sequence
    description: Homozygous variant reported in seven patients from four families in the same Israeli village. Co-immunoprecipitation demonstrates impaired Mediator association; this result should not be generalized to all MED25 missense alleles.
    evidence:
    - reference: PMID:25792360
      reference_title: Homozygous MED25 mutation implicated in eye-intellectual disability syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Using exome sequencing, we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four unrelated families, all originating from the same village.
      explanation: The defining clinical series establishes the association between biallelic MED25 variation and a multisystem developmental syndrome; it does not measure the cellular pathway to each manifestation.
    - reference: PMID:25792360
      reference_title: Homozygous MED25 mutation implicated in eye-intellectual disability syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: The MED25 point mutation is located in the von Willebrand factor type A (MED25 VWA) domain which is responsible for MED25 recruitment into the Mediator complex; co-immunoprecipitation experiment demonstrated that this mutation dramatically impairs MED25 interaction with the Mediator complex in mammalian cells.
      explanation: The recruitment defect was demonstrated for Tyr39Cys; it has not been established experimentally for every reported MED25 allele.
  - name: c.518T>C (p.Ile173Thr)
    gene:
      preferred_term: MED25
      term:
        id: hgnc:28845
        label: MED25
    type: Missense
    variant_type: single nucleotide variant
    genomic_contexts:
    - coding sequence
    description: Homozygous in two affected siblings born to nonconsanguineous Lebanese parents. An earlier patient also carried a COQ8A variant, complicating phenotype attribution. Haplotype analysis did not support a shared founder origin between the families.
    evidence:
    - reference: PMID:31602195
      reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: This NM_030973.3:c.518T>C variant is predicted to result in a p.Ile173Thr change in the MED25 protein
      explanation: The primary report specifies the transcript-level and protein-level variant.
    - reference: PMID:31602195
      reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: 'In addition, haplotype analysis around the variant in both the families revealed that although the variant occurs within a run of homozygosity in the previously reported patients from the consanguineous family, this is not so in the case of the probands reported here: the variant seems to have an independent origin in the 2 alleles, ruling out the presence of a founder mutation.'
      explanation: The full-text haplotype result argues against treating Ile173Thr as an established shared founder allele in these families.
    - reference: PMID:30800049
      reference_title: 'COQ8A and MED25 Mutations in a Child with Intellectual Disability, Microcephaly, Seizures, and Spastic Ataxia: Synergistic Effect of Digenic Variants?'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Potentially causal homozygous variants in the MED25 (p.Ile173Thr) and COQ8A (p.Arg512Trp) genes were found.
      explanation: The earlier patient carried variants in two genes; the proposed synergistic contribution was not functionally demonstrated. This complicates assigning the ataxia and elevated lactate exclusively to MED25.
  - name: c.377A>T (p.Asp126Val)
    gene:
      preferred_term: MED25
      term:
        id: hgnc:28845
        label: MED25
    type: Missense
    variant_type: single nucleotide variant
    genomic_contexts:
    - coding sequence
    description: Recurrent homozygous allele in the three epilepsy-ascertained Calgary patients from two Lebanese families. The authors describe it as likely pathogenic in their discussion and as a founder allele in their cohort. This does not establish the same founder history for Ile173Thr.
    evidence:
    - reference: PMID:40990994
      reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: In this case series, we described 3 patients from 2 unrelated Lebanese families in Calgary, Alberta, with the same MED25 c.377A>T p.Asp126Val likely pathogenic variant.
      explanation: Reported classification and clinical recurrence; no variant-specific molecular assay is presented.
    clinical_significance: LIKELY_PATHOGENIC
  - name: c.418C>T (p.Arg140Trp)
    gene:
      preferred_term: MED25
      term:
        id: hgnc:28845
        label: MED25
    type: Missense
    variant_type: single nucleotide variant
    genomic_contexts:
    - coding sequence
    description: Homozygous variant segregating with syndromic intellectual disability in a Brazilian kindred with seven affected adults. The report identifies two linked regions and computational deleteriousness predictions; those data alone are not an experimentally demonstrated functional defect or an independent ACMG classification.
    evidence:
    - reference: PMID:25527630
      reference_title: Homozygous missense mutation in MED25 segregates with syndromic intellectual disability in a large consanguineous family.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: WES disclosed in the critical region of chromosome 19 a homozygous variant (c.418C>T, p.Arg140Trp) in Mediator complex subunit 25 (MED25), predicted as deleterious by PolyPhen-2, Provean, Mutation Taster and Sorting Intolerant From Tolerant (SIFT).
      explanation: The family report provides segregation and computational support, without a functional assay in the accessible abstract.
  - name: c.1778_1779delAG (p.Gln593Argfs)
    gene:
      preferred_term: MED25
      term:
        id: hgnc:28845
        label: MED25
    type: Frameshift
    variant_type: deletion
    genomic_contexts:
    - coding sequence
    description: Homozygous two-base deletion in two sisters with perisylvian polymicrogyria. The reported protein notation does not specify a termination distance, which is not inferred here.
    evidence:
    - reference: PMID:32816121
      reference_title: 'Improving the phenotype description of Basel-Vanagaite-Smirin-Yosef syndrome, MED25-related: polymicrogyria as a distinctive neuroradiological finding.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: 'Whole exome sequencing detected a homozygous frameshift variant in the MED25 gene: NM_030973.3:c.1778_1779delAG, p.(Gln593Argfs).'
      explanation: The reported homozygous frameshift extends the allelic spectrum beyond VWA-domain missense variants.
  - name: c.1965+1dup
    gene:
      preferred_term: MED25
      term:
        id: hgnc:28845
        label: MED25
    type: Splice-altering intronic duplication
    variant_type: duplication
    genomic_contexts:
    - intron
    description: Maternally inherited NM_030973.4 allele in trans with Arg224Gly. Minigenes show intron-16 one-base retention and exon-16 skipping, whereas carrier-mother blood RNA confirms only the retention product. The authors classify the allele as pathogenic after functional assessment; neuronal protein expression was not measured.
    evidence:
    - reference: PMID:40909439
      reference_title: Unraveling the pathogenicity role of the novel compound heterozygous mutations of MED25 gene in a Chinese patient with BVSYS.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: 'In vitro MSA results indicated that the variant c.670C > G (p.R224G) did not disrupt the normal splicing of the MED25 gene (Supplementary Figure S3). In contrast, the variant c.1965 + 1dup affected normal splicing, resulting in two abnormal transcripts: retention of 1 bp in intron 16; skipping of exon 16 (Figure 2).'
      explanation: Minigenes in HEK293T and HeLa cells distinguish an experimentally demonstrated splice defect from the normal splicing of the missense allele.
    - reference: PMID:40909439
      reference_title: Unraveling the pathogenicity role of the novel compound heterozygous mutations of MED25 gene in a Chinese patient with BVSYS.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Using the proband’s father’s sample as a control, we assessed the impact of the mutation on MED25 mRNA splicing in the mother’s blood sample. The results indicated that the mutation c.1965 + 1dup affects the splicing of the MED25 gene in vivo, producing only one abnormal splicing product, a 1 bp retention at the left side of intron 16.
      explanation: Carrier-parent blood RNA supports intron retention, but not the exon-skipping product observed in minigenes. These are blood assays, not neuronal or whole-animal experiments.
    clinical_significance: PATHOGENIC
  - name: c.670C>G (p.Arg224Gly)
    gene:
      preferred_term: MED25
      term:
        id: hgnc:28845
        label: MED25
    type: Missense
    variant_type: single nucleotide variant
    genomic_contexts:
    - coding sequence
    description: Paternally inherited NM_030973.4 allele in trans with c.1965+1dup. Minigene assays found normal splicing. The authors classify it as likely pathogenic using clinical and computational evidence; a damaging protein-structure effect is predicted, not experimentally demonstrated.
    evidence:
    - reference: PMID:40909439
      reference_title: Unraveling the pathogenicity role of the novel compound heterozygous mutations of MED25 gene in a Chinese patient with BVSYS.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: 'In vitro MSA results indicated that the variant c.670C > G (p.R224G) did not disrupt the normal splicing of the MED25 gene (Supplementary Figure S3). In contrast, the variant c.1965 + 1dup affected normal splicing, resulting in two abnormal transcripts: retention of 1 bp in intron 16; skipping of exon 16 (Figure 2).'
      explanation: Minigenes in HEK293T and HeLa cells distinguish an experimentally demonstrated splice defect from the normal splicing of the missense allele.
    - reference: PMID:40909439
      reference_title: Unraveling the pathogenicity role of the novel compound heterozygous mutations of MED25 gene in a Chinese patient with BVSYS.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: and was classified as a likely pathogenic variant (PM2 + PP3 + PM1 + PP4).
      explanation: The authors’ final classification concerns Arg224Gly. Their protein effect evidence is computational, not a direct biochemical assay.
    clinical_significance: LIKELY_PATHOGENIC
  - name: c.180+5G>C
    gene:
      preferred_term: MED25
      term:
        id: hgnc:28845
        label: MED25
    type: Splice-region substitution
    variant_type: single nucleotide variant
    genomic_contexts:
    - intron
    description: Maternal NM_030973.3 allele reported in trans with paternal Arg132Gly. RNA sequencing supports intron-2 retention. The authors classify this allele as likely pathogenic; the second allele remains a VUS, so the pair is not recorded as two established pathogenic alleles.
    evidence:
    - reference: PMID:42663018
      reference_title: '[Clinical phenotype and genetic analysis of a child with Basel-Vanagaite-Smirin-Yosef syndrome due to variant of MED25 gene].'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Transcriptome sequencing confirmed that the c.180+5G>C variant may cause aberrant splicing with retention of intron 2.
      explanation: The abstract reports RNA evidence of intron retention; the tissue and detailed assay performance cannot be established from this abstract.
    - reference: PMID:42663018
      reference_title: '[Clinical phenotype and genetic analysis of a child with Basel-Vanagaite-Smirin-Yosef syndrome due to variant of MED25 gene].'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Based on the ACMG guidelines, this variant met the criteria PS3+PM2_Supporting+PP3 and was classified as likely pathogenic.
      explanation: This is the authors’ classification for c.180+5G>C.
    clinical_significance: LIKELY_PATHOGENIC
  - name: c.394C>G (p.Arg132Gly)
    gene:
      preferred_term: MED25
      term:
        id: hgnc:28845
        label: MED25
    type: Missense
    variant_type: single nucleotide variant
    genomic_contexts:
    - coding sequence
    description: Paternally inherited allele in the 2026 child with maternal c.180+5G>C. It remains of uncertain significance despite computational deleteriousness predictions; it is distinct from the previously reported Arg132Cys allele.
    evidence:
    - reference: PMID:42663018
      reference_title: '[Clinical phenotype and genetic analysis of a child with Basel-Vanagaite-Smirin-Yosef syndrome due to variant of MED25 gene].'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: The c.394C>G (p.Arg132Gly) variant resulted in an amino acid substitution and was predicted to be deleterious by in silico analysis. Based on the ACMG criteria (PM2_Supporting+PMS+PP3), it was classified as a variant of uncertain significance.
      explanation: The abstract explicitly retains VUS status. The printed criterion string is quoted as reported, not endorsed as an independent ACMG reassessment.
    clinical_significance: UNCERTAIN_SIGNIFICANCE
  - name: c.1366C>T (p.Gln456Ter)
    gene:
      preferred_term: MED25
      term:
        id: hgnc:28845
        label: MED25
    type: Nonsense
    variant_type: single nucleotide variant
    genomic_contexts:
    - coding sequence
    description: Maternal truncating allele reported in trans with paternal Leu144Phe in a nine-year-old girl. Functional protein abundance and Mediator incorporation were not measured in the accessible abstract.
    evidence:
    - reference: PMID:42714655
      reference_title: 'Expansion of the allelic and phenotypic spectrum of MED25-related developmental disorder: novel compound heterozygous variants with structural domain implications.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: 'Trio-based whole-exome sequencing revealed compound heterozygous variants in MED25: a maternally transmitted truncating variant (c.1366 C > T; p.Gln456*) and a paternally inherited missense variant (c.430 C > T; p.Leu144Phe).'
      explanation: Trio sequencing establishes the reported compound-heterozygous pair and parental origins; the abstract does not provide a directly measured functional effect.
  - name: c.430C>T (p.Leu144Phe)
    gene:
      preferred_term: MED25
      term:
        id: hgnc:28845
        label: MED25
    type: Missense
    variant_type: single nucleotide variant
    genomic_contexts:
    - coding sequence
    description: Paternal allele reported in trans with Gln456Ter. The abstract calls it potentially pathogenic on segregation, phenotype, and computational grounds. No standardized classification is inferred from that wording. Its claimed ACID localization is not used as mechanistic evidence.
    evidence:
    - reference: PMID:42714655
      reference_title: 'Expansion of the allelic and phenotypic spectrum of MED25-related developmental disorder: novel compound heterozygous variants with structural domain implications.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: 'Trio-based whole-exome sequencing revealed compound heterozygous variants in MED25: a maternally transmitted truncating variant (c.1366 C > T; p.Gln456*) and a paternally inherited missense variant (c.430 C > T; p.Leu144Phe).'
      explanation: Trio sequencing establishes the reported compound-heterozygous pair and parental origins; the abstract does not provide a directly measured functional effect.
  - name: c.316G>A (p.Gly106Arg)
    gene:
      preferred_term: MED25
      term:
        id: hgnc:28845
        label: MED25
    type: Missense
    variant_type: single nucleotide variant
    genomic_contexts:
    - coding sequence
    description: Reported with c.1165del (p.Leu389SerfsTer35) in a 2020 patient, as summarized in the later epilepsy review. No variant-specific functional assay is established by this table.
    evidence:
    - reference: PMID:40990994
      reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: '| MED25 variant | c.377A>T p.D126V homozygous | c.377A>T p.D126V homozygous | c.377A>T p.D126V homozygous | c.418C > T p.R140W homozygous | c.116A > G p.Y39C homozygous | c. 518T>C p.I173T homozygous | c. 518T>C p.I173T homozygous | c.316G > A p.G106R and c.1165delp.L389Sfs*35 | c.394C > T p.R132C homozygous | c.377A>T p.D126V homozygous | c. 1778 1779delAG p.Q593Rfs? Homozygous |'
      explanation: The comparative table summarizes Haynes et al. 2020 variants; this is secondary evidence for those earlier patients.
  - name: c.1165del (p.Leu389SerfsTer35)
    gene:
      preferred_term: MED25
      term:
        id: hgnc:28845
        label: MED25
    type: Frameshift
    variant_type: deletion
    genomic_contexts:
    - coding sequence
    description: Reported with Gly106Arg in a 2020 patient in the later comparative table. Protein notation is retained as reported, without inferring an unprovided transcript accession.
    evidence:
    - reference: PMID:40990994
      reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: '| MED25 variant | c.377A>T p.D126V homozygous | c.377A>T p.D126V homozygous | c.377A>T p.D126V homozygous | c.418C > T p.R140W homozygous | c.116A > G p.Y39C homozygous | c. 518T>C p.I173T homozygous | c. 518T>C p.I173T homozygous | c.316G > A p.G106R and c.1165delp.L389Sfs*35 | c.394C > T p.R132C homozygous | c.377A>T p.D126V homozygous | c. 1778 1779delAG p.Q593Rfs? Homozygous |'
      explanation: The comparative table summarizes Haynes et al. 2020 variants; this is secondary evidence for those earlier patients.
  - name: c.394C>T (p.Arg132Cys)
    gene:
      preferred_term: MED25
      term:
        id: hgnc:28845
        label: MED25
    type: Missense
    variant_type: single nucleotide variant
    genomic_contexts:
    - coding sequence
    description: Homozygous in a 2020 patient, as summarized in the later review. This allele differs from c.394C>G (Arg132Gly), whose 2026 report retains uncertain significance.
    evidence:
    - reference: PMID:40990994
      reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: '| MED25 variant | c.377A>T p.D126V homozygous | c.377A>T p.D126V homozygous | c.377A>T p.D126V homozygous | c.418C > T p.R140W homozygous | c.116A > G p.Y39C homozygous | c. 518T>C p.I173T homozygous | c. 518T>C p.I173T homozygous | c.316G > A p.G106R and c.1165delp.L389Sfs*35 | c.394C > T p.R132C homozygous | c.377A>T p.D126V homozygous | c. 1778 1779delAG p.Q593Rfs? Homozygous |'
      explanation: The comparative table summarizes Haynes et al. 2020 variants; this is secondary evidence for those earlier patients.
  notes: 'The clinical spectrum is variable and published series can overlap. Robust allele-specific penetrance estimates and formal molecular subtypes have not been established in the cited reports. The older MED25–CMT2B2 attribution should not be treated as an established allelic neuropathy: subsequent segregation implicates PNKP as the principal cause in that pedigree.'
treatments:
- name: Supportive Care
  description: Supportive care is tailored to developmental and organ-specific needs. Reported accommodations include ankle-foot orthoses, a walker, and an eye-gaze communication device. These observations do not establish comparative efficacy of a rehabilitation program.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Developmentally, she is able to ambulate independently with bilateral ankle foot orthoses at 2.5 years of age.
    explanation: Orthoses were used for mobility support in N3; this is an individual care observation.
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: She uses an eye-gaze, “yes-no” communication device.
    explanation: Patient N2 used an assistive communication device.
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: At 17 years of age, she sits independently and requires a walker to ambulate.
    explanation: Patient N2 used a walker for mobility.
- name: Genetic Counseling
  description: Genetic counseling addresses autosomal recessive inheritance, parental carrier testing, and reproductive options after the familial variants have been interpreted. Recurrence counseling should not depend on assuming a founder origin for every recurrent allele.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:25792360
    reference_title: Homozygous MED25 mutation implicated in eye-intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we have been able to identify homozygous mutation p.(Tyr39Cys) in MED25 as the cause of a syndrome characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability in seven patients from four unrelated families
    explanation: A homozygous MED25 variant in affected individuals provides the genetic basis for counseling; this clinical series is not a trial of a counseling intervention.
- name: Levetiracetam
  description: Seizure freedom was reported in N3, while N2 initially responded and later had recurrence after discontinuation for adverse effects. N1 had behavioral adverse effects. These small uncontrolled observations do not establish a syndrome-specific first-line regimen.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levetiracetam
      term:
        id: CHEBI:6437
        label: levetiracetam
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: She was seizure-free since levetiracetam was started.
    explanation: The primary report documents seizure freedom in N3.
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Although the seizures were initially controlled on levetiracetam, the family declined to continue antiseizure medications after the age of 17 years because of adverse effects. This led to a recurrence of monthly generalized tonic-clonic seizures.
    explanation: N2 initially responded, then relapsed after medication withdrawal.
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The patient eventually developed side effects to both levetiracetam (withdrawn, hallucination) and clonazepam (sedation), and the family declined to continue antiseizure medication.
    explanation: N1 stopped both agents because of adverse effects; this cannot be equated with pharmacologic nonresponse.
- name: Clonazepam
  description: Used with levetiracetam in N1, but sedation contributed to discontinuation. The report does not establish independent clonazepam efficacy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: clonazepam
      term:
        id: CHEBI:3756
        label: clonazepam
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The patient eventually developed side effects to both levetiracetam (withdrawn, hallucination) and clonazepam (sedation), and the family declined to continue antiseizure medication.
    explanation: N1 stopped both agents because of adverse effects; this cannot be equated with pharmacologic nonresponse.
- name: Valproate
  description: The later review lists valproate use in the founding cohort. Patient-level dosing, response, and tolerability cannot be determined from this comparative table.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: valproic acid
      term:
        id: CHEBI:39867
        label: valproic acid
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: '| Antiseizure medication | Levetiracetam, clonazepam | Levetiracetam | Levetiracetam | NA | Valproate | NA, seizures well controlled | - | NA | NA | NA | Topiramate, oxcarbazepine, levetiracetam |'
    explanation: The comparative table reports medication exposure in earlier publications, not a comparative trial or agent-specific efficacy estimate.
- name: Topiramate
  description: Listed among antiseizure medications used in the Maini sisters in a later review. The table does not establish an independent response to topiramate.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: topiramate
      term:
        id: CHEBI:63631
        label: topiramate
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: '| Antiseizure medication | Levetiracetam, clonazepam | Levetiracetam | Levetiracetam | NA | Valproate | NA, seizures well controlled | - | NA | NA | NA | Topiramate, oxcarbazepine, levetiracetam |'
    explanation: The comparative table reports medication exposure in earlier publications, not a comparative trial or agent-specific efficacy estimate.
- name: Oxcarbazepine
  description: Listed among antiseizure medications used in the Maini sisters in a later review. The table does not establish an independent response to oxcarbazepine.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: oxcarbazepine
      term:
        id: CHEBI:7824
        label: oxcarbazepine
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: '| Antiseizure medication | Levetiracetam, clonazepam | Levetiracetam | Levetiracetam | NA | Valproate | NA, seizures well controlled | - | NA | NA | NA | Topiramate, oxcarbazepine, levetiracetam |'
    explanation: The comparative table reports medication exposure in earlier publications, not a comparative trial or agent-specific efficacy estimate.
mechanistic_hypotheses:
- hypothesis_group_id: MED25_SOX9_PALATE
  hypothesis_label: MED25-dependent SOX9 transcription and palatal development
  status: EMERGING
  description: A model-supported hypothesis for a subset of palatal manifestations. Human variant effects on the SOX9–WWP2–MED25 transcriptional complex and cartilage matrix production have not been established.
  evidence:
  - reference: PMID:21427722
    reference_title: Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Knockdown of either Wwp2 or Med25 in C3H10T1/2 cells resulted in significant downregulation of Col2a1 transcripts (Fig. 5b,c).
    explanation: Med25 depletion reduces a cartilage matrix transcript in mouse mesenchymal cells; this is not a patient-allele experiment.
  - reference: PMID:21427722
    reference_title: Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Importantly, knockdown of Wwp2 in ATDC5 cells attenuated the physical interaction between endogenous Sox9 and HA-tagged Med25 (Fig. 5g).
    explanation: The chondrogenic cell assay supports Wwp2-dependent Sox9–Med25 association.
  - reference: PMID:21427722
    reference_title: Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: Intriguingly, morpholino-mediated knockdown of med25 in zebrafish resulted in palatal malformation (Fig. 4d), which closely resembled the palatal phenotype of wwp2 or sox9 mutants23 (Fig. 2f).
    explanation: Transient zebrafish med25 depletion affects palatal cartilage; neither a stable mutation nor a human disease allele was tested.
experimental_models:
- name: Tyr39Cys MED25 expression in 293-HEK cells
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Established 293-HEK cell line
  culture_system: Transient expression of wild-type or Tyr39Cys Flag-NLS-MED25
  publication: PMID:25792360
  description: Tagged MED25 proteins were compared by anti-Flag immunoprecipitation and detection of associated Mediator subunits.
  evidence:
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/figures/4
    reference_title: Figure 4 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: mutation impaired Mediator recruitment. WT or YC mutated Flag-NLS-MED25 was expressed in 293-HEK cells.
    explanation: The figure caption identifies this as the Y39C MED25 experiment and specifies the tested cell system.
  - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/figures/4
    reference_title: Figure 4 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Anti-Flag detection was also performed to assess precipitation efficiency and comparable WT and YC MED25 production levels
    explanation: Comparable tagged-protein production and precipitation controls support an incorporation defect rather than simply absent expression.
  modeled_mechanisms:
  - target: MED25 Mediator incorporation failure
    relationship: MEASURES
    description: Tests variant-specific MED25 association with Mediator.
    model_scale: MOLECULAR
    fidelity: UNKNOWN
    limitations: Overexpression in an established cell line does not establish the magnitude of the defect in patient neurons or palatal tissues. Only Tyr39Cys was compared with wild type.
    evidence:
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/figures/4
      reference_title: Figure 4 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: mutation impaired Mediator recruitment. WT or YC mutated Flag-NLS-MED25 was expressed in 293-HEK cells.
      explanation: The figure caption identifies this as the Y39C MED25 experiment and specifies the tested cell system.
    - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/figures/4
      reference_title: Figure 4 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Anti-Flag detection was also performed to assess precipitation efficiency and comparable WT and YC MED25 production levels
      explanation: Comparable tagged-protein production and precipitation controls support an incorporation defect rather than simply absent expression.
    readouts:
    - target: MED25 Mediator incorporation failure
      name: Mediator co-immunoprecipitation
      description: Mediator recruitment was impaired by Tyr39Cys.
      evidence:
      - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/figures/4
        reference_title: Figure 4 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: mutation impaired Mediator recruitment. WT or YC mutated Flag-NLS-MED25 was expressed in 293-HEK cells.
        explanation: The figure caption identifies this as the Y39C MED25 experiment and specifies the tested cell system.
      direction: DECREASED
    - target: MED25 Mediator incorporation failure
      name: Tagged MED25 production
      description: Wild-type and mutant production was comparable.
      evidence:
      - reference: url:https://link.springer.com/article/10.1007/s00439-015-1541-x/figures/4
        reference_title: Figure 4 | Homozygous MED25 mutation implicated in eye–intellectual disability syndrome | Human Genetics | Springer Nature Link
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: Anti-Flag detection was also performed to assess precipitation efficiency and comparable WT and YC MED25 production levels
        explanation: Comparable tagged-protein production and precipitation controls support an incorporation defect rather than simply absent expression.
      direction: UNCHANGED
- name: MED25 minigene splice assays in HEK293T and HeLa cells
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Established HEK293T and HeLa cell lines
  culture_system: Wild-type and mutant minigene transfection followed by RT-PCR and sequencing
  publication: PMID:40909439
  description: The c.1965+1dup construct produces intron retention and exon skipping, whereas c.670C>G does not disrupt splicing in the tested constructs.
  evidence:
  - reference: PMID:40909439
    reference_title: Unraveling the pathogenicity role of the novel compound heterozygous mutations of MED25 gene in a Chinese patient with BVSYS.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: 'In vitro MSA results indicated that the variant c.670C > G (p.R224G) did not disrupt the normal splicing of the MED25 gene (Supplementary Figure S3). In contrast, the variant c.1965 + 1dup affected normal splicing, resulting in two abnormal transcripts: retention of 1 bp in intron 16; skipping of exon 16 (Figure 2).'
    explanation: Minigenes in HEK293T and HeLa cells distinguish an experimentally demonstrated splice defect from the normal splicing of the missense allele.
  - reference: PMID:40909439
    reference_title: Unraveling the pathogenicity role of the novel compound heterozygous mutations of MED25 gene in a Chinese patient with BVSYS.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: The successfully constructed wild-type/mutant recombinant minigene were transfected into Hela or HEK293T cells.
    explanation: The assay uses transfected cell lines rather than patient-derived neurons.
  modeled_mechanisms:
  - target: Abnormal MED25 pre-mRNA splicing
    relationship: MEASURES
    description: Directly assays RNA-processing consequences of the two reported variants.
    model_scale: MOLECULAR
    fidelity: UNKNOWN
    limitations: Minigenes incompletely reproduce endogenous genomic and tissue context. Carrier-mother blood confirms one-base intron retention but not the exon-skipping product; neither experiment measures neuronal protein function.
    evidence:
    - reference: PMID:40909439
      reference_title: Unraveling the pathogenicity role of the novel compound heterozygous mutations of MED25 gene in a Chinese patient with BVSYS.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: 'In vitro MSA results indicated that the variant c.670C > G (p.R224G) did not disrupt the normal splicing of the MED25 gene (Supplementary Figure S3). In contrast, the variant c.1965 + 1dup affected normal splicing, resulting in two abnormal transcripts: retention of 1 bp in intron 16; skipping of exon 16 (Figure 2).'
      explanation: Minigenes in HEK293T and HeLa cells distinguish an experimentally demonstrated splice defect from the normal splicing of the missense allele.
    - reference: PMID:40909439
      reference_title: Unraveling the pathogenicity role of the novel compound heterozygous mutations of MED25 gene in a Chinese patient with BVSYS.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: The successfully constructed wild-type/mutant recombinant minigene were transfected into Hela or HEK293T cells.
      explanation: The assay uses transfected cell lines rather than patient-derived neurons.
    readouts:
    - target: Abnormal MED25 pre-mRNA splicing
      name: c.1965+1dup transcript products
      description: One-base intron-16 retention and exon-16 skipping occurred in minigenes.
      evidence:
      - reference: PMID:40909439
        reference_title: Unraveling the pathogenicity role of the novel compound heterozygous mutations of MED25 gene in a Chinese patient with BVSYS.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: 'In vitro MSA results indicated that the variant c.670C > G (p.R224G) did not disrupt the normal splicing of the MED25 gene (Supplementary Figure S3). In contrast, the variant c.1965 + 1dup affected normal splicing, resulting in two abnormal transcripts: retention of 1 bp in intron 16; skipping of exon 16 (Figure 2).'
        explanation: Minigenes in HEK293T and HeLa cells distinguish an experimentally demonstrated splice defect from the normal splicing of the missense allele.
      direction: ALTERED
    - target: Abnormal MED25 pre-mRNA splicing
      name: Arg224Gly transcript splicing
      description: No splice disruption was observed for c.670C>G.
      evidence:
      - reference: PMID:40909439
        reference_title: Unraveling the pathogenicity role of the novel compound heterozygous mutations of MED25 gene in a Chinese patient with BVSYS.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: 'In vitro MSA results indicated that the variant c.670C > G (p.R224G) did not disrupt the normal splicing of the MED25 gene (Supplementary Figure S3). In contrast, the variant c.1965 + 1dup affected normal splicing, resulting in two abnormal transcripts: retention of 1 bp in intron 16; skipping of exon 16 (Figure 2).'
        explanation: Minigenes in HEK293T and HeLa cells distinguish an experimentally demonstrated splice defect from the normal splicing of the missense allele.
      direction: UNCHANGED
- name: Med25 siRNA in C3H10T1/2 mesenchymal cells
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Mus musculus
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  cell_source: Mouse C3H10T1/2 mesenchymal cell line
  culture_system: Med25 siRNA with cartilage matrix transcript and reporter assays
  publication: PMID:21427722
  description: Med25 depletion reduces Col2a1 transcripts in a cell system used to study Sox9-dependent chondrogenesis.
  evidence:
  - reference: PMID:21427722
    reference_title: Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Knockdown of either Wwp2 or Med25 in C3H10T1/2 cells resulted in significant downregulation of Col2a1 transcripts (Fig. 5b,c).
    explanation: Med25 depletion reduces a cartilage matrix transcript in mouse mesenchymal cells; this is not a patient-allele experiment.
  modeled_mechanisms:
  - target: Reduced SOX9-dependent cartilage matrix transcription
    relationship: PERTURBS
    description: Perturbs the candidate transcriptional mechanism by depleting Med25.
    model_scale: MOLECULAR
    fidelity: UNKNOWN
    limitations: Mouse cell depletion does not test human variants, palatal morphogenesis, or neurodevelopment. The result supports a hypothesis for human palatal disease.
    evidence:
    - reference: PMID:21427722
      reference_title: Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Knockdown of either Wwp2 or Med25 in C3H10T1/2 cells resulted in significant downregulation of Col2a1 transcripts (Fig. 5b,c).
      explanation: Med25 depletion reduces a cartilage matrix transcript in mouse mesenchymal cells; this is not a patient-allele experiment.
    readouts:
    - target: Reduced SOX9-dependent cartilage matrix transcription
      name: Col2a1 transcript abundance
      description: Col2a1 mRNA decreased after Med25 knockdown.
      evidence:
      - reference: PMID:21427722
        reference_title: Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: Knockdown of either Wwp2 or Med25 in C3H10T1/2 cells resulted in significant downregulation of Col2a1 transcripts (Fig. 5b,c).
        explanation: Med25 depletion reduces a cartilage matrix transcript in mouse mesenchymal cells; this is not a patient-allele experiment.
      direction: DECREASED
- name: Sox9–Med25 association in ATDC5 cells
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Mus musculus
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  cell_source: Mouse ATDC5 chondrogenic cell line
  culture_system: Tagged Med25 expression and Wwp2 knockdown with co-immunoprecipitation
  publication: PMID:21427722
  description: Wwp2 knockdown attenuates interaction between endogenous Sox9 and HA-tagged Med25.
  evidence:
  - reference: PMID:21427722
    reference_title: Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Importantly, knockdown of Wwp2 in ATDC5 cells attenuated the physical interaction between endogenous Sox9 and HA-tagged Med25 (Fig. 5g).
    explanation: The chondrogenic cell assay supports Wwp2-dependent Sox9–Med25 association.
  modeled_mechanisms:
  - target: Reduced SOX9-dependent cartilage matrix transcription
    relationship: MEASURES
    description: Measures association of components of the candidate transcriptional complex.
    model_scale: MOLECULAR
    fidelity: UNKNOWN
    limitations: This assay perturbs Wwp2, not a BVSYS MED25 allele; physical association is not itself a measurement of human palatal development.
    evidence:
    - reference: PMID:21427722
      reference_title: Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Importantly, knockdown of Wwp2 in ATDC5 cells attenuated the physical interaction between endogenous Sox9 and HA-tagged Med25 (Fig. 5g).
      explanation: The chondrogenic cell assay supports Wwp2-dependent Sox9–Med25 association.
    readouts:
    - target: Reduced SOX9-dependent cartilage matrix transcription
      name: Sox9–Med25 association after Wwp2 knockdown
      description: The physical interaction was attenuated.
      evidence:
      - reference: PMID:21427722
        reference_title: Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: Importantly, knockdown of Wwp2 in ATDC5 cells attenuated the physical interaction between endogenous Sox9 and HA-tagged Med25 (Fig. 5g).
        explanation: The chondrogenic cell assay supports Wwp2-dependent Sox9–Med25 association.
      direction: DECREASED
animal_models:
- name: Med25-null mouse
  species: Mus musculus
  genotype: Med25−/−
  background: C57BL/6N
  genes:
  - preferred_term: MED25
    term:
      id: hgnc:28845
      label: MED25
  category: Knockout
  publication: PMID:36551904
  description: Homozygous Med25-null embryos show variable craniofacial and brain abnormalities at E12.5–E15.5, including anophthalmia, telencephalon hypoplasia, facial clefts, cyclopia, and exencephaly. Perinatal lethality was observed in the E18.5 viability assessment.
  evidence:
  - reference: PMID:36551904
    reference_title: Large-Scale Functional Assessment of Genes Involved in Rare Diseases with Intellectual Disabilities Unravels Unique Developmental and Behaviour Profiles in Mouse Models.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: Gross morphological analysis of Med25−/− mutants at E12.5 and E15.5 revealed different ranges of abnormalities including anophthalmia
    explanation: The Med25-null embryos underwent direct anatomical assessment; the study’s adult behavioral findings from other lines cannot be assigned to Med25.
  - reference: PMID:36551904
    reference_title: Large-Scale Functional Assessment of Genes Involved in Rare Diseases with Intellectual Disabilities Unravels Unique Developmental and Behaviour Profiles in Mouse Models.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: hypoplasia of the telencephalon (three out of twelve mice) (Figure S4, panel D), rhinocephaly with cyclopia (one out of twelve mice) (Figure S4, panels K, H), proboscis (one out of twelve mice) (Figure S4, panel G), facial clefts (two out of twelve mice) (Figure S4, panel E) and exencephaly (three out of twelve mice) (Figure S4, panels G, J).
    explanation: The reported abnormalities are variable within the 12 Med25-null embryos; these proportions are model observations, not human phenotype frequencies.
  - reference: PMID:36551904
    reference_title: Large-Scale Functional Assessment of Genes Involved in Rare Diseases with Intellectual Disabilities Unravels Unique Developmental and Behaviour Profiles in Mouse Models.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: three lines displayed perinatal lethality and died during the viability test at E18.5 (Tubb3M388V/+, Kdm5c−/y, Med25−/−)
    explanation: Med25-null lethality limits transfer to surviving human patients with other alleles.
  - reference: PMID:36551904
    reference_title: Large-Scale Functional Assessment of Genes Involved in Rare Diseases with Intellectual Disabilities Unravels Unique Developmental and Behaviour Profiles in Mouse Models.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: All mouse lines were either generated in a C57BL/6N genetic background or backcrossed on the C57BL/6N background.
    explanation: The methods specify the shared strain background.
  modeled_mechanisms:
  - target: Biallelic MED25 dysfunction
    relationship: PERTURBS
    description: Removes Med25 and tests consequences for embryonic development and viability.
    model_scale: TISSUE
    fidelity: UNKNOWN
    limitations: A null allele is not equivalent to the patient missense alleles. Severe prenatal malformations and lethality limit extrapolation to surviving patients. The paper reports no adult Med25 behavioral results.
    evidence:
    - reference: PMID:36551904
      reference_title: Large-Scale Functional Assessment of Genes Involved in Rare Diseases with Intellectual Disabilities Unravels Unique Developmental and Behaviour Profiles in Mouse Models.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: Gross morphological analysis of Med25−/− mutants at E12.5 and E15.5 revealed different ranges of abnormalities including anophthalmia
      explanation: The Med25-null embryos underwent direct anatomical assessment; the study’s adult behavioral findings from other lines cannot be assigned to Med25.
    - reference: PMID:36551904
      reference_title: Large-Scale Functional Assessment of Genes Involved in Rare Diseases with Intellectual Disabilities Unravels Unique Developmental and Behaviour Profiles in Mouse Models.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: hypoplasia of the telencephalon (three out of twelve mice) (Figure S4, panel D), rhinocephaly with cyclopia (one out of twelve mice) (Figure S4, panels K, H), proboscis (one out of twelve mice) (Figure S4, panel G), facial clefts (two out of twelve mice) (Figure S4, panel E) and exencephaly (three out of twelve mice) (Figure S4, panels G, J).
      explanation: The reported abnormalities are variable within the 12 Med25-null embryos; these proportions are model observations, not human phenotype frequencies.
    - reference: PMID:36551904
      reference_title: Large-Scale Functional Assessment of Genes Involved in Rare Diseases with Intellectual Disabilities Unravels Unique Developmental and Behaviour Profiles in Mouse Models.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: three lines displayed perinatal lethality and died during the viability test at E18.5 (Tubb3M388V/+, Kdm5c−/y, Med25−/−)
      explanation: Med25-null lethality limits transfer to surviving human patients with other alleles.
    readouts:
    - target: Biallelic MED25 dysfunction
      name: Embryonic craniofacial and brain morphology
      description: Anatomical abnormalities varied among 12 mutant embryos.
      evidence:
      - reference: PMID:36551904
        reference_title: Large-Scale Functional Assessment of Genes Involved in Rare Diseases with Intellectual Disabilities Unravels Unique Developmental and Behaviour Profiles in Mouse Models.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        snippet: Gross morphological analysis of Med25−/− mutants at E12.5 and E15.5 revealed different ranges of abnormalities including anophthalmia
        explanation: The Med25-null embryos underwent direct anatomical assessment; the study’s adult behavioral findings from other lines cannot be assigned to Med25.
      - reference: PMID:36551904
        reference_title: Large-Scale Functional Assessment of Genes Involved in Rare Diseases with Intellectual Disabilities Unravels Unique Developmental and Behaviour Profiles in Mouse Models.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        snippet: hypoplasia of the telencephalon (three out of twelve mice) (Figure S4, panel D), rhinocephaly with cyclopia (one out of twelve mice) (Figure S4, panels K, H), proboscis (one out of twelve mice) (Figure S4, panel G), facial clefts (two out of twelve mice) (Figure S4, panel E) and exencephaly (three out of twelve mice) (Figure S4, panels G, J).
        explanation: The reported abnormalities are variable within the 12 Med25-null embryos; these proportions are model observations, not human phenotype frequencies.
      direction: ALTERED
    - target: Biallelic MED25 dysfunction
      name: Perinatal viability
      description: Med25-null mice died during the E18.5 viability test.
      evidence:
      - reference: PMID:36551904
        reference_title: Large-Scale Functional Assessment of Genes Involved in Rare Diseases with Intellectual Disabilities Unravels Unique Developmental and Behaviour Profiles in Mouse Models.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        snippet: three lines displayed perinatal lethality and died during the viability test at E18.5 (Tubb3M388V/+, Kdm5c−/y, Med25−/−)
        explanation: Med25-null lethality limits transfer to surviving human patients with other alleles.
- name: med25 morpholino zebrafish
  species: Danio rerio
  background: AB
  category: Morpholino knockdown
  publication: PMID:21427722
  description: Transient med25 translation blockade with 5–10 ng morpholino injected at the one- to two-cell stage produces palatal cartilage malformation.
  evidence:
  - reference: PMID:21427722
    reference_title: Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: Intriguingly, morpholino-mediated knockdown of med25 in zebrafish resulted in palatal malformation (Fig. 4d), which closely resembled the palatal phenotype of wwp2 or sox9 mutants23 (Fig. 2f).
    explanation: Transient zebrafish med25 depletion affects palatal cartilage; neither a stable mutation nor a human disease allele was tested.
  - reference: PMID:21427722
    reference_title: Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: We injected one- or two-cell stage zebrafish embryos with ~1–2 nl of morpholinos (20–25 ng for wwp2 splice blocker-MO and 5–10 ng for med25 ATG blocker).
    explanation: The med25 intervention was a translation-blocking morpholino at 5–10 ng; the larger dose applies to wwp2.
  modeled_mechanisms:
  - target: Reduced SOX9-dependent cartilage matrix transcription
    relationship: PERTURBS
    description: Tests a developmental consequence of med25 depletion consistent with the Sox9-associated palatal hypothesis.
    model_scale: TISSUE
    fidelity: UNKNOWN
    limitations: Transient knockdown in fish is not a stable genetic allele or a patient variant. Palatal cartilage morphology does not directly measure human cleft palate or neuronal impairment.
    evidence:
    - reference: PMID:21427722
      reference_title: Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: Intriguingly, morpholino-mediated knockdown of med25 in zebrafish resulted in palatal malformation (Fig. 4d), which closely resembled the palatal phenotype of wwp2 or sox9 mutants23 (Fig. 2f).
      explanation: Transient zebrafish med25 depletion affects palatal cartilage; neither a stable mutation nor a human disease allele was tested.
    - reference: PMID:21427722
      reference_title: Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: We injected one- or two-cell stage zebrafish embryos with ~1–2 nl of morpholinos (20–25 ng for wwp2 splice blocker-MO and 5–10 ng for med25 ATG blocker).
      explanation: The med25 intervention was a translation-blocking morpholino at 5–10 ng; the larger dose applies to wwp2.
    readouts:
    - target: Reduced SOX9-dependent cartilage matrix transcription
      name: Palatal cartilage morphology
      description: med25 morphants had palatal malformation.
      evidence:
      - reference: PMID:21427722
        reference_title: Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        snippet: Intriguingly, morpholino-mediated knockdown of med25 in zebrafish resulted in palatal malformation (Fig. 4d), which closely resembled the palatal phenotype of wwp2 or sox9 mutants23 (Fig. 2f).
        explanation: Transient zebrafish med25 depletion affects palatal cartilage; neither a stable mutation nor a human disease allele was tested.
      direction: ALTERED
  notes: Co-injected sox9a/sox9b or wwp2 mRNA did not rescue the med25 morphant palate. This is a pathway experiment, not a therapeutic rescue of a human disease allele.
diagnosis:
- name: Molecular diagnosis and parental segregation
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: Exome or genome sequencing can identify biallelic MED25 candidates, followed by confirmation and parental segregation. Variant interpretation must distinguish uncertain missense alleles from functionally supported variants; a VUS is not independently diagnostic.
  evidence:
  - reference: PMID:31602195
    reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Direct sequencing of the MED25 gene in both affected sibs confirmed the presence of the variant in a homozygous state (Fig. 2).
    explanation: Molecular confirmation was used in the affected siblings.
  - reference: PMID:42663018
    reference_title: '[Clinical phenotype and genetic analysis of a child with Basel-Vanagaite-Smirin-Yosef syndrome due to variant of MED25 gene].'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The c.394C>G (p.Arg132Gly) variant resulted in an amino acid substitution and was predicted to be deleterious by in silico analysis. Based on the ACMG criteria (PM2_Supporting+PMS+PP3), it was classified as a variant of uncertain significance.
    explanation: The abstract explicitly retains VUS status. The printed criterion string is quoted as reported, not endorsed as an independent ACMG reassessment.
- name: EEG characterization of suspected seizures
  diagnosis_term:
    preferred_term: Electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
  description: EEG can characterize focal, generalized, and photosensitive discharges and help distinguish epileptic events from behavioral episodes. Laughter or staring alone does not establish a seizure diagnosis.
  evidence:
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Other event types included staring spells and laughing spells that were deemed nonepileptic (behavioral) because of lack of ictal correlate on the EEG.
    explanation: The N1 evaluation explicitly distinguishes nonepileptic spells from seizures.
- name: Brain MRI assessment
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  description: Brain MRI documents variable cortical, callosal, ventricular, and white matter findings. A normal scan does not exclude the disorder.
  evidence:
  - reference: PMID:40990994
    reference_title: Epilepsy due to a MED25 Homozygous Pathogenic Founder Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Magnetic response imaging (MRI) of the brain performed at 2 months of age was normal.
    explanation: Patient N1 had a normal early brain MRI despite the clinical and molecular diagnosis.
  - reference: PMID:40909439
    reference_title: Unraveling the pathogenicity role of the novel compound heterozygous mutations of MED25 gene in a Chinese patient with BVSYS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Additionally, there was bilateral hippocampal volume loss with widening of the temporal horns, and the cavum septum pellucidum was present (Figure 1C).
    explanation: The later case illustrates an abnormal MRI phenotype.
- name: Ophthalmological assessment
  diagnosis_term:
    preferred_term: Eye Examination
    term:
      id: NCIT:C38060
      label: Eye Examination
  description: Assessment characterizes cataracts and other ocular findings. Normal ophthalmological examination has been documented in affected individuals.
  evidence:
  - reference: PMID:31602195
    reference_title: 'Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Ophthalmological examination, brainstem auditory evoked response, and brain MRI were normal (Table 1).
    explanation: The affected boy had a normal eye examination, illustrating variable ocular involvement.