Gene mutation detection of hereditary deafness

(I) Preface

Hearing impairment is one of the most common sensory system defects. When dealing with hearing impaired patients, clinicians or audiologists usually have to find out the causes before making further decisions. Common causes include infection, trauma, noise, ototoxic drugs, aging, heredity and so on. Most of the pathogenesis and prevention and treatment of these causes have been known by clinicians for a long time, but our understanding of hereditary hearing loss has only made a significant breakthrough in recent years.

Before introducing the new discovery of hereditary deafness, there are two ideas that readers must clarify. First, the generalized hereditary deafness, in addition to the hereditary deafness that we are familiar with in infants, young children and adolescents, can also include the ear diseases that may play a certain role in such genetic factors as senile deafness, Meniere’s disease and otosclerosis, but these diseases are interfered and influenced by too many environmental factors, so they are not included in the following content we will introduce 。 Second, hereditary hearing loss is not equal to congenital hearing loss. Congenital deafness refers to the hearing impairment that occurs at birth. Of course, genetic inheritance accounts for a considerable proportion. However, other factors, such as vertical infection of mother and child viruses or complications of weekly delivery, can also lead to congenital deafness. On the other hand, the patients with hereditary deafness are not all congenital deafness, because some of them may have normal hearing at birth and gradually become worse with age.

In general, in developed countries, one out of about 1000 babies born is deaf with two ears, two-thirds of which can be attributed to genetic factors. At first glance, readers may think hereditary deafness is a rare disease. However, in fact, hereditary deafness is quite common among all kinds of genetic diseases. Because children suffering from hereditary deafness is a heavy burden on individuals, families and medical system, if we can make a correct diagnosis early in prenatal or early childhood, it will be extremely positive for the sick children, their families and the society.

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(2) classification and epidemiology of hereditary deafness

Genetic deafness can be divided into syndrome type and non syndrome type according to whether the other organs of the body are abnormal or not. The latter is the majority, the ratio of which is about 30:70. In addition to hearing impairment, patients with hereditary deafness of syndrome type will also have various abnormalities such as eye, muscle, bone, kidney, nerve or pigment. The more common syndromes of deafness are: Pendred’s syndrome (deafness with goiter), Usher’s syndrome (deafness with retinitis pigmentosa), wardenburg’s syndrome (deafness with white hair on forehead and heterotopic inner canthus), je Rvell & Lange Nielsen’s syndrome, etc. Because the syndrome type hereditary deafness has other body characteristics for identification, which is helpful for the collection and classification of cases, we have more understanding of the pathogenic genes of the syndrome type hereditary deafness. At present, about 100 genes are known to be related to the syndrome type hereditary deafness.

On the contrary, the majority of genetic research on non symptomatic hereditary deafness did not make a breakthrough until 6 or 7 years ago. At present, more than 30 genes have been found to be related to the development of non symptomatic hearing impairment, including Cx26 (GJB2), cx3l (gjb3), CX30 (GJB6), Cx32 (GJB1), diamh1, MYO7A, myo15, OTOF, SLC26A4 (PDS). Among them, the most common abnormal genes in clinic are: Cx26 gene, SLC26A4 gene, granulosome DNA mutation and OTOF gene. Like the biology that readers have learned in primary and secondary schools, we can divide these hearing-impaired genes into four types according to their genetic forms: somatic dominant inheritance, somatic recessive inheritance, sex linked inheritance, and granulosome inheritance. Generally speaking, the degree of hearing impairment of recessive hereditary deafness of somatic chromosome is usually more serious, and also occurs before idioms (pre lingual); while the degree of hearing impairment of dominant hereditary deafness of somatic chromosome is relatively minor, and more often occurs after idioms (post lingual). In the non symptomatic hereditary deafness, the recessive inheritance of somatic chromosome is the most common. Most mutations of common deafness genes such as Cx26 gene, SLC26A4 gene and OTOF gene are inherited in this way. The classification and epidemiological data of hereditary deafness are summarized in Figure 1.

(3) common pathogenic genes and mutations of hereditary deafness

 as mentioned above, the genes that are more frequently abnormal in clinic are: Cx26 (GJB2) gene, SLC26A4 (PDS) gene, granulosomal DNA mutation, and OTOF gene, etc., which are introduced as follows:

(1) Cx26 (GJB2) gene

Cx26 is the gene for making Connexin26 molecule, and Connexin26 is considered to be related to the transport of potassium ions. If there is a problem in the synthesis of connexin, it may affect the transport of potassium ions between cells, and then affect the electrophysiology of inner ear, resulting in hearing impairment. In a large-scale study conducted by otolaryngology and genetic medicine department of Taida hospital for Chinese people, we found that out of 324 patients with congenital hearing impairment, up to 48 (14.8%) of them showed mutations in Cx26. It can be seen that mutations in Cx26 gene are one of the important genes causing congenital hearing impairment in Chinese people. Among all the mutations of Cx26, “235delc” is the most common one, which is consistent with the results of previous studies in Japan and South Korea. According to the research in the past few years, we have gradually summed up some clinical features of patients with Cx26 gene mutation, including the patients’ hearing impairment is mostly moderate or severe before the idiom, the degree of hearing impairment varies from person to person, some patients’ hearing may gradually become worse, and the patients’ temporal bone imaging is not combined with abnormalities. Figure 2 shows the family spectrum and audiogram of a typical patient with Cx26 gene mutation.

(2) SLC26A4 (PDS) gene

SLC26A4 (PDS) gene was first identified in 1997 as the pathogenic gene of Pendred’s syndrome. In addition to goiter, Pendred’s syndrome is often associated with two common malformations of the inner ear: enlarged vestibular aqueduct and Mondini’s dysplasia. Later, it was found that SLC26A4 gene mutation could also be found in patients who only had large vestibular aqueduct or Mondini’s hypoplasia and did not have goiter. In other words, SLC26A4 gene mutations, in addition to causing Pendred’s syndrome, can also lead to nonsyndromic hereditary deafness. SLC26A4 gene, or PDS gene, produces a protein called pendrin, which is a transport protein of chloride and iodine ions. It is generally believed that it plays the role of regulating ion balance and inner lymph in inner ear. If mutation occurs, it will lead to inner ear malformation and hearing impairment. In the past, a large-scale epidemiological study has been carried out in the otorhinolaryngology Department of Taida hospital to find out whether hearing-impaired children have inner ear malformations. We found that about 25% of the patients have two kinds of inner ear malformations: large vestibular aqueduct or Mondini’s hypoplasia. Among these 25% patients, about 80% to 90% can find SLC26A4 gene mutation, so it is estimated conservatively that about 15% to 20% of hearing-impaired children have SLC26A4 gene mutation, so its importance may not be less than Cx26 gene mutation. Our study also confirmed that IVS7-2A & gt; G is the most common mutation of SLC26A4 gene in China, accounting for about 79% of all mutations, which is different from that in Japan, Europe and the United States. There are two main clinical characteristics of patients with SLC26A4 gene mutation: one is the combination of large vestibular aqueduct or Mondini’s hypoplasia; the other is the fluctuating hearing loss, that is, the hearing is very easy to deteriorate due to external factors such as head impact, so the degree of hearing impairment of patients is also very different from each other. Figure 3 shows the family spectrum, imaging results and audiogram of typical SLC26A4 mutation patients.

(3) DNA mutation of granulosome

Each cell in the human body contains hundreds to thousands of granulosomes, which are the places where cells carry out oxidative phosphorylation to generate energy, so it can be said that they are the power plants of cells. Each of them contains two to ten sets of DNA. Because the mitochondria are the power plant of cells, the DNA mutation of the mitochondria is particularly easy to affect the tissues in the human body that need more energy metabolism, such as the nervous or muscle system, etc., while the inner ear hair cells are specialized nerve cells, so they are also one of the organs that are easy to be affected. The mutation of granulosome DNA can lead to hereditary deafness of syndrome type and non syndrome type. In the former, 3243A & gt; G mutation is the most common, in addition to hearing impairment, patients also have diabetes symptoms; in the latter, 1555A & gt; G mutation is the most common, and patients’ clinical manifestations are mainly hearing impairment. Because of the mutation of 1555A & gt; G, the 12S rRNA produced by 1555A & gt; G will be more easily combined with antibiotics such as “aminoglycoside”, which will aggravate the ototoxicity of aminoglycoside. Therefore, people with this mutation will be particularly vulnerable to hearing damage if they are not carefully treated by aminoglycoside. In addition, the mitochondria are located in the cytoplasm. When the sperm and egg combine, only the eggs contain a lot of cytoplasm. Therefore, only the mother’s DNA will be passed on to the next generation, and the father’s DNA will not be passed on. This maternal inheritance is also a major feature of the genetic disease of the granulosome. It is generally estimated that about 3% of the deaf people in the East have a mutation of 1555A & gt; G. However, 1555A & gt; G mutation can be found in 15-25% of patients with hearing impairment caused by aminoglycosyl ototoxicity. On the other hand, about 2-6% of the population with diabetes have 3243A & gt; G mutations if the patient