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\*Address all correspondence to: kikkawa-ys@igakuken.or.jp

1 Mammalian Genetics Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

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Effects of Genetic Background on Susceptibility and the Acceleration of Hearing Loss in Mice

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*Ush1gjs*: Jackson shaker mouse

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Shumpei P. Yasuda1

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22 An Excursus into Hearing Loss

10.1007/BF00292434

science.1093139


**Chapter 2**

**Provisional chapter**

**Genetic Basis of Hearing Loss**

**Genetic Basis of Hearing Loss**

DOI: 10.5772/intechopen.73557

Etiology of hearing impairment (HI) is complex and comprises genetic and environmental factors. Currently, the background of genetic hearing impairment is an area of intensive research and we are witnessing fast progress in this field. The story has begun in 1997 when the DFNB1 locus was discovered with *GJB*2 and *GJB*6 genes causative for almost 50% of cases of recessive, profound, prelingual hearing loss. Nowadays, we have much more possibilities for dissecting the reason of HI, but proper assessment of clinical symptoms is essential for selecting the most optimal diagnostic pathway. In the first stage, the detailed characteristic of hearing loss including its level established by pure tone audiometry (PTA) or auditory brainstem responses (ABR), age of onset, and other helpful features as progressive or no progressive type should be provided. Subsequently, the presence or absence of accompanying symptoms should be established and followed by a detailed analysis of pedigree. In addition, modern assistive algorithms such as AudioGene, Face2Gene, and POSSUM are also discussed. Taking into account the variety of causative genes and pathogenic variants underling hearing loss, searching for causative genes, after exclusion of the DFNB1 variants, should be performed with multigenic panels based on next-generation sequencing technology. **Keywords:** gene, pathogenic variant, phenotype, diagnostic, pedigree, next-generation

The dynamic development of new DNA sequencing technologies in recent years has given us unprecedented insight into the information encoded in the human genome. Introduction of these techniques into a clinical practice has put the diagnosis of genetic disorders to a much more advanced level with a very high detection rate of pathogenic variants. Hearing loss (HL) has also greatly benefited from the technological revolution as it is a genetically

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Agnieszka Pollak and Monika Ołdak

Agnieszka Pollak and Monika Ołdak

http://dx.doi.org/10.5772/intechopen.73557

**Abstract**

sequencing

**1. Introduction**

**Chapter 2 Provisional chapter**

#### **Genetic Basis of Hearing Loss Genetic Basis of Hearing Loss**

Agnieszka Pollak and Monika Ołdak Agnieszka Pollak and Monika Ołdak

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.73557

#### **Abstract**

Etiology of hearing impairment (HI) is complex and comprises genetic and environmental factors. Currently, the background of genetic hearing impairment is an area of intensive research and we are witnessing fast progress in this field. The story has begun in 1997 when the DFNB1 locus was discovered with *GJB*2 and *GJB*6 genes causative for almost 50% of cases of recessive, profound, prelingual hearing loss. Nowadays, we have much more possibilities for dissecting the reason of HI, but proper assessment of clinical symptoms is essential for selecting the most optimal diagnostic pathway. In the first stage, the detailed characteristic of hearing loss including its level established by pure tone audiometry (PTA) or auditory brainstem responses (ABR), age of onset, and other helpful features as progressive or no progressive type should be provided. Subsequently, the presence or absence of accompanying symptoms should be established and followed by a detailed analysis of pedigree. In addition, modern assistive algorithms such as AudioGene, Face2Gene, and POSSUM are also discussed. Taking into account the variety of causative genes and pathogenic variants underling hearing loss, searching for causative genes, after exclusion of the DFNB1 variants, should be performed with multigenic panels based on next-generation sequencing technology.

DOI: 10.5772/intechopen.73557

**Keywords:** gene, pathogenic variant, phenotype, diagnostic, pedigree, next-generation sequencing

#### **1. Introduction**

The dynamic development of new DNA sequencing technologies in recent years has given us unprecedented insight into the information encoded in the human genome. Introduction of these techniques into a clinical practice has put the diagnosis of genetic disorders to a much more advanced level with a very high detection rate of pathogenic variants. Hearing loss (HL) has also greatly benefited from the technological revolution as it is a genetically

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

heterogeneous condition with more than 100 different genes being involved in its pathogenesis, and novel genes are still being discovered (www.herediataryhearingloss.org; accessed 10/2017). As compared to the strategy of sequential analysis of single genes, the application of high-throughput DNA sequencing has increased the diagnostic yield of genetic causes of HL by approximately four times [1].

The most commonly used pedigree symbols, definitions, and abbreviations in compliance

Genetic Basis of Hearing Loss

27

http://dx.doi.org/10.5772/intechopen.73557

With the symbols listed in **Figure 1**, a family tree should be created according to the following

• At the beginning, a shaded symbol (square for male, circle for female) denoting the proband (an affected person from a family who came for a medical consultation as first) should be placed. In the bottom left corner, an arrow and letter "P" should be placed to uniquely

• Above the symbols for proband's, ancestors starting with parents should be placed. The symbol denoting male partner should be placed to the left of the female's one if possible. Furthermore, symbols denoting both parents should be connected by a horizontal line (relationship line) and doubled if the parents are consanguineous. The line of descent should be placed in the middle of the horizontal line, which connects parents with the offspring

• All symbols representing siblings should be placed in the birth order starting from the left side, at the same height as the proband's symbol. Vertical lines (individual's line), linking symbols to the horizontal line (sibship line) above the symbols, must be placed for all

• According to the above-described rules, symbols representing all remaining family mem-

• Some additional, useful information such as disease, age, age at death, initials, or the first

The pedigree line definitions and rules of placing them within the pedigree are presented in

Since drawing pedigrees, especially for large families, is complicated and time consuming, it is worth to use computer programs that facilitate and accelerate this task. There are many professional and public tools, which are useful in the process of creating accurate family diagrams for both, clinical and educational purposes, e.g., Genial Pedigree Draw (http://www.pedigreedraw.com/), Progeny Online Pedigree Tool (http://www.progenygenetics.com/onlinepedigree/), and CeGaT Pedigree Chart Designer (http://www.cegat.de/en/for-physicians/

Understanding the elementary rules of inheritance is the key to appreciate how traits or diseases are passed on within a family. It should be reminded here that every individual has two copies of almost every gene localized on chromosome (autosome), one of them derives from biological mother and the second one from biological father. The situation is different in case of sex chromosomes—every male has only one X (inherited from mother) and Y chromosome (inherited from father). The Y chromosome is transmitted in its entirety exclusively from

Additional most common symbols, rules, and family situations are gathered in **Figure 3**.

with the PSWG revised recommendations are presented in **Figure 1**.

bers should be placed and joined with the appropriate lines.

name may be placed below appropriate symbols.

mark that this individual is the proband.

rules:

(sibship line).

siblings' symbols.

pedigree-chart-designer/).

**Figure 2**.

At the same time, the technological advancements have brought us to a higher level of complexity. Searching for HL-causing variants, often hundreds of genes have to be analyzed and we are flooded by huge amounts of information that are difficult to interpret [2]. It is partially overcome by still-improving computational tools and growing data from population studies, but an indispensable part of better planning of genetic testing and understanding its results is the information gathered from a thorough clinical examination and family history. Sometimes, the primary clinical data collected prior to genetic testing do not completely match the phenotypic features that could be expected from molecular findings. In such cases, clinical reevaluation is needed to better delineate the phenotype and verify whether the identified genetic variants are indeed responsible for the observed clinical features [3, 4].
