| Domain | Key evidence/statistic | Evidence type/year | Suggested ontology terms |
|---|---|---|---|
| Disease definition / identifiers | EYA1-related branchiootorenal spectrum disorder is the EYA1-associated subset of BOR/BO syndrome, an autosomal-dominant developmental disorder with hearing loss, branchial anomalies, preauricular pits/auricular malformations, and variable renal involvement; BOR OMIM 113650, BO OMIM 602588, EYA1 gene OMIM 601653; classic prevalence estimate ~1:40,000 and ~2% of profound childhood deafness (pqac-00000021, pqac-00000022, pqac-00000023) | Review 2007; primary genetics 2004 | branchiootorenal syndrome; branchio-otic syndrome; hereditary hearing impairment; preauricular pit; branchial fistula; renal anomaly |
| Synonyms / scope | Common synonyms include branchio-oto-renal syndrome, BOR syndrome, branchio-otic syndrome, BO syndrome, branchiootorenal spectrum disorder; BO is generally used when renal anomalies are absent (pqac-00000002, pqac-00000023) | Review 2007; case report 2024 | branchiootorenal spectrum disorder; branchio-otic syndrome |
| Inheritance / expressivity | Inheritance is autosomal dominant with reduced penetrance and marked intra- and interfamilial variable expressivity; age of hearing-loss onset may range from early childhood to young adulthood (pqac-00000021, pqac-00000023) | Primary genetics 2004; review 2007 | autosomal dominant inheritance; variable expressivity; reduced penetrance |
| Clinical diagnostic criteria | Typical BOR/BO can be diagnosed by 3 major criteria, or 2 major + 2 minor criteria, or 1 major criterion plus an affected first-degree relative; major features include hearing loss, preauricular pits, branchial anomalies, renal anomalies, auricular deformities; minor features include external auditory canal, middle ear, inner ear anomalies, preauricular tags, facial asymmetry, palatal anomalies (pqac-00000016, pqac-00000022, pqac-00000012) | Cohort 2024; review 2007; case report 2022 | hearing loss; preauricular pit; branchial anomaly; renal anomaly; auricular malformation; external auditory canal anomaly; middle ear anomaly; inner ear anomaly; facial asymmetry; palate abnormality |
| Major phenotype frequencies (2024 Korean cohort) | Among 41 patients from 23 families: hearing loss 98% (40/41), preauricular pits 83% (34/41), branchial anomalies 66% (27/41), renal anomalies 15% (6/41); minor criteria frequencies: middle ear anomalies 54%, inner ear anomalies 39%, EAC anomalies 20% (pqac-00000016, pqac-00000015) | Human cohort 2024 | hearing loss; preauricular pit; branchial anomaly; renal anomaly; middle ear anomaly; inner ear anomaly; external auditory canal anomaly |
| Historical phenotype frequencies (genotyped BOR families) | In the EYA1-genotyped BOR review based on Chang et al., common phenotypes were deafness 98.5%, preauricular pits 83.6%, branchial anomalies 68.5%, renal anomalies 38.2%, external ear abnormalities 31.5% (pqac-00000022) | Review of genotyped families 2007 | deafness; preauricular pit; branchial anomaly; renal anomaly; external ear anomaly |
| Causal gene / molecular role | EYA1 is the principal causal gene in this disease subset; EYA1 encodes a transcriptional co-activator/phosphatase that lacks intrinsic DNA-binding specificity and functions with SIX proteins, especially SIX1, in the EYA-SIX-PAX developmental network controlling ear and kidney organogenesis (pqac-00000002, pqac-00000021, pqac-00000023) | Case report + in vitro 2024; primary mechanism 2004; review 2007 | EYA1; transcriptional coactivator activity; phosphatase activity; organogenesis; ear development; kidney development |
| EYA1 variant mechanism | Over 200 EYA1 pathogenic variants have been reported; disease mechanism is predominantly loss of function/haploinsufficiency, including nonsense, frameshift, canonical splice, exon-skipping, deletions, complex rearrangements, and cryptic inversions (pqac-00000002, pqac-00000006, pqac-00000017) | Case report + minigene 2024; cohort/mechanistic 2024 | haploinsufficiency; loss of function variant; nonsense-mediated mRNA decay; abnormal RNA splicing; exon skipping; structural variant |
| Example functional splice evidence | A novel EYA1 c.639+3A>C variant caused exon 8 skipping in a minigene assay, predicted premature termination and nonsense-mediated decay; another splice variant c.1050+4A>C/G showed exon 11 skipping, impaired EYA1-SIX1 interaction, cellular mislocalization, and reduced protein expression (pqac-00000006, pqac-00000018) | In vitro family report 2024; in vitro family report 2023 | abnormal RNA splicing; exon skipping; protein mislocalization; reduced protein expression; nonsense-mediated decay |
| Structural variant burden / recent genomics | In the 2024 Korean cohort, ~52% of families had EYA1 variants; 13% had structural variants involving EYA1. Across reviewed cohorts, most BOR structural variants affect EYA1 and are mainly deletions (~89% of SVs) (pqac-00000017, pqac-00000010, pqac-00000011) | Human cohort/review 2024 | EYA1 deletion; inversion; complex genomic rearrangement; copy number variant |
| Diagnostic pipeline yields | Stepwise testing in 23 Korean families achieved 78.3% yield after panel/WES (18/23), 82.6% after CNV screening + MLPA, and 91.3% after WGS; WGS added 8.7% by resolving difficult structural variants (pqac-00000016, pqac-00000024) | Human cohort 2024 + figure extraction | whole exome sequencing; whole genome sequencing; CNV analysis; MLPA; molecular diagnosis |
| Legacy mutation-detection data | In a cohort of 140 patients from 124 families, 36 EYA1 mutations were found in 42 unrelated patients and SIX1 mutations in 3 unrelated patients; the study questioned the pathogenic role of SIX5 (pqac-00000020) | Large mutation cohort 2011 | EYA1; SIX1; SIX5; mutation screening |
| Hearing phenotype / management | Hearing loss may be conductive, sensorineural, or mixed, with severity from mild to profound; cochlear implantation can provide hearing gains in selected BOR/BOS patients, whereas middle-ear surgery has shown mixed results across reports, including unsuccessful outcomes in one Chinese series but improvement in a 2023 BOS family case (pqac-00000023, pqac-00000000, pqac-00000008, pqac-00000018) | Review 2007; cohort 2021; case/in vitro 2023 | conductive hearing loss; sensorineural hearing loss; mixed hearing loss; cochlear implantation; otologic surgery; audiologic rehabilitation |
| Renal phenotype / management | Renal involvement is highly variable, from absent to hypoplasia/small kidneys, hydronephrosis, proteinuria, focal glomerulosclerosis, or end-stage renal disease; practical management is surveillance with renal ultrasound and nephrology follow-up because BO/BOR distinction may not be evident initially (pqac-00000006, pqac-00000012, pqac-00000023) | Family case 2024; case report 2022; review 2007 | renal hypoplasia; hydronephrosis; chronic kidney disease; focal segmental glomerulosclerosis; renal ultrasound; nephrology follow-up |
| Developmental mechanism / model organisms | Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia; SIX1 BOR mutations disrupt EYA1-SIX1-DNA complexes; Xenopus, zebrafish, and mouse models support roles in otic placode/vesicle patterning and kidney morphogenesis (pqac-00000021, pqac-00000019, pqac-00000014) | Primary model/mechanistic 2004; review/model 2024 | apoptosis; organ morphogenesis; otic vesicle development; kidney morphogenesis; craniofacial development |
| Prevention / counseling | No primary environmental prevention is established for this monogenic congenital disorder; most actionable prevention is genetic counseling, family testing/cascade testing, reproductive counseling, and early surveillance for hearing and renal complications (pqac-00000008, pqac-00000016) | Cohort/review 2021; cohort 2024 | genetic counseling; cascade testing; family screening; prenatal diagnosis; hearing surveillance; renal surveillance |
| Evidence gaps / not established | No disease-specific pharmacotherapy, gene therapy, RNA therapy, cell therapy, or validated circulating biomarker was identified in the searched evidence; no relevant interventional clinical trials were retrieved; environmental/infectious risk factors are not established beyond the monogenic cause (pqac-00000019, pqac-00000016) | Review 2024; cohort 2024 | evidence gap; no established targeted therapy; no validated biomarker; no relevant clinical trial identified |


*Table: This table condenses the most useful knowledge-base fields for EYA1-related branchiootorenal spectrum disorder, emphasizing recent cohort statistics, molecular mechanisms, diagnostic yield, and practical management. It also flags important areas where evidence is limited or not established.*