Dfnx1 Nonsyndromic Hearing Loss And Deafness
Summary
Clinical characteristics.
DFNX1 nonsyndromic hearing loss and deafness is part of the spectrum of PRPS1-related disorders. Hearing loss in hemizygous males is bilateral, sensorineural, and moderate to profound; prelingual or postlingual in onset; and progressive or non-progressive. The audiogram shape is variable. Hearing in female carriers can be normal or abnormal.
Diagnosis/testing.
Diagnosis relies on the presence of characteristic hearing loss in males and detection of a hemizygous PRPS1 pathogenic variant.
Management.
Treatment of manifestations: Routine management of sensorineural hearing loss. Cochlear implantation can improve auditory and oral communication skills in affected males.
Surveillance: Regular audiologic evaluation to assess hearing status and progression of hearing loss.
Evaluation of relatives at risk: Evaluate at-risk males at birth with detailed audiometry to assure early diagnosis and treatment of hearing loss.
Genetic counseling.
DFNX1 is inherited in an X-linked manner. The father of an affected male will not have the disorder nor will he be a carrier of the pathogenic variant. If the mother of an affected male has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the variant will be affected; females who inherit the variant will be carriers and may have hearing loss. Carrier testing for at-risk female relatives, prenatal diagnosis for pregnancies at increased risk, and preimplantation genetic diagnosis are possible if the PRPS1 pathogenic variant in the family has been identified.
Diagnosis
Suggestive Findings
DFNX1 nonsyndromic hearing loss and deafness, part of the spectrum of PRPS1-related disorders, should be considered in a male proband with the following clinical, laboratory, and imaging findings and family history.
Clinical findings
- Sensorineural hearing loss is:
- Bilateral moderate to profound;
- Prelingual or postlingual in onset;
- Progressive or non-progressive.
- Audiograms are usually flat across all frequencies. However, some individuals have severe hearing loss in the low frequencies and some have residual hearing in the high frequencies.
- Vestibular function is normal.
Imagining. Temporal bone imaging is normal.
Family history consistent with X-linked inheritance. In heterozygous females hearing can be normal or abnormal.
Establishing the Diagnosis
Male proband. The diagnosis of DFNX1 is established in a male proband with sensorineural hearing loss and a hemizygous pathogenic variant in PRPS1 identified by molecular genetic testing [Liu et al 2010, Kim et al 2016] (see Table 1).
Female carrier. The diagnosis of DFNX1 is usually established in a female carrier who may have normal hearing or sensorineural hearing loss and a heterozygous pathogenic variant in PRPS1 identified by molecular genetic testing [Liu et al 2010] (see Table 1).
Molecular genetic testing. Because the phenotype of DFNX1 is indistinguishable from many other inherited disorders with hearing loss, recommended molecular genetic testing approaches include use of a multigene panel (see Option 1) or comprehensive genomic testing (see Option 2).
Note: Single-gene testing (sequence analysis of PRPS1 followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.
Option 1
A multigene panel that includes PRPS1 and other genes of interest (see Hereditary Hearing Loss and Deafness Overview) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of DFNX1 nonsyndromic hearing loss and deafness some panels for hearing loss may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is another good option. Exome sequencing is most commonly used; genome sequencing is also possible.
Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in DFNX1
| Gene 1 | Test Method | Proportion of Pathogenic Variants 2 Detectable by This Method |
|---|---|---|
| PRPS1 | Sequence analysis 3, 4 | 5/5 5 |
| Gene-targeted deletion/duplication analysis 6 | Unknown 7 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
- 5.
Sequencing of the seven exons of the coding region and the intron/exon boundaries of PRPS1 in the five families reported to date with DFNX1 nonsyndromic hearing loss and deafness identified five different pathogenic missense variants [Liu et al 2010, Kim et al 2016]. To date no intragenic deletions or duplications have been observed.
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Clinical Characteristics
Clinical Description
Hearing loss in individuals with DFNX1 nonsyndromic hearing loss and deafness can be prelingual or postlingual (in which onset ranges from 3 years to 20 years), progressive or non-progressive, and severe to profound [Liu et al 2010, Liu et al 2013, Kim et al 2016].
Synofzik et al [2014] concluded that the three PRPS1-related phenotypes (CMTX5, Arts syndrome, and DFNX1) constitute a continuum after observing all three phenotypes in one family with a loss-of-function pathogenic variant: a male with CMT and Arts syndrome and a heterozygous female with hearing loss due to skewing of X-chromosome inactivation. On detailed clinical and neurophysiologic examination manifestations of peripheral neuropathy that range from a subclinical axonal motor neuropathy to an axonal sensory-motor neuropathy were found in males with PRPS1-related hearing loss [Robusto et al 2015]. In addition, optic atrophy and retinitis pigmentosa have been described in females heterozygous for a PRPS1 pathogenic variant [Almoguera et al 2014].
Heterozygous females. Hearing in heterozygous females can be normal or abnormal. When hearing is abnormal, hearing loss can be either symmetric or asymmetric and ranges from mild to moderate [Liu et al 2013].
In the family described by Almoguera et al [2014], both the proband and her mother have peripheral neuropathy and ophthalmologic manifestations, whereas the phenotype of the affected sister is milder and confined to eye, with no hearing loss.
Genotype-Phenotype Correlations
The established PRPS1-related disorders are not distinct entities, but rather clusters on a phenotypic continuum as evidenced by overlap of the features of CMTX5 / Arts syndrome / DFNX1 both in affected individuals and within families. A wide and continuous spectrum of clinical manifestations has been associated with PRPS1 missense variants (see Genetically Related Disorders). A relationship between the type (location) of PRS-I disruption and phenotype has been suggested, with the most severe phenotypes caused by variants predicted to affect allosteric and active sites and the milder phenotypes caused by variants predicted to disrupt the structure locally [de Brouwer et al 2010].
In females, who predictably have a less severe presentation, the ratio of X chromosome inactivation adds an additional variable in predicting clinical outcome [Synofzik et al 2014].
Prevalence
Prevalence has not been determined. Five families with DFNX1 have been reported [Liu et al 2010, Kim et al 2016].
Differential Diagnosis
See Deafness and Hereditary Hearing Loss Overview for complete differential diagnosis of hereditary hearing loss.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with DFNX1 nonsyndromic hearing loss and deafness, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
- Pure tone audiograms, auditory brain stem response testing
- Evaluation for peripheral neuropathy and ophthalmologic findings (optic atrophy and retinitis pigmentosa)
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Sensorineural hearing loss. Cochlear implantation in affected males can improve auditory and oral communication skills.
See Deafness and Hereditary Hearing Loss Overview.
Surveillance
Hearing loss in DFNX1 is prelingual or postlingual and progressive; regular audiologic evaluation is recommended to assess hearing status and progression of hearing loss.
Periodic reevaluation of clinical findings by a neurologist is indicated for males with clinical evidence of peripheral neuropathy.
Evaluation of Relatives at Risk
Determining in infancy whether at-risk male and female relatives of a person with DFNX1 nonsyndromic hearing loss and deafness have inherited the PRPS1 pathogenic variant allows for early support and management of the child and the family.
Evaluations may include:
- Molecular genetic testing if the pathogenic PRPS1 variant in the family is known.
- Audiometry if molecular genetic testing for the at-risk relative is not available.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.