EYA1 – Branchio-otic syndrome

Branchio-otic syndrome is an autosomal dominant disorder characterized by hearing loss and branchial arch anomalies without renal involvement. Pathogenic variants in the EYA1 gene disrupt otic and branchial development, leading to the Branchio-otic syndrome phenotype (EYA1, HGNC:3519; Branchio-otic syndrome).

Initial reports in an Afrikaner kindred identified a novel heterozygous nonsense variant in EYA1 that co-segregated with preauricular malformations and hearing impairment in all affected individuals but was absent in unaffected relatives and controls ([PMID:16813606]).

In a Chinese family, targeted next-generation sequencing revealed a frameshift mutation c.1075_1077delinsAT (p.Gly359IlefsTer7) in affected members (n=4), consistent with autosomal dominant inheritance and complete co-segregation ([PMID:32717629]). Hearing loss, preauricular pits, branchial fistulae, and pinna anomalies were reported in all four patients.

A study of a large non-consanguineous Malian family confirmed a monoallelic missense variant c.1286A>G (p.Asp429Gly) in EYA1 in eight enrolled individuals (four affected), expanding the ethnic spectrum of Branchio-otic syndrome and demonstrating intra-familial phenotypic variability ([PMID:35698919]).

Across published cohorts, over 20 probands harbor diverse EYA1 variants including nonsense, frameshift, and splicing alterations, with no clear founder allele identified. Loss-of-function is the predominant mechanism, supported by truncating variants that ablate the conserved EYA homologous region essential for transcriptional coactivation and phosphatase activity.

Functional assays corroborate haploinsufficiency as the pathogenic mechanism: minigene studies of splice variants confirm exon skipping and premature termination ([PMID:38627775]); Xenopus laevis models expressing human BOR/BOS-associated missense mutations show impaired otic vesicle development ([PMID:19951260]); and zebrafish eya1 knockdown disrupts lateral-line primordium chemotaxis ([PMID:39381636]).

Integration of genetic and experimental data supports a Strong EYA1-Branchio-otic syndrome association. Molecular diagnosis via EYA1 sequencing guides early auditory rehabilitation and surveillance for branchial anomalies. Genetic testing for EYA1 variants is recommended in patients with Branchio-otic features.

References

• Clinical genetics • 2006 • A novel nonsense mutation in the EYA1 gene associated with branchio-oto-renal/branchiootic syndrome in an Afrikaner kindred. PMID:16813606
• International journal of pediatric otorhinolaryngology • 2020 • Targeted next-generation sequencing identifies a novel frameshift EYA1 variant causing branchio-otic syndrome in a Chinese family. PMID:32717629
• Molecular genetics & genomic medicine • 2022 • A monoallelic variant in EYA1 is associated with Branchio-Otic syndrome in a Malian family. PMID:35698919
• Frontiers in genetics • 2023 • Case report: A novel mutation in the EYA1 gene in a child with branchiootic syndrome with secretory otitis media and bilateral vestibular hypofunction. PMID:38259619
• BMC medical genomics • 2024 • Novel likely pathogenic variant in the EYA1 gene causing Branchio oto renal syndrome and the exploration of pathogenic mechanisms. PMID:38627775
• Human molecular genetics • 2001 • Molecular effects of Eya1 domain mutations causing organ defects in BOR syndrome. PMID:19951260
• microPublication Biology • 2024 • Incoherent collective cell chemotaxis underlies organ dysmorphia in a model of branchio-oto-renal syndrome. PMID:39381636

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