Deafness, X-Linked 1

A number sign (#) is used with this entry because of evidence that X-linked deafness-1 (DFNX1) is caused by loss-of-function mutation in the PRPS1 gene (311850) on chromosome Xq22.

Loss-of-function PRPS1 mutations, resulting in decreased enzyme activity, can also cause X-linked recessive Charcot-Marie-Tooth disease-5 (CMTX5; 311070) and Arts syndrome (ARTS; 301835). There is considerable phenotypic overlap between DFNX1, CMTX5, and Arts syndrome, as well as intrafamilial variability depending on gender, X-inactivation ratio, residual enzyme activity, and additional factors. Males tend to be more severely affected than females in all 3 disorders, although some females can show severe features. These disorders are best considered as representing a phenotypic spectrum (summary by Almoguera et al., 2014; Synofzik et al., 2014).

Another allelic disorder, PRPS-related gout (300661), results from increased PRPS1 enzyme activity. Some affected patients also have neurologic symptoms, including sensorineural deafness.

Clinical Features

Tyson et al. (1996) reevaluated a 4-generation British American family with congenital profound sensorineural hearing loss in males, similar to that ascribed to the previously unmapped locus DFN2. In this family, female carriers had a mild/moderate hearing loss affecting the high frequencies.

Liu et al. (2010) studied 14 affected and 29 unaffected members of a large 5-generation Chinese family segregating X-linked nonsyndromic hearing loss. Age at onset of hearing impairment was between 5 and 15 years for males and in the fifth decade for females. Affected males exhibited symmetric, progressive, severe-to-profound hearing loss with flat-shaped audio profiles at 24 years to 50 years of age. Obligate female carriers had either symmetric or asymmetric hearing loss that varied from mild to moderate in degree.

Synofzik et al. (2014) reported a German family with variable manifestations of PRPS1 deficiency, illustrating that the disorder can present as a continuous spectrum of clinical features, even within the same family. A 42-year-old woman had only prelingual-onset hearing loss without symptoms of neurologic dysfunction, consistent with DFNX1, whereas her 36-year-old brother had a protracted form of Arts syndrome, including prelingual sensorineural hearing loss. Brain imaging in both patients showed mild cerebellar and parietal cortical atrophy. The mother of these sibs had no hearing deficit or neurologic dysfunction at age 66. Genetic analysis identified a missense mutation in the PRPS1 gene (Q277P; 311850.0019) that was heterozygous in the females and hemizygous in the male proband. Erythrocyte PRPS1 activity was not detectable in the proband, was decreased in the sister, and was normal in the mother. X-chromosome inactivation was extremely skewed in the sister with DFNX1 (94%; 6%), but only moderately skewed in the mother (80%; 20%). The findings indicated that females with DFNX1 can also show early-onset hearing loss starting at birth.

Mapping

By linkage analysis using polymorphic microsatellite markers in a 4-generation British American family with congenital sensorineural hearing loss, Tyson et al. (1996) found that the DFN2 locus maps to Xq22. A maximum 2-point lod score of 2.91 at theta = 0.0 was observed with a fully informative dinucleotide repeat at COL4A5 (303630), which had previously been mapped to Xq22, and flanking recombinations were observed at DXS990 and DXS1001.

In a large 5-generation Chinese family segregating X-linked nonsyndromic hearing loss, Liu et al. (2010) performed linkage analysis and obtained a maximum 2-point lod score of 4.25 with marker DXS8096 (theta = 0). Recombination events defined a 5.4-cM critical interval between DXS8020 and DXS8055, overlapping the DFN2 locus.

Molecular Genetics

In a large 5-generation Chinese family segregating X-linked nonsyndromic hearing loss mapping to the DNF2 locus, Liu et al. (2010) analyzed 14 candidate genes and identified a missense mutation in the PRPS1 gene (D65N; 311850.0013) that cosegregated with the phenotype. Analysis of the PRPS1 gene in the British American DFN2 family previously reported by Tyson et al. (1996) revealed a different missense mutation (A87T; 311850.0014); missense mutations were also detected in DFN2 families previously reported by Manolis et al. (1999) and Cui et al. (2004) (311850.0015 and 311850.0016, respectively).

In 2 Italian brothers with postlingual DFNX1, Robusto et al. (2015) identified a hemizygous missense mutation in the PRPS1 gene (A113S; 311850.0021). The mother, who had late-onset moderate hearing loss, was heterozygous for the mutation. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Erythrocyte PRPS1 activity was mildly decreased in the 2 affected males (25-35% of normal controls).

Nomenclature

Petersen et al. (2008) proposed the designation DFNX1 for this locus.

History

There are many early reports of an X-linked form of congenital deafness (e.g., Dow and Poynter, 1930; Mitsuda et al., 1952; Stevenson, cited by Deraemaeker, 1958; Deraemaeker, 1958; Sataloff et al., 1955; Parker, 1958; Fraser, 1965). In the family reported by Dow and Poynter (1930), 4 affected males married deaf-mute women who probably had the autosomal recessive form of the disease because no children were affected. The deafness is of the sensorineural type.

William Wilde (1815-1876), the father of Oscar Wilde and a distinguished ear, nose, and throat surgeon, conducted a large survey of deafness in Ireland in 1851 (Wilde, 1853). In his report he noted that 'the proportion of male deaf mutes exceeds the female considerably but it differs somewhat in the 2 great classes of congenital and acquired deafness.' In the Wilde data, the ratio of males to females was 100:75 for congenital deafness and 100:91 for acquired deafness. Reardon (1990) reanalyzed the data from the Wilde survey and suggested that 5% of congenital male deafness was the result of X-linked inheritance. The result correlated well with the estimate of Fraser (1965) that X-linked inheritance accounts for 6.2% of male genetic deafness.

Wellesley and Goldblatt (1992) reported a kindred in which 5 male members of 3 generations connected through normal females had an identical nonprogressive isolated form of sensorineural hearing loss. Audiograms in 2 brothers, who were noted at age 3 and 4, respectively, to have speech difficulties, showed hearing loss in the 1,500-8,000 Hz range. A maternal uncle had not been aware of any hearing problem, but was found on audiogram to have hearing loss in the 4,000-8,000 Hz range. Two maternal great-uncles who had worked in the motor industry and had received compensation for apparent work-related noise damage had only a vague history of poor hearing; their audiograms showed identical hearing loss to that in the young brothers. Wellesley and Goldblatt (1992) noted that the finding of only affected males with no male-to-male transmission supports X-linked inheritance.

Many families with congenital sensorineural deafness are found to have the gusher-deafness syndrome (304400) with typical radiologic changes in the temporal bone (Reardon et al., 1991). Some congenital sensorineural deafness may represent the entity that Lalwani et al. (1994) found to be linked to Xp21.2; see 300030.

Willems (2000) reviewd the genetic causes of nonsyndromic sensorineural hearing loss.