CDC14A – Autosomal recessive nonsyndromic hearing loss 32

Autosomal recessive nonsyndromic hearing loss 32 (DFNB32) is caused by biallelic loss-of-function variants in CDC14A, leading to congenital sensorineural hearing impairment with or without male infertility. Two consanguineous kindreds (A, B) presented with homozygous stop-gain (c.1000C>T (p.Gln334Ter)) and missense (c.684C>A (p.Asn228Lys)) variants segregating with deafness and, in family B, infertile male syndrome (PMID:39119445). A subsequent study in Iranian and Pakistani probands identified a novel splice donor variant (c.1421+2T>C) activating a cryptic splice site (c.1414_1421del, p.Val472LeufsTer20) and a frameshift (c.1041dup (p.Ser348GlnfsTer2)), both resulting in nonsense-mediated decay (PMID:31906439).

Segregation analysis in three unrelated families confirms autosomal recessive inheritance; homozygosity in multiple affected individuals supports variant pathogenicity. No additional phenocopies or unaffected homozygotes have been reported. The phenotypic spectrum ranges from isolated sensorineural hearing loss (HP:0000365) to combined hearing impairment and male infertility (HP:0000789). Carrier frequency data are not yet established.

Variant spectrum in DFNB32 comprises two premature termination variants (c.1000C>T (p.Gln334Ter), c.1041dup (p.Ser348GlnfsTer2)), one cryptic splice-altering variant (c.1421+2T>C), and at least one missense substitution (c.684C>A (p.Asn228Lys)). The splice and frameshift alleles have been functionally validated by minigene assay and RT-qPCR, respectively, confirming transcript truncation and degradation (PMID:31906439). No founder variants have been reported.

Animal models deficient for Cdc14a recapitulate both auditory and reproductive defects, corroborating a loss-of-function mechanism. In yeast, Cdc14 phosphatase functionally associates with cell cycle kinases, underscoring conserved roles in cellular division but not directly modelling hearing loss (PMID:9613578).

No studies have refuted the CDC14A–DFNB32 association or described dominant-negative effects. The collective genetic and experimental data delineate a consistent autosomal recessive mechanism of pathogenicity.

Given the strong genotype–phenotype correlation, functional validation of novel variants, and supportive animal data, CDC14A testing is recommended for individuals with unexplained congenital sensorineural hearing loss, particularly in consanguineous populations. Key take-home: CDC14A loss-of-function variants reliably predict autosomal recessive nonsyndromic hearing loss 32, guiding molecular diagnosis and genetic counseling.

References

• Unspecified Journal • Unspecified Year • Hereditary hearing loss study detailing CDC14A variants in NSHL and HIIMS PMID:39119445
• International Journal of Molecular Sciences • 2020 • Novel Loss-of-Function Variants in CDC14A are Associated with Recessive Sensorineural Hearing Loss in Iranian and Pakistani Patients. PMID:31906439
• Molecular & General Genetics • 1998 • The Cdc14 phosphatase is functionally associated with the Dbf2 protein kinase in Saccharomyces cerevisiae. PMID:9613578

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