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ESRRB encodes estrogen-related receptor beta, a nuclear receptor critical for inner ear development and function. Autosomal recessive nonsyndromic hearing loss 35 (DFNB35) presents as prelingual, bilateral sensorineural hearing loss with no additional syndromic features. Evidence to date supports a moderate clinical validity for the ESRRB–DFNB35 association.
Genetic evidence includes biallelic ESRRB variants in two unrelated probands (2 probands) ([PMID:39261511]; [PMID:31835641]). In a consanguineous Pakistani family, a homozygous splice-site variant segregated with hearing loss, while in an unrelated individual compound heterozygosity for a novel splice donor variant and a missense variant was demonstrated ([PMID:39261511]). Both families exhibited an autosomal recessive inheritance pattern with segregation consistent with disease.
Variant spectrum comprises one canonical splice donor alteration (c.397+1G>A) causing exon 4 skipping and nonsense-mediated decay ([PMID:39261511]) and one missense change c.1144C>T (p.Arg382Cys) disrupting protein stability and transcriptional activity ([PMID:39261511]). No recurrent or founder alleles have yet been described in population cohorts. Carrier frequencies of these rare alleles remain below detection thresholds in public databases.
Functional assays in vitro demonstrate that c.397+1G>A abrogates normal ESRRB transcript formation leading to loss of function, whereas p.Arg382Cys destabilizes the ligand-binding domain, reduces transcriptional activation of known ESRRB targets, and perturbs downstream gene expression critical for cochlear homeostasis ([PMID:39261511]). Complementary studies in mouse models of ERRβ deficiency show inner ear developmental arrest, aligning with the human phenotype.
No studies to date have refuted the ESRRB–DFNB35 link. All available reports are concordant regarding autosomal recessive inheritance, variant pathogenicity, and functional impact. No alternative phenotypes or benign variation clusters have been described in multiple affected families.
Integration of genetic and experimental findings confirms that biallelic ESRRB loss-of-function or destabilizing missense variants underlie DFNB35. Although the number of reported cases is limited, functional data solidify a disease-causing mechanism. ESRRB variant screening should be included in diagnostic panels for early-onset sensorineural hearing loss. Key Take-home: ESRRB fulfills ClinGen criteria for a moderate gene–disease association in DFNB35, with diagnostic and potential therapeutic implications.
Gene–Disease AssociationModerate2 unrelated probands with biallelic ESRRB variants; supportive functional data Genetic EvidenceModerateBiallelic ESRRB variants identified in two probands; segregation consistent with autosomal recessive inheritance Functional EvidenceModerateSplicing assays and transcriptional activity studies demonstrate loss of function and disrupted downstream targets |