GREB1L – Autosomal Dominant Hearing Loss (DFNA80)

GREB1L encodes a retinoic acid receptor coactivator with key roles in embryonic development of the kidney and inner ear. Heterozygous variants in GREB1L have been implicated in autosomal dominant sensorineural hearing loss (DFNA80) based on familial segregation and functional concordance ([PMID:32585897]).

Autosomal dominant inheritance is supported by two multigenerational families with profound sensorineural hearing impairment. In these families, the c.347C>T (p.Thr116Ile) and c.848A>G (p.Asn283Ser) missense variants co-segregate with disease ([PMID:32585897]). A third unrelated Ghanaian proband carrying c.3041G>A (p.Gly1014Glu) expands the allelic series and supports heterogeneity in diverse populations ([PMID:36357908]).

All reported DFNA80 alleles are heterozygous missense changes affecting conserved residues. No loss-of-function or splice site variants have been described in the context of hearing loss. In silico tools uniformly predict these variants to be damaging to GREB1L function.

Functional studies in a greb1l knockout zebrafish model demonstrate abnormal sensory epithelium innervation mirroring human hearing impairment ([PMID:32585897]). Computational protein modeling of p.Gly1014Glu reveals local secondary structure destabilization consistent with pathogenicity ([PMID:36357908]).

No studies to date have refuted the association or described alternative genetic etiologies in these pedigrees. Incomplete penetrance appears low, and there is no evidence of biallelic inheritance in DFNA80.

Taken together, segregation in multiple families and concordant functional data support a Moderate clinical validity for GREB1L in DFNA80. Further case series and mechanistic studies will refine penetrance estimates and expand the mutational spectrum. Key take-home: GREB1L should be included in diagnostic gene panels for autosomal dominant sensorineural hearing loss.

References

• Genes • 2020 • Autosomal Dominantly Inherited GREB1L Variants in Individuals with Profound Sensorineural Hearing Impairment PMID:32585897
• BMC Medical Genomics • 2022 • A novel autosomal dominant GREB1L variant associated with non-syndromic hearing impairment in Ghana PMID:36357908

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