PTPRQ – DFNB84A Autosomal Recessive Nonsyndromic Hearing Loss

PTPRQ encodes protein tyrosine phosphatase receptor Q, essential for hair bundle maturation in the cochlea. Heterozygous or biallelic loss-of-function variants in PTPRQ underlie autosomal recessive nonsyndromic hearing loss 84A. Clinical validity is rated as Strong given multiple unrelated families with co-segregating PTPRQ variants and concordant functional data.

Genetic Evidence

Multiple independent AR families have been reported. In a Kazakh DFNB84 pedigree, compound heterozygous frameshift variants c.2716del (p.Thr906HisfsTer18) co-segregated with prelingual sensorineural hearing loss and were absent in 200 controls ([PMID:25557914]). A canonical splice-site variant c.55-2A>G segregated with severe-to-profound hearing loss in a Pakistani family ([PMID:33997018]). A noncanonical splice variant c.6087-3T>G was identified in an AR simplex family and demonstrated exon skipping/intron retention on minigene assay ([PMID:34956325]). A novel nonsense variant p.Gln1336Ter was found in an Indian DFNB84A family with postlingual progressive HL ([PMID:34374074]).

Functional Evidence

Minigene splicing assays confirmed that c.6087-3T>G disrupts normal exon recognition ([PMID:34956325]). A Ptprq c.3697del knock-in mouse model recapitulates hair bundle disorganization and progressive hearing loss, supporting a loss-of-function mechanism ([PMID:39434500]).

Integration and Conclusion

Collectively, biallelic PTPRQ LoF and splice variants have been observed in at least four unrelated families with autosomal recessive nonsyndromic hearing loss 84A, with functional studies corroborating disrupted RNA splicing and hair cell morphology. Additional deep intronic and structural variants uncovered by whole-genome sequencing suggest an even broader mutational spectrum.

Key Take-home: PTPRQ sequencing, including noncanonical splice regions and intronic segments, is critical for comprehensive molecular diagnosis of autosomal recessive nonsyndromic hearing loss.

References

• Molecular genetics and genomics • 2015 • Identification of a novel compound heterozygous mutation in PTPRQ in a DFNB84 family with prelingual sensorineural hearing impairment. PMID:25557914
• Frontiers in genetics • 2021 • Detection and Functional Verification of Noncanonical Splice Site Mutations in Hereditary Deafness. PMID:34956325
• BioMed research international • 2021 • Identification of Hearing Loss-Associated Variants of PTPRQ, MYO15A, and SERPINB6 in Pakistani Families. PMID:33997018
• Annals of human genetics • 2022 • PNPT1, MYO15A, PTPRQ, and SLC12A2-associated genetic and phenotypic heterogeneity among hearing impaired assortative mating families in Southern India. PMID:34374074
• Clinical genetics • 2025 • A Novel PTPRQ c.3697del Variant Causes Autosomal Dominant Progressive Hearing Loss in Both Humans and Mice. PMID:39434500

Evidence Based Scoring (AI generated)