CDC14A

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0100069

Submitter: ClinGen

The *CDC14A* gene was first associated with autosomal recessive hearing impairment and infertile male syndrome (HIIMS) in 2017 (Imtiaz et al., PMID: 29293958). In five families reported with HIIMS, females homozygous for *CDC14A* variants had prelingual sensorineural hearing loss, and homozygous males had hearing loss and infertility (PMID: 29293958). Three families segregated truncating variants predicted to affect all isoforms of the gene. Two families had two different missense variants in the dual-specificity phosphatase domain of *CDC14A*. One additional family had a third missense variant in this domain, but the fertility status of the affected males could not be determined. This gene-disease relationship is supported by expression studies and animal models (PMIDs: 27259055, 29293958). There are four mouse models for this syndrome, including one with a predicted deleterious missense variant in the phosphatase domain generated by CRISPR/Cas9 (PMID: 29293958). Of note, this gene has also been implicated in autosomal recessive nonsyndromic hearing loss which has been​ assessed separately. In summary, there is strong evidence to support the association between *CDC14A* and autosomal recessive hearing impairment and infertile male syndrome. Additional reports in humans are needed to reach a definitive classification. This gene-disease pair was originally classified as Strong by the ClinGen Hearing Loss​ Working Group on 2/26/2018 as per SOP v5. It was reevaluated on 6/1/2023. As of June 2023, this record underwent an update in scoring to be consistent with SOP v9. No new evidence has been reviewed or added. As a result of this reevaluation, the classification did not change.

Inheritance Pattern: AR

Disease ID:MONDO:0012091

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0014849

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

CDC14A was first reported in relation to autosomal recessive nonsyndromic hearing loss in 2016 (Delmaghani et al., PMID 27259055). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms. Therefore, the following disease entities have been split into two disease entities, hearing impairment and infertility in males syndrome (OMIM:608653) and autosomal recessive nonsyndromic hearing loss (OMIM:601071). The split curation for autosomal recessive hearing impairment and infertility in males syndrome (HIIMS) has been curated separately. For males, fertility is directly associated with the location of variants within this gene. Variants that preserve the function of the NM_033313.2 transcript result in nonsyndromic hearing loss instead of HIIMS, while variants that truncate this transcript are expected to result in HIIMS. Six homozygous variants (nonsense, missense, and frameshift) that have been reported in 18 probands in 5 publications (PMIDs: 29293958, 36056583, 33187236, 32231217, 27259055) are included in this curation. This gene-disease association is also supported by animal models (PMIDs: 29293958, 27259055) that demonstrate hearing loss associated with CDC14A heterozygotes. The models also indicate an effect on the length of the kinocilia in inner-ear hair cells, which can impact the differentiation of the auditory sensory cells’ hair bundles. This gene-disease pair was originally evaluated by the Hearing Loss GCEP on 2/26/2018. It was re-evaluated on 1/15/2025. As a result of this reevaluation, the classification changed from limited to definitive, due to the addition of genetic evidence and experimental evidence (PMIDs: 36056583, 33187236, 32231217, 27259055). In summary, CDC14A is definitively associated with autosomal recessive nonsyndromic hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss GCEP on the meeting date 1/15/2025 (SOP Version 11).