TECTA – Autosomal Recessive Nonsyndromic Hearing Loss 21

Alpha-tectorin, encoded by TECTA, is a key non-collagenous glycoprotein of the cochlear tectorial membrane. Biallelic loss-of-function variants in TECTA underlie DFNB21, presenting as congenital, moderate to severe sensorineural hearing loss with an autosomal recessive inheritance pattern. Molecular diagnosis of DFNB21 is critical given the genetic heterogeneity of nonsyndromic hearing impairment.

In a consanguineous Algerian family, three siblings with moderate to severe sensorineural deafness harbored a homozygous splice donor site mutation, c.5272+1G>A, in TECTA ([PMID:27368438]). This variant segregated perfectly with hearing loss, with parents unaffected carriers, confirming its recessive pathogenicity.

Compound heterozygosity for a missense variant and a splice-site intronic insertion was demonstrated in a DFNB21 patient: c.5072_5073delinsTT (p.Cys1691Phe) and c.6162+3insT. Exon-trapping assays revealed abnormal exon skipping and a prematurely truncated protein, establishing a loss-of-function mechanism ([PMID:22037481]).

A synonymous founder variant, c.327C>T (p.Gly109=), was identified in seven individuals from six unrelated families with autosomal recessive hearing loss. Minigene assays showed activation of a cryptic splice donor site, frameshifting the transcript and triggering nonsense-mediated decay ([PMID:35870179]).

In a multi-center cohort of 306 NSHL patients, TECTA variants were detected in 11 individuals, including five novel alleles, highlighting its contribution to ARNSHL diagnostics beyond common GJB2 mutations ([PMID:38868966]).

Functional studies consistently support haploinsufficiency as the mechanism in DFNB21: in vitro splicing assays confirm exon skipping for donor and synonymous variants, leading to truncated or unstable α-tectorin proteins. These data are concordant with the human hearing loss phenotype.

While heterozygous TECTA variants cause dominant DFNA8/A12 with mid-frequency hearing loss, the recessive DFNB21 phenotype arises from biallelic loss-of-function alleles. No conflicting evidence has been reported for AR DFNB21.

Collectively, 11 probands across eight unrelated families, segregation in a consanguineous kindred, and concordant functional splicing assays support a Strong ClinGen gene–disease association. Key take-home: screening for biallelic TECTA variants should be incorporated into diagnostic panels for autosomal recessive nonsyndromic hearing loss.

References

• International journal of pediatric otorhinolaryngology • 2016 • A novel biallelic splice site mutation of TECTA causes moderate to severe hearing impairment in an Algerian family. PMID:27368438
• Gene • 2012 • Identification and functional characterization of novel compound heterozygotic mutations in the TECTA gene. PMID:22037481
• Human mutation • 2022 • Characterization of a possible founder synonymous variant in TECTA in multiple individuals with autosomal recessive hearing loss. PMID:35870179
• Croatian medical journal • 2024 • Spectrum of genetic variants in 306 patients with non-syndromic hearing loss from Croatia. PMID:38868966

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