SALL1
The current research confirms that TBS syndrome is an autosomal dominant genetic disease. The heterozygous mutation of the zinc finger protein transcription regulation gene SALL1 at 16q12.1 is the molecular basis of the disease. In 2005, Botzenhart et al. reported that most of the SALL1 gene mutations occurred in or within the 5-prime encoding the first double zinc finger region among the 35 identified genetic mutations [21]. The SALL1 gene contains three determined exons, with 11 WT1-binding sites and 1 SIX1-binding site. The 5 prime number flanking regions do not contain TATA or CAAT boxes, although they are rich in GC and contain more GC boxes [22]. In addition to the SALL1 gene, recent studies found that mutations in the Dishevelled Binding Antagonist Of Beta Catenin 1 (DACT1) gene located on chromosome 14q23 may also lead to TBS, which is called Townes-Brocks syndrome-2 (TBS2; 617466) [23].
Some families with Townes-Brocks syndrome have shown increased clinical severity over generations, thus presenting genetic anticipation. Sudo et al. reported an antedating Japanese family in which a four-year-old female proband was heterozygous for a frameshift mutation in the SALL1 gene, the first generation of affected patients (the proband’s grandfather and great aunt) showed polydactyly and deafness, the second generation (the proband’s mother and uncle) had kidney and anal abnormalities, and the third generation (the proband) showed the most serious symptoms of anteriorly placed and stenosed anus and ventricular septal defects (VSDs) [2]. Researchers noted that the severity of the phenotype with each succeeding generation was an anticipation-like increase in this family and showed that similar increases in clinical severity had been observed in other TBS families, frequently in patients who inherited the disease from their mothers.
In our study, we identified a novel heterozygous mutation (ENST00000251020: c.1428_1429insT, p. K478QfsX38) of SALL1 in a two-generation family with TBS. The first generation (II-4) only showed toe deformities, deafness, external ear deformities and PS, although more serious complications, including multiple CHDs and ARMs, were present in the second generation (III-3). At present, this proband (III-3) has no sensorineural deafness and only shows mild conductive deafness, which is related to otitis media that was present during the examination. Moreover, the child may not show sensorineural deafness; thus, follow-up review is still needed in the future.
PTPRQ
PTPRQ plays an important role in inner ear development and hair cell differentiation and maturation [24, 25] and is necessary for the normal maturation of shaft connectors and developing hair bundles in the mammalian cochlea. There are four PTPRQ isotypes, and each isotype is composed of a transmembrane domain, fibronectin type 3 domain and phosphatase domain [26]. Previous studies suggested that PTPRQ and myosin VI can form a complex, which may dynamically maintain the organization coated on the surface of the stereocilia base cells and may help maintain the overall structure of the stereocilia bundles [27]. PTPRQ knockout mice have significantly longer hair strands and suffer from the loss and fusion of hair cell static cilia. Researchers have also observed a simultaneous loss of function of the vestibular system in these mice [24]. Vestibular evoked potentials do not occur in most PTPRQ gene knockout mice, and subtle but obvious defects of evoked potentials are detected in mutant mice [24]. Goodyear et al. pointed out that the lack of PTPRQ in mice causes the apical membrane of hair cells to separate from the potential actin cytoskeleton and leads to the fusion of stereocilia [28]. PTPRQ mutations may alter the morphology and stereocilia and further lead to the gradual loss of cochlear hair cells and subsequent deafness [28].
Previous studies have proven that homozygous mutation of PTPRQ may lead to nonsyndromic hearing loss. In 2010, Arg457Gly (currently Arg239Gly) and Tyr497X (currently Tyr279X) were first identified by Schraders et al. in deaf families from Morocco and the Netherlands. Hashem et al. found that the cause of DFNB84 in Palestinian deaf families was Gln429X in PTPRQ [26]. In 2015, Qing Sang et al. identified c.1617insT (p. L8fsX18) and c.2714delA (p. E909fsX922) as new compound heterozygous mutations in the PTPRQ gene in a Kazakh family from Xinjiang, which was the first report of a PTPRQ gene mutation in China [29]. In the last coding exon (exon 45) of the PTPRQ gene, Eisenberger et al. identified a heterozygous c.6881G > A transition, which resulted in a p. W2294X substitution in affected members in four generations of German families in which the age at onset of hearing loss ranged from early childhood to the third decade, thus confirming that the PTPRQ gene was also a new autosomal dominant nonsyndromic hearing loss gene [16].
In this study, we identified a new homozygous mutation (ENST00000266688: c.1057_1057delC, p. L353SfsX8) of PTPRQ in a consanguineous family with nonsyndromic hearing loss. This family came from the remote Wuling Mountains in southern China, which is a gathering place for ethnic minorities and economically suppressed, where intimate marriages often occur. Close marriages greatly increase the probability that future generations will suffer from deafness. Alleles from a common ancestor reached a homozygous state in the mother (II-3) and uncle (II-2) of the proband (III-3).