Genetics is the only research tool available, the authors say.

2. Analysis of genetic research progress and the role of molecular epidemiological data in hearing loss

The cloning of genetic causes of deafness and molecular epidemiological studies have given us strong confidence in the interpretation of the mechanisms of hearing loss, which has had a profound impact on the leap in the diagnosis and treatment of hearing loss in recent years.

We can now do this: when we look at a child with severe congenital deafness, we can explore the etiology and consider that 50% of it may be caused by mutations in the GJB2 gene in the DFNB1 locus.

When a patient was found to be sensitive to aminoglycoside drugs and detected mitochondrial 12srrna1555g or 12SrRNAC1494T mutations, it could reveal the characteristics of maternal inheritance and provide effective early warning.

When a patient was detected to have POU3F4 gene mutation in DFN3 loci, it suggested that the doctor should pay attention to avoid stirrup surgery, because the patient was at risk of stirrup blowout.

Early prevention and early warning as well as genetic diagnosis (SLC26A4) can help identify the cause and prevent progressive hearing loss as much as possible when vestibular canal enlargement is found.

These advances provide a more comprehensive approach to the diagnosis of clinical diseases and more effective counselling for patients.

The genes associated with hearing loss have obvious heterogeneity.

Still, it is surprising that people with very severe non-syndromic hearing loss can experience hearing loss as high as 30 to 50 percent 20 percent in people of different ethnic groups with a single mutation in the GJB2 gene.

The GJB2 gene encodes a protein called connexin 26, which is a gap junction protein composed of six monomers and widely distributed in cochlear support cells and connective tissues.

Gap junction proteins form a channel between cells on the surface of adjacent cells and are involved in the potassium ion circulation from hair cells to vascular veins.

Through these channels, potassium ions are pumped back to the endolymphatic cochlea, thereby maintaining the potential of the endolymphatic cochlea and sensing incoming sounds 21.

Initial understanding of the GJB2 gene suggested that it was only associated with severe congenital hearing loss.

However, studies have shown that the hearing loss caused by mutation of GJB2 gene has great variability, and some of the hearing loss caused by mutation of GJB2 gene is not congenital. This study is a retrospective analysis of cases 22,23, and it is impossible to confirm whether the hearing of these cases is completely normal or subclinical in the neonatal period.

Therefore, the establishment of a comprehensive expression map of GJB2 gene mutation has become a primary task.

Although more than 100 mutations have been identified in the GJB2 gene, the 35delG mutation accounts for as much as 70% of all pathogenic mutations in most people.

The most common form of mutation in China was 235delC, accounting for 74.14% of the pathogenic mutations.

Most genetic hearing loss is caused by mutations in a single gene. A small percentage of hearing loss is related to the interaction between mutations in two unrelated genes, and the number of such hearing loss is increasing.

For example, DFNB1 type hearing loss can be caused by two mutations in the GJB2 gene, or by two mutations in the GJB6 gene located near the GJB2 gene, or even two mutations from the GJB2 and GJB6 genes can cause DFNB1 type hearing loss 24].

GJB6 gene is similar to GJB2 gene, and its encoding gene connexin30 is also expressed in cochlea, which can form the gap junction protein channel on the opposite side together with the subunit of connexin26, revealing the molecular pathological mechanism of hearing loss caused by the joint action of GJB2 and GJB6 mutations.

For the GJB2 gene heterozygous deafness patients with hearing loss between the interpretation of the mechanism from the deaf intermarried, this kind of marriage is based on sign language to communicate the salient feature of deaf patients, this phenomenon will continue for generations, thus lead to deafness related all kinds of rare genetic mutation frequency is random mating increased significantly.

Rare deafness gene frequencies in the ancient transfer to result in increased gene frequency of deaf people at the same time, make the dominant hereditary gene causes deafness incidence also increases accordingly, and merge carry GJB2 gene mutation probability also increases accordingly, therefore, may explain the GJB2 gene heterozygous deafness patients can also show the hearing loss.

Therefore, the reasons for the high incidence of mutated GJB2 deafness may include the existence of frequent mutations, the weak links in the population, the heterozygous advantage and the primordium effect [26].

Recent study shows that deaf people (reproductive) genetic fitness increased (sign language started 400 years ago in western social intervention) and the choice of language with the mating type (choose a spouse based on communication way and began about the establishment of a boarding school for disabled children) combined deafness caused the GJB2 correlation in multiplying 27 on earth 200 years ago in the United States.

Computer simulations have shown that this mechanism leads to the preferred transmission of GJB2, the most common recessive inherited deafness gene in the population. This mechanism could well explain an abnormally accelerated accumulation in human evolution between 15,000 and 200,000 years ago, after the first genes related to language emerged.

Therefore, in practice the newborn hearing screening monitor, people ignore or are unaware of the genetic cumulative phenomenon exists, it could make us have very confident the word "through" hearing screening is lack of power, because the newborn is likely to be passed GJB2 homozygous or heterozygous TuBianZhe, his or her hearing problems will arise later.

Ototoxicity of drugs is an important environmental and genetic interaction factor leading to preverbal hearing loss.

In the United States, 10% of ototoxic drug-related hearing loss patients have a 1555G mutation in the 12SrRNA gene, which increases the sensitivity of the cochlea to aminoglycosides.

The incidence of patients with 1555G mutation in American prehearing loss is approximately 1/20,000 to 1/40,000.

In Spain, the 1555G mutation is associated with 15-20% of familial non-syndromic hearing loss, and many older family members can experience hearing loss due to this mutation even without the use of aminoglycoside drugs [30].

In China, the incidence of drug-induced deafness is beyond the original imagination, in a series of articles report, found that deafness patients in the detection of outpatient service is about 5% of the patients, due to 12 srrna 1555 g mutation in deaf school such a special group, compared with 12% of the patients is due to the 12 srrna 1555 g mutation amino glucoside drugs and contact deafness 31.

The association between the 12SrRNAC1494T mutation and drug-induced deafness has also been found in the Chinese population, and at least three large families have been identified as being caused by this mutation.

Therefore, hearing loss caused by drug-induced deafness is difficult to detect and predict in advance without molecular screening.

Among various syndromes, Pendred syndrome is relatively common. The hereditary mode is autosomal recessive, and the incidence of deafness is mostly in the neonatal period or early childhood.

Another clinical feature of patients with Pendred syndrome, goiter, is caused by an iodine transport disorder in thyroid cells, which occurs during adolescence or adulthood.

Thus, goiter in adolescence and hearing loss in childhood are the typical features of Pendred syndrome 34.

Structural abnormalities in the cochlea in patients with Pendred syndrome can manifest as Mondini abnormalities or enlarged vestibular aqueducts.

Some patients simply presented with enlarged vestibular aqueduct combined with deafness, without the manifestation of goiter.

Studies have shown that patients with Pendred syndrome often carry two mutations in SLC26A4 gene testing, while 61 percent of patients with simple vestibular canal dilatation carry only a single mutation, suggesting that in 1.7 percent of carriers of SLC26A4 gene mutation, more than 30 percent may have a risk of developing 36.

It also suggests that in these patients with simple vestibular canal enlargement, there may be mutations in other genes that interact with a single mutation of SLC26A4.

A recent study showed that of 810 children with sensorineural hearing loss, 20.8 percent had symptoms of enlarged vestibular canals and sensorineural hearing loss. Theoretically, these children had symptoms immediately after birth, but the average age of these symptoms was 5.8 years and 38 years.

Presumably, at least a third of them, or about 7%, had preverbal hearing loss, which would have benefited from early detection and intervention.

This article 39 of 101 large vestibular pipes, such as authors ya-li zhao family - 107 patients (including 95 patients with vestibular conduit to expand a single family and 6 patients with double family) has carried on the system research, reveals the onset of 97.2% of the patients in preschool, 73.3% of the patients of severe - extremely severe sensorineural or mixed hearing loss, 69.1% of the patients have low bones guide.

In all 12 of the 6 dual patient families, mutations in the double allele were detected in all 12 patients, and a total of 6 mutation types were detected, including 3 internationally unreported mutations (G209E, E303Q and 1746delG, which also occurred in a single patient family) and 3 reported mutations (ivs7-2a >

G, H723R, N392Y).

Among the 95 patients with vestibular conduit enlargement in a single patient, 97.9%(93/95) had the mutation of this gene, of which 88.4%(84/95), 9.5%(9/95) and 2.1%(2/95) had double allele mutation, single allele mutation and no mutation, respectively.

A total of 38 mutation types were found, including 23 new mutations E37X, P76L, T94I, P112S, 349delC, 387delC, G197R, G204V, D271G, 916_917insG, G316X, N392S, Q421P, K440X, Q446X, Q514X, I529S, S532R, N558I, D573Y, 1746delG, V659L, R685I.

Fifteen mutations have been reported: K77I, M147V, ivs7-2a >

G, A387V, N392Y, 1181_1183delTCT, R409H, T410M, S448X, S448L, IVS14+1G>

A, IVS14-1 g & gt;

C, IVS15 + 5 g & gt;

A, L676Q, H723R.

These mutation sites were found in 17 exons except for 1, 9, 20 and 21, among which exons 8, 19, 10, 15 and 17 were more susceptible to mutation.

Ivs7-2a &gt in exon 8 flanking sequence;

G is a common mutation site in this population, accounting for 57.63%(102/177) of all mutants, and 75/95 families (78.9%).

The next is H723R on exon 19, accounting for about 16.8%.

The high incidence of SLC26A4 gene mutation and double allele mutation, the diversity of SLC26A4 gene mutation and the unique mutation of SLC26A4 gene in patients with vestibular canal enlargement in China, the common mutation and the specificity of the common mutation area constitute the characteristic mutation spectrum of SLC26A4 gene in patients with vestibular canal enlargement in China.

In addition, among 159 patients with severe sensorineural deafness, 33 patients were found to have detected the mutation of SLC26A4 gene, accounting for 20.8%, including 21 double allele mutants and 12 single allele mutants.

Zhao yali's study for the first time completed the complete sequence detection of SLC26A4 gene in 107 patients with vestibular canal enlargement distributed in 16 provinces and cities in China, and proposed the theory that 97.9% of the patients had the mutation of this gene, which is the highest mutation rate report in the world.

In addition, the mutant map of SLC26A4 gene related to vestibular canal enlargement in Chinese population was preliminarily drawn. 40 mutations of SLC26A4 gene in Chinese population were found, and 25 mutations not yet reported in the world were described.

The study also identified five hot spots for mutations in the SLC26A4 gene: exons 8, 19, 10, 15 and 17, with almost every patient having at least one mutation in this region.

Genetic studies and molecular epidemiological data have led us to recognize the importance of genetic genes in the maintenance of hearing health and the detection of hearing abnormalities.

Screening newborns for delayed hearing loss, then, seems even more impotent.

For these late before and in the clinical symptoms of patients with hearing loss is the best detection method of blood of all the newborn screening for molecular genetics, in order to find whether these people have caused the high risk of late-onset hearing loss causes, if any will these newborn as last hearing monitoring objects.

Molecular detection of hearing loss associated with mutations in GJB2 and A1555G is easy to carry out.

The SLC26A4 gene is large, with 21 exons. However, if the exons where several hot spots are mutated are detected, 70% of the heterozygotes and 90% of the homozygotes in patients with Pendred syndrome or large vestibular conduit syndrome can be found.

If all newborns for late-onset hearing loss related three genes (GJB2 mutation, SLC26A4 and A1555G, 1494 t), plus to examine the cytomegalovirus infection, then these newborns have a late-onset hearing loss in high-risk infants, 60% in the neonatal period do symptoms before diagnosis, so also check of at least 40% in children with congenital hearing loss, can clear the cause.

This is an encouraging statistic and revolutionary work with good prospects.

However, it is important to be aware that it is not feasible to diagnose genetic hearing loss by molecular testing alone, because of the numerous uncertainties and unexplained factors in the results of molecular testing.