TRIOBP – Autosomal Recessive Nonsyndromic Hearing Loss 28

Autosomal recessive nonsyndromic hearing loss 28 (DFNB28) is caused by biallelic pathogenic variants in TRIOBP (HGNC:17009), which encodes actin-bundling proteins critical for stereocilia rootlet integrity. Originally associated with prelingual severe to profound sensorineural HI, recent reports expand the phenotype to moderate, stable, and postlingual forms across diverse populations.

Two unrelated Dutch probands with congenital moderate HI were compound heterozygous for truncating variants in TRIOBP, including c.5014G>T (p.Gly1672Ter) and c.2653del (p.Arg885AlafsTer120) ([PMID:28089734]). Longitudinal audiometry over 15 years confirmed stability of moderate HI and normal vestibular function. Exon location of variants suggests isoform-specific effects: p.Gly1672Ter is the first DFNB28 variant sparing TRIOBP-4, highlighting TRIOBP-5 indispensability for hearing.

In a Polish family, three siblings exhibited peri- to postlingual moderate-to-severe HI with compound heterozygous truncating variants c.802_805del (p.Gln268LeufsTer610) and c.5014G>T (p.Gly1672Ter) ([PMID:29197352]). In an indigenous South African pedigree (TS005), homozygous truncating alleles c.572del (p.Pro191ArgfsTer50) and c.3510_3513dup (p.Pro1172CysfsTer13) cosegregated perfectly with deafness ([PMID:36029164]). These reports comprise 2 probands, 3 siblings, and 1 family, demonstrating AR inheritance and variant segregation.

Truncating variants predominate in DFNB28, with at least seven different frameshift or nonsense alleles reported. The recurrent p.Gly1672Ter appears in both Dutch and Polish cases. Missense changes in TRIOBP are generally tolerated and do not segregate with HL.

Functional studies confirm haploinsufficiency of TRIOBP isoforms 4/5. Deletion of both R1 and R2 motifs abolishes F-actin bundling in vitro; R1 is the principal actin-binding domain ([PMID:23789641]). Mouse models lacking TRIOBP-4/5 exhibit absent stereocilia rootlets and profound HL, mirroring human DFNB28.

Collectively, genetic and experimental data place TRIOBP in the Strong ClinGen category for AR NSHL 28. This association underscores the value of TRIOBP sequencing in hearing loss panels and supports pathogenicity interpretation of truncating variants. Key Take-Home: TRIOBP truncating alleles disrupt stereocilia rootlet formation via loss of actin bundling and should be included in diagnostic testing for AR nonsyndromic hearing impairment.

References

• Hearing research • 2017 • Broadening the phenotype of DFNB28: Mutations in TRIOBP are associated with moderate, stable hereditary hearing impairment. PMID:28089734
• BMC medical genetics • 2017 • Whole exome sequencing identifies TRIOBP pathogenic variants as a cause of post-lingual bilateral moderate-to-severe sensorineural hearing loss. PMID:29197352
• Molecular genetics & genomic medicine • 2022 • Elucidation of repeat motifs R1- and R2-related TRIOBP variants in autosomal recessive nonsyndromic hearing loss DFNB28 among indigenous South African individuals. PMID:36029164
• Biochemistry • 2013 • R1 motif is the major actin-binding domain of TRIOBP-4. PMID:23789641

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