Investigation of seven new genes causing non-syndromic recessive deafness in 100 Iranian families

Master's Thesis in Genetics

Persian Abstract

Deafness is one of the most common sensory diseases that affects 1 in 1000 babies. 60% of deafness is genetic, which is 70% of non-syndromic cases with autosomal recessive inheritance. To date, more than 50 genes for autosomal non-syndromic deafness have been identified. In Iran, deafness due to consanguineous marriages is one of the most common hereditary diseases.

The aim of this study is to investigate the prevalence of seven genes (GJB4, GJC3, SLITRK6, SERPINB6, NESP4, CABP2, and OTOGL) known for non-syndromic recessive deafness in one hundred Iranian families that have consanguineous marriages and more than two affected individuals.

The method of conducting the above study is to check the linkage analysis using STR markers that are located in the vicinity of the mentioned gene. If the linkage pattern is observed, sequencing analysis and additional studies will be done.

The results of the study, two families showed linkage to the GJB4 gene, six families showed linkage to the GJC3 gene, one family showed linkage to the SLITRK6 gene, one family showed linkage to the SERPINB6 gene, eight families showed linkage to the NESP4 gene, two families showed linkage to the CABP2 gene, and six families showed linkage to the CABP2 gene. They showed a connection to the OTOGL gene, and no change was observed in the gene by sequencing the exons of the relevant gene. These results indicate a very low prevalence of mutations in these seven genes in the Iranian population.

Key words: non-syndromic deafness, autosomal recessive inheritance, homozygosity mapping, Sanger sequencing, Iran.

Introduction

Deafness is one of the sensory disabilities that Many people in the world are suffering from it.  There is no special danger for deaf people, but it affects their daily life. In developed countries, one in every thousand children suffer from severe deafness at the time of birth or during the pre-linguistic period. Deafness that occurs before speaking is called prelinguistic deafness [1] and deafness after the child speaks is called postlinguistic deafness [2]. Post-verbal deafness is much more common than pre-verbal deafness and it affects 4 percent of the population under 45 years old, 10 percent of the population over 65 years old, and 50 percent of the population over 80 years old. Most patients with postverbal deafness have multifactorial inheritance, but in monogenic cases, they mainly follow autosomal dominant inheritance [1]. About 60 percent of the causes of deafness are genetic, 30 percent are acquired, and 10 percent are idiopathic. [1] Deafness can be classified in different ways: prelingual or postlingual, syndromic (20-30%) or non-syndromic (70-80%) and classified based on the presence or absence of clinical or laboratory symptoms. Types of syndromic deafness are accompanied by other clinical symptoms, while in non-syndromic deafness, the only clinical symptom of the patient is his deafness. [2] Syndromic deafness is less heterogeneous compared to the non-syndromic type. Also, deafness can be caused in a balanced way in the middle and outer ear or neurologically in the inner ear.

Inheritance of deafness can be Autosomal recessive (80%), autosomal dominant (20%), X-linked and mitochondrial (1%) [3]

In most cases, genetic deafness is caused by a disorder in a gene. About 70% of deaf children who are born have non-syndromic genetic deafness in which no other physical symptoms are seen. In the remaining 30%, deafness is accompanied by other symptoms and is called syndromic deafness.[4]

Single gene deafness can be inherited in different ways. Non-syndromic deafness with autosomal recessive inheritance[3] occurs in 80% of cases and usually occurs preverbally. Whereas, non-syndromic deafness with dominant inheritance [4] occurs in about 20% of cases and usually occurs postverbally. In less than one percent of cases, the inheritance is sex-linked or mitochondrial. [4]

In Iran, deafness after mental retardation.[4]

In Iran, deafness is the second most common disability after mental retardation, which affects 1 in 166 people [5] and due to the high rate of consanguineous marriages in Iran, autosomal recessive deafness has a higher rate than other types of inheritance. [4]

-2 Problem As mentioned, 70% of genetic deafness is non-syndromic, of which 80% is autosomal recessive, and non-syndromic autosomal deafness is one of the most common forms of severe deafness [6]. So far, 55 genes and 102 genetic loci have been found for non-syndromic autosomal recessive deafness. has been [7]. The most common factor found in non-syndromic autosomal recessive deafness was a deletion mutation (35delG) in GJB2, which is the most common cause of this type of deafness. 35delG is the most common mutation in non-syndromic recessive deafness in Northern Europe [8]. The mutation in this DFNB1 position causes recessive deafness and the DFNA3 position causes dominant deafness. More than 50 different types of mutations have been found in this gene, but three mutations are more common among them: 35delG (common in white populations), 167delT (common in Jewish populations) and 35delC (common in Asian populations).

Welfare and rehabilitation was done in Tehran, 35delG was not seen in Baloch people. Dr. Najmabadi et al. in 2008 concluded that 80% of deafness in Baloch is due to the mutation in the W24X position on the GJB2 gene. [4] This phenomenon indicates that the mutation in GJB2 is racial and geographical. W24X is a locus on the GJB2 gene that is very common in southern Iran. [9]

Abstract

Hearing loss (HL) is the most common sensory disorder that affects 1 in 1000 newborns. About 60% of HL is due to genetics and 70% of them are non-syndromic with the recessive pattern of inheritance. Up to now, more than 50 genes have been detected which are responsible for autosomal recessive non-syndromic hearing loss (ARNSHL). In Iran HL is one of the most common disabilities due to consanguineous marriage.

Objectives: The aim of this study was to investigate the prevalence of seven new ARHL genes (GJB4, GJC3, SLITRK6, SERPINB6, NESP4, CABP2, and OTOGL) reported in the neighboring countries among Iranian families with ARNSHL.

Method: One hundred unrelated families with at least two affected siblings in consanguineous marriage, who were negative for GJB2 gene mutations, were selected. By using three STR markers for each gene, homozygosity mapping was performed.

Results: Two families showed linkage to GJB4, six families were linked to GJC3, only one family linked to SLITRK6, One family was linked to SERPINB6, eight families were linked to NESP4, two families were linked to CABP2, and six families were linked to OTOGL. The samples of these families who showed linkage were sent for Sanger sequencing to detect the causative mutations, however, after analyzing the sequencing results, no mutation could be detected in either of the families. Molecular analysis for these nine families is underway in order to determine the pathogenic mutations using whole exome sequencing.

Discussion: These data explain a very low prevalence mutation in these seven genes, GJB4, GJC3, SLITRK6, SERPINB6, NESP4, CABP2, and OTOGL, in Iranian population since no mutation was detected in our study group of one hundred families.