**2. Pedigree construction and analysis**

The fundamental and basic element of genetic evaluation in the consultation room is the creation of a precise and accurate family pedigree based on the detailed medical interview. A genetic pedigree is a diagram of genetic relationship enriched with an information about health history, which allows to easily trace the transmission of symptoms, estimate whether symptoms may be caused by genetic reason, and evaluate the risk for other family members (including unborn) of an inherited disorder. Although in the archival literature, readers may encounter many different systems of constructing pedigrees [5], the current, uniform, and precise guidelines in this area should be followed and applied in both clinical practice and publications. Taking into account the dynamic rise of genetic knowledge within the last years, triggered by new technologies such as next-generation sequencing (NGS), clinicians and scientists should be familiar with preparation and interpretation of a pedigree. This allows a proper interpretation of medical and genetic information of the studied family. At the time of writing, an authority dealing with the standardization of the terminology used to describe a pedigree is the National Society of Genetic Counselors (NSGC, http://www. nsgc.org) established in 1979 in the United States of America (USA), with its two official journals: "Journal of Genetic Counseling" and "Perspectives in Genetic Counseling." The Pedigree Standardization Work Group (PSWG) operating within the NSGC established unified recommendations for standardized human pedigree in 1995 [6, 7], and updated it in 2008 [8]. Regarding the fact that no alternative comprehensive, analogous recommendations have been proposed, along with lack of critical comments on the proposed system, the PSWG established rules have become an accepted and international symbolic language of human genetic clinicians and researchers.

The most commonly used pedigree symbols, definitions, and abbreviations in compliance with the PSWG revised recommendations are presented in **Figure 1**.

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

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 fea-

The fundamental and basic element of genetic evaluation in the consultation room is the creation of a precise and accurate family pedigree based on the detailed medical interview. A genetic pedigree is a diagram of genetic relationship enriched with an information about health history, which allows to easily trace the transmission of symptoms, estimate whether symptoms may be caused by genetic reason, and evaluate the risk for other family members (including unborn) of an inherited disorder. Although in the archival literature, readers may encounter many different systems of constructing pedigrees [5], the current, uniform, and precise guidelines in this area should be followed and applied in both clinical practice and publications. Taking into account the dynamic rise of genetic knowledge within the last years, triggered by new technologies such as next-generation sequencing (NGS), clinicians and scientists should be familiar with preparation and interpretation of a pedigree. This allows a proper interpretation of medical and genetic information of the studied family. At the time of writing, an authority dealing with the standardization of the terminology used to describe a pedigree is the National Society of Genetic Counselors (NSGC, http://www. nsgc.org) established in 1979 in the United States of America (USA), with its two official journals: "Journal of Genetic Counseling" and "Perspectives in Genetic Counseling." The Pedigree Standardization Work Group (PSWG) operating within the NSGC established unified recommendations for standardized human pedigree in 1995 [6, 7], and updated it in 2008 [8]. Regarding the fact that no alternative comprehensive, analogous recommendations have been proposed, along with lack of critical comments on the proposed system, the PSWG established rules have become an accepted and international symbolic language of human

by approximately four times [1].

26 An Excursus into Hearing Loss

**2. Pedigree construction and analysis**

genetic clinicians and researchers.

tures [3, 4].

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


The pedigree line definitions and rules of placing them within the pedigree are presented in **Figure 2**.

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

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/ pedigree-chart-designer/).

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


**Figure 1.** Most common pedigree symbols according to Bennett et al. [8].

father to son. In contrast, every female has two X chromosomes (inherited from both parents) [9]. Another derogation from basic inheritance rules is mitochondrial inheritance, in which the entire independent small genome is passed only from mother to offspring [10]. Typically,

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**Figure 3.** Symbols useful in uncommon clinical situations.

**Figure 2.** Definition of pedigree lines.


**Figure 3.** Symbols useful in uncommon clinical situations.

**Figure 2.** Definition of pedigree lines.

28 An Excursus into Hearing Loss

**Figure 1.** Most common pedigree symbols according to Bennett et al. [8].

father to son. In contrast, every female has two X chromosomes (inherited from both parents) [9]. Another derogation from basic inheritance rules is mitochondrial inheritance, in which the entire independent small genome is passed only from mother to offspring [10]. Typically, there are four most common inheritance patterns, depending on the genomic localization and influence on the protein function of pathogenic variants or genes i.e., autosomal dominant (AD), autosomal recessive (AR), sex-linked, and mitochondrial [11]. Diseases caused by pathogenic variants localized in a single gene are mostly inherited in an AD or AR pattern and are referred to as Mendelian inheritance (tribute to Gregor Mendel, who first noted this pattern in pea plants).

The AD mode of inheritance occurs when a single copy of the disrupted (mutated) gene is causative of the disease. It should be emphasized that for AD disorders, a variety of inter and intrafamilial variability of symptoms may occur. Nevertheless, there are few substantial features, which make this mode of inheritance rather simple to distinguish. Dominantly inherited genetic diseases tend to occur in every generation of a family, they affect males and females equally; furthermore, the disorder may be transmitted from males and females. The risk for offspring to inherit the pathogenic variant is 50%. Due to the variability of symptoms severity, characteristic for this type of inheritance, the risk of becoming symptomatic may be less than 50%. A typical family tree representing the AD mode of inheritance is shown in **Figure 4**.

number of genes and there are only few Y-linked disorders, none of them related to hearing and speech disorders, this type of inheritance will not be described here. The XLD and XLR type of inheritance relate to genes located on the X chromosome, and for the occurrence of XLD symptoms, only one copy of a disrupted X-linked gene is required. XLD diseases usually manifest very severely in males, which may lead to spontaneous abortion or neonatal death. The characteristic feature for this type of inheritance is that there is no transmission of the disease from male to male, and all of the female offspring of affected male will inherit the pathogenic variant and the disease. A characteristic family tree for the XLD mode of inheri-

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**Figure 5.** Two typical family trees representing the AR type of inheritance.

**Figure 6.** Exemplary pedigree of a family with the XLD type of inheritance.

tance is shown in **Figure 6**.

The AR type of inheritance requires two disrupted copies of a gene for a disease to occur. Thus, both parents of an affected individual are obligatory asymptomatic carriers (due to an assumption that heterozygotes do not manifest a disease). Furthermore, the symptoms are not typically seen in every generation. AR diseases are much more common in offspring of consanguineous pairs (which is evident within small, isolated populations e.g., Icelanders, Bedouins, or Amish [12]. In contrast to the AD inheritance mode, affected individuals present more consistent clinical picture. The risk for offspring to inherit both pathogenic variants is 25%, whereas the risk to inherit one heterozygous variant is 50%. It should be also noted that all children of an affected parent and a noncarrier partner, regardless of their gender, will be obligate carriers. A typical family pedigree illustrating the AR mode of inheritance is shown in **Figure 5**.

A sex-linked mode of inheritance consists of three subtypes: X-linked dominant (XLD), X-linked recessive (XLR), and Y-linked. Whereas the Y chromosome contains very limited

**Figure 4.** Pedigree of a family with the AD pattern of inheritance.

**Figure 5.** Two typical family trees representing the AR type of inheritance.

there are four most common inheritance patterns, depending on the genomic localization and influence on the protein function of pathogenic variants or genes i.e., autosomal dominant (AD), autosomal recessive (AR), sex-linked, and mitochondrial [11]. Diseases caused by pathogenic variants localized in a single gene are mostly inherited in an AD or AR pattern and are referred to as Mendelian inheritance (tribute to Gregor Mendel, who first noted this

The AD mode of inheritance occurs when a single copy of the disrupted (mutated) gene is causative of the disease. It should be emphasized that for AD disorders, a variety of inter and intrafamilial variability of symptoms may occur. Nevertheless, there are few substantial features, which make this mode of inheritance rather simple to distinguish. Dominantly inherited genetic diseases tend to occur in every generation of a family, they affect males and females equally; furthermore, the disorder may be transmitted from males and females. The risk for offspring to inherit the pathogenic variant is 50%. Due to the variability of symptoms severity, characteristic for this type of inheritance, the risk of becoming symptomatic may be less than 50%. A typical family tree representing the AD mode of inheritance is shown in

The AR type of inheritance requires two disrupted copies of a gene for a disease to occur. Thus, both parents of an affected individual are obligatory asymptomatic carriers (due to an assumption that heterozygotes do not manifest a disease). Furthermore, the symptoms are not typically seen in every generation. AR diseases are much more common in offspring of consanguineous pairs (which is evident within small, isolated populations e.g., Icelanders, Bedouins, or Amish [12]. In contrast to the AD inheritance mode, affected individuals present more consistent clinical picture. The risk for offspring to inherit both pathogenic variants is 25%, whereas the risk to inherit one heterozygous variant is 50%. It should be also noted that all children of an affected parent and a noncarrier partner, regardless of their gender, will be obligate carriers. A typical family pedigree illustrating the AR mode of inheritance is shown

A sex-linked mode of inheritance consists of three subtypes: X-linked dominant (XLD), X-linked recessive (XLR), and Y-linked. Whereas the Y chromosome contains very limited

pattern in pea plants).

30 An Excursus into Hearing Loss

**Figure 4**.

in **Figure 5**.

**Figure 4.** Pedigree of a family with the AD pattern of inheritance.

number of genes and there are only few Y-linked disorders, none of them related to hearing and speech disorders, this type of inheritance will not be described here. The XLD and XLR type of inheritance relate to genes located on the X chromosome, and for the occurrence of XLD symptoms, only one copy of a disrupted X-linked gene is required. XLD diseases usually manifest very severely in males, which may lead to spontaneous abortion or neonatal death. The characteristic feature for this type of inheritance is that there is no transmission of the disease from male to male, and all of the female offspring of affected male will inherit the pathogenic variant and the disease. A characteristic family tree for the XLD mode of inheritance is shown in **Figure 6**.

**Figure 6.** Exemplary pedigree of a family with the XLD type of inheritance.

For an XLR disease to occur in females, both copies of a gene must be impaired. Characteristic features for an XLR inheritance mode are affected males, but an extremely low number or no affected females, in every generation. A distinct feature of the XLR inheritance pattern is that the pedigree tree shows no male to male transmission of the disease. All males harboring a pathogenic variant in an X-linked gene present severe symptoms of the disease, whereas carrier females are in general unaffected or present significantly less severe symptoms. A typical family tree representing the XLR mode of inheritance is shown in **Figure 7**.

Although within small families, which currently are very common, especially in European countries, the recognition of an X-linked inheritance pattern is rather challenging and remains unknown until the results of genetic testing [4].

The mitochondrial mode of inheritance has distinctive features differentiating it from others. Briefly, this unique features come directly from mitochondrial DNA (mtDNA) specificity: mtDNA is a small, independent, circular genome; furthermore, an average human cell contains up to 1000 mitochondria and in every mitochondrion several copies of the mtDNA genome may be present. If all mitochondria in a given individual contain an mtDNA variant it is defined as homoplasmy. In contrast, heteroplasmy indicates the coexistence of more than one mtDNA type within an individual. As all mitochondria of offspring are of maternal origin, the pathogenic variants localized within mtDNA are exclusively passed from mother to children and they may affect males and females equally. Consistently, males do not transmit the mtDNA disorders to their offspring. A representative family tree demonstrating mitochondrial mode of inheritance is shown in **Figure 8**.

It should be emphasized that in many cases distinction between the mitochondrial and AD

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It has to be stressed that all patients with a positive family history of HL should be referred for genetic counseling. Over generations, an inherited disorder automatically raises a suspicion of a genetic underlying cause. A careful analysis of a family pedigree enables to identify or to presume the mode in which hearing impairment is inherited. This in turn is an important step in directing genetic testing at specific genes that are causally involved in the pathogenesis of autosomal dominant, recessive, X-linked, or mitochondrial HL. In case of marriages between individuals with hearing impairment or between individuals coming from families with hearing impairment, the family pedigrees should be analyzed especially carefully. In the offspring of such couples, different HL causative variants of different genes may be found. Interestingly, in a study of 80 deafness genes, the DNA samples of HL patients were significantly enriched in potentially pathogenic variants [13]. One possible explanation of the phenomenon may the above-mentioned marriages between hearing impaired individuals. Attention should also be paid to the consanguinity between parents, which is common in certain populations. Looking for a genetic cause of HL in offspring of a consanguineous couple, the autosomal recessive mode of inheritance with pathogenic variants in a homozygous state is primarily expected. A diagnostic challenge represents an HL patient without other affected family members, also referred to as a sporadic case. Here, a family history of HL is negative and a genetic cause is strongly suspected after exclusion of environmental factors, such as prenatal infection (with toxoplasmosis, rubella, cytomegalovirus, and herpesvirus—"TORCH" organisms), postnatal infections (mainly bacterial meningitis, mumps), prematurity, traumatic injury, blood vessels

inheritance is a difficult task based only on the family tree analysis.

**Figure 8.** Pedigree of a family with mitochondrial mode of inheritance.

**3. Nonsyndromic hearing loss**

**Figure 7.** Pedigree of a family with the XLR pattern of inheritance.

**Figure 8.** Pedigree of a family with mitochondrial mode of inheritance.

It should be emphasized that in many cases distinction between the mitochondrial and AD inheritance is a difficult task based only on the family tree analysis.

### **3. Nonsyndromic hearing loss**

For an XLR disease to occur in females, both copies of a gene must be impaired. Characteristic features for an XLR inheritance mode are affected males, but an extremely low number or no affected females, in every generation. A distinct feature of the XLR inheritance pattern is that the pedigree tree shows no male to male transmission of the disease. All males harboring a pathogenic variant in an X-linked gene present severe symptoms of the disease, whereas carrier females are in general unaffected or present significantly less severe symptoms. A typical

Although within small families, which currently are very common, especially in European countries, the recognition of an X-linked inheritance pattern is rather challenging and remains

The mitochondrial mode of inheritance has distinctive features differentiating it from others. Briefly, this unique features come directly from mitochondrial DNA (mtDNA) specificity: mtDNA is a small, independent, circular genome; furthermore, an average human cell contains up to 1000 mitochondria and in every mitochondrion several copies of the mtDNA genome may be present. If all mitochondria in a given individual contain an mtDNA variant it is defined as homoplasmy. In contrast, heteroplasmy indicates the coexistence of more than one mtDNA type within an individual. As all mitochondria of offspring are of maternal origin, the pathogenic variants localized within mtDNA are exclusively passed from mother to children and they may affect males and females equally. Consistently, males do not transmit the mtDNA disorders to their offspring. A representative family tree demonstrating mito-

family tree representing the XLR mode of inheritance is shown in **Figure 7**.

unknown until the results of genetic testing [4].

32 An Excursus into Hearing Loss

chondrial mode of inheritance is shown in **Figure 8**.

**Figure 7.** Pedigree of a family with the XLR pattern of inheritance.

It has to be stressed that all patients with a positive family history of HL should be referred for genetic counseling. Over generations, an inherited disorder automatically raises a suspicion of a genetic underlying cause. A careful analysis of a family pedigree enables to identify or to presume the mode in which hearing impairment is inherited. This in turn is an important step in directing genetic testing at specific genes that are causally involved in the pathogenesis of autosomal dominant, recessive, X-linked, or mitochondrial HL. In case of marriages between individuals with hearing impairment or between individuals coming from families with hearing impairment, the family pedigrees should be analyzed especially carefully. In the offspring of such couples, different HL causative variants of different genes may be found. Interestingly, in a study of 80 deafness genes, the DNA samples of HL patients were significantly enriched in potentially pathogenic variants [13]. One possible explanation of the phenomenon may the above-mentioned marriages between hearing impaired individuals. Attention should also be paid to the consanguinity between parents, which is common in certain populations. Looking for a genetic cause of HL in offspring of a consanguineous couple, the autosomal recessive mode of inheritance with pathogenic variants in a homozygous state is primarily expected.

A diagnostic challenge represents an HL patient without other affected family members, also referred to as a sporadic case. Here, a family history of HL is negative and a genetic cause is strongly suspected after exclusion of environmental factors, such as prenatal infection (with toxoplasmosis, rubella, cytomegalovirus, and herpesvirus—"TORCH" organisms), postnatal infections (mainly bacterial meningitis, mumps), prematurity, traumatic injury, blood vessels or autoimmune disease, Meniere's disease, acoustic neuroma, exposure to chemical agents, or noise that may be responsible for HL development. While describing HL, four major terms related to its presentation such as (I) the age of onset, (II) the type, (III) the degree of HL, and (IV) stability are usually used. The onset of HL can be congenital, prelingual (before a child develops speech), postlingual (after the acquisition of speech and language, usually after the age of six), adult-onset or age-related late-onset (presbyacusis). The different types of HL (conductive, sensorineural, or mixed) indicate which part of the ear is affected. Genetically determined HL is usually bilateral although families with asymmetric and unilateral HL are also reported [14, 15].

**Locus DFNB1, gene** *GJB***2, inheritance type: AR Remarks**

**Locus DFNB4, gene** *SLC***26***A***4, inheritance type: AR Remarks**

**Locus DFNA6/14/38, gene** *WFS***1, inheritance type: AD Remarks**

**Locus DFNX2, gene** *POU***3***F***4, inheritance type: X-linked Remarks**

**Gene** *MT-TS***1**, **inheritance type: X-linked Remarks**

**Table 2.** Pedigrees and audiometric features characteristic for different genes and pathogenic variants causative of HL.

Congenital, bilateral, profound

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Postlingual, bilateral, mild-to-

Enlarged vestibular aqueduct, vestibular dysfunction, Mondini malformation, early-onset, fluctuating HL [25]

Postlingual, low-frequency HL, deteriorating with time [26]

Congenital, profound, sensorineural HL (may be accompanied by a conductive component). Inner ear IP3 type malformation—comprises of enlarged internal auditory canal and vestibular aqueduct,

Postlingual, high-frequency HL [27]

underdeveloped cochlear modiolus and malformations of the vestibule. Due to the inner ear malformation perilymphatic gusher may occur during inner ear surgery [4]

moderate HL [24]

HL [23]

Truncating pathogenic variants (e.g., c.35delG)

Nontruncating pathogenic variants (e.g., p.Met34Thr)

Nontruncating, pathogenic variants (e.g.,

Nontruncating, pathogenic variants (e.g.,

p.Asp771His)

Truncating pathogenic variants (e.g., p.Glu187\*)

Pathogenic variants (e.g.,

m.7511T>C)

p.Glu29Gln)

It has been estimated that about 80% of prelingual HL results from genetic factors. It is most often inherited as an autosomal recessive feature without other accompanying medical problems The second most common inheritance pattern of prelingual HL is autosomal dominant (20%), while X-linked and mitochondrial constitute together approximately 1–1.5% [16]. Most of the reported families with nonsyndromic postlingual HL present an autosomal dominant pattern of inheritance. Currently, 36 different genes causally involved in autosomal dominant HL have been identified (www.herediataryhearingloss.org; accessed 10/2017) and only a few of them are associated with prelingual HL [17].

If hearing impairment represents an isolated finding that can be associated with abnormalities of the middle and/or inner ear but is not accompanied by visible abnormalities of the outer ear or any other medical problems, it is referred to as nonsyndromic or isolated. The major cause of prelingual severe-to-profound autosomal recessive nonsyndromic HL in many populations are pathogenic variants of the *GJB*2 gene. The *GJB*2 and *GJB*6 genes, contained within the *DFNB*1 locus, should be tested in the first line in patients with nonsyndromic bilateral sensorineural HL of the prelingual onset [18].

Pathogenic *GJB*2 variants are also identified as the second most frequent cause of mild-tomoderate autosomal recessive HL. The most common causes of HL in this group of patients are pathogenic variants of the *STRC* gene and the third causative gene in this category is *TECTA*, but the prevalences vary among different ethnic groups [13, 19].

Discussing the genetic causes underlying partial deafness, defined as normal or slightly deteriorated thresholds involving low frequencies combined with profound HL in high frequencies [20], pathogenic variants localized within mtDNA and *TMPRSS*3 should be considered for diagnostic purposes [21, 22]. Nevertheless, the contribution of other genes should be also taken into account.


**Table 1.** Genes involved in the pathogenesis of hearing disorders grouped according to the type of inheritance—examples.

#### **Locus DFNB1, gene** *GJB***2, inheritance type: AR Remarks**

Truncating pathogenic variants (e.g., c.35delG)

or autoimmune disease, Meniere's disease, acoustic neuroma, exposure to chemical agents, or noise that may be responsible for HL development. While describing HL, four major terms related to its presentation such as (I) the age of onset, (II) the type, (III) the degree of HL, and (IV) stability are usually used. The onset of HL can be congenital, prelingual (before a child develops speech), postlingual (after the acquisition of speech and language, usually after the age of six), adult-onset or age-related late-onset (presbyacusis). The different types of HL (conductive, sensorineural, or mixed) indicate which part of the ear is affected. Genetically determined HL is usually bilateral although families with asymmetric and unilateral HL are also reported [14, 15]. It has been estimated that about 80% of prelingual HL results from genetic factors. It is most often inherited as an autosomal recessive feature without other accompanying medical problems The second most common inheritance pattern of prelingual HL is autosomal dominant (20%), while X-linked and mitochondrial constitute together approximately 1–1.5% [16]. Most of the reported families with nonsyndromic postlingual HL present an autosomal dominant pattern of inheritance. Currently, 36 different genes causally involved in autosomal dominant HL have been identified (www.herediataryhearingloss.org; accessed 10/2017) and only a few

If hearing impairment represents an isolated finding that can be associated with abnormalities of the middle and/or inner ear but is not accompanied by visible abnormalities of the outer ear or any other medical problems, it is referred to as nonsyndromic or isolated. The major cause of prelingual severe-to-profound autosomal recessive nonsyndromic HL in many populations are pathogenic variants of the *GJB*2 gene. The *GJB*2 and *GJB*6 genes, contained within the *DFNB*1 locus, should be tested in the first line in patients with nonsyndromic bilat-

Pathogenic *GJB*2 variants are also identified as the second most frequent cause of mild-tomoderate autosomal recessive HL. The most common causes of HL in this group of patients are pathogenic variants of the *STRC* gene and the third causative gene in this category is

Discussing the genetic causes underlying partial deafness, defined as normal or slightly deteriorated thresholds involving low frequencies combined with profound HL in high frequencies [20], pathogenic variants localized within mtDNA and *TMPRSS*3 should be considered for diagnostic purposes [21, 22]. Nevertheless, the contribution of other genes should be also

AD *COCH* (DFNA9)*, WFS*1 (DFNA6/14/38)*, MYO*6 (DFNA22)*, GJB*2 (DFN3A)*, MYO*7*A*

AR *GJB*2 (DFNB1A)*, SLC*26*A*4 (DFNB4)*, MYO*15*A* (DFNB3)*, TMC*1 (DFNB7/11)*, TMPRSS*3

X-linked *POU*3*F*4 (DFNX2)*, PRPS*1 (DFNX1)*, SMPX* (DFNX4)*, COL*4*A*6 (DFNX6)*, AIFM*1 (DFNX5)

**Table 1.** Genes involved in the pathogenesis of hearing disorders grouped according to the type of inheritance—examples.

*TECTA*, but the prevalences vary among different ethnic groups [13, 19].

of them are associated with prelingual HL [17].

eral sensorineural HL of the prelingual onset [18].

taken into account.

34 An Excursus into Hearing Loss

**Inheritance pattern Genes and loci involved**

(DFNA11)

Mitochondrial *MT-TL*1*, MT-TK, MT-TS*1*, MT-TE, MT-RNR*1

(DFNB8/10)*, STRC* (DFNB16)

Nontruncating pathogenic variants (e.g., p.Met34Thr)

#### **Locus DFNB4, gene** *SLC***26***A***4, inheritance type: AR Remarks**

#### **Locus DFNA6/14/38, gene** *WFS***1, inheritance type: AD Remarks**

#### **Locus DFNX2, gene** *POU***3***F***4, inheritance type: X-linked Remarks**

Truncating pathogenic variants (e.g., p.Glu187\*)

m.7511T>C)

#### **Gene** *MT-TS***1**, **inheritance type: X-linked Remarks**

Congenital, bilateral, profound HL [23]

Postlingual, bilateral, mild-tomoderate HL [24]

Enlarged vestibular aqueduct, vestibular dysfunction, Mondini malformation, early-onset, fluctuating HL [25]

Postlingual, low-frequency HL, deteriorating with time [26]

Congenital, profound, sensorineural HL (may be accompanied by a conductive component). Inner ear IP3 type malformation—comprises of enlarged internal auditory canal and vestibular aqueduct, underdeveloped

cochlear modiolus and malformations of the vestibule. Due to the inner ear malformation perilymphatic gusher may occur during inner ear surgery [4]

Postlingual, high-frequency HL [27]

**Table 2.** Pedigrees and audiometric features characteristic for different genes and pathogenic variants causative of HL.

Considering the significant contribution of genetic factors to HL and the recent guideline for clinical evaluation and etiologic diagnosis of HL, one may conclude that single-gene testing is justified if a specific genetic etiology of HL is suspected. If there are no specific clinical indications, testing for the DFNB1-related HL should be performed. If the investigations do not provide conclusive results, HL genes may be analyzed by the NGS approaches such as multigene panels, whole exome or whole genome sequencing [16]. All known nonsyndromic deafness loci (locus denotes the position in the genome linked with the disease) are labeled as DFN (DeaFNess) and classified according to the type of inheritance (DFNA: autosomal dominant; DFNB: autosomal recessive; DFNX: X-linked) followed by a number indicating the order of locus discovery. In **Table 1**, some of the most common HL causative loci are gathered.

early-onset osteoarthritis [31]. Currently, four types of STL syndrome are distinguished autosomal dominant STL1 (OMIM#108300) and STL2 (OMIM# 604841) caused by pathogenic variants in *COL*2*A*1 and *COL*11*A*1, and autosomal recessive STL4 (OMIM#614134) and STL5 (OMIM#614284) due to pathogenic variants in *COL*9*A*1 and *COL*9*A*2 genes, respectively. The **Usher syndrome** (USH) is a combination of HL and visual impairment as a consequence of retinitis pigmentosa. The autosomal recessive condition is classified into three types: USH1 (OMIM#276900) with severe-to-profound deafness and defective vestibular function, USH2 (OMIM#276901) with mild-to-severe hearing impairment and normal vestibular function and USH3 (OMIM#276902) with progressive postlingual HL and vestibular dysfunction. Pathogenic variants in one of six genes (*MYO*7*A*, *USH*1*C*, *CDH*23, *PCDH*15, *USH*1*G*, or *CIB*2) may lead to USH1 [32], in one of three genes (*ADGRV*1, *WHRN*, or *USH*2*A*) to USH2 and in one of two genes (*CLRN*1 or *HARS*) to USH3. The second most common autosomal recessive syndrome with sensorineural HL is the **Pendred syndrome** (PDS, OMIM#274600), characterized by severe-to profound deafness that is congenital or develops in early childhood and euthyroid/hypothyroid goiter that arises in early puberty or adulthood. It is associated with developmental abnormalities of the cochlea (Mondini dysplasia or enlarged vestibular aqueduct) that can be diagnosed by a CT examination of temporal bones. The cause of the PDS is pathogenic variants in the *SLAC*26*A*4 gene encoding an anion transporter named pendrin. The third most common autosomal recessive syndrome with deafness is the **Jervell and Lange-Nielsen syndrome** (JLN), which is marked by congenital profound sensorineural HL and prolongation of the QT interval (corrected QT (QTc) > 440 msec), syncopal episodes due to ventricular arrhythmias and a high risk of sudden death. In patients with JLNS1 (OMIM#220400) pathogenic variants in *KCNQ*1 and in patients with JLNS2 (OMIM#612347) pathogenic variants in *KCNE*1 are

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The two following autosomal recessive syndromic forms of HL represent rare metabolic disorders that, however, should not be missed out as their symptoms may resolve by appropriate treatment and dietary modifications. The **Biotinidase deficiency** (BTD, OMIM#253260) is a form of multiple carboxylase deficiency characterized by primarily neurologic (seizures, hypertonia, developmental delay, ataxia) and cutaneous (skin rash, dermatitis, alopecia) features. Patients lose vision and three-fourth of those who become symptomatic have some degree of HL. Laboratory findings show organic aciduria, mild hyperammonemia, and biotinidase deficiency. The BTD begins usually within the two first years of life and results from recessive pathogenic variants in the *BTD* gene. Treatment with biotin resolves neurologic

and cutaneous manifestations, while HL and optic atrophy are usually irreversible.

green vegetables (phytanic acid), and animal fat (phytol), and plasmapheresis) are used.

The **Refsum disease** (OMIM#266500) is an inborn error of lipid metabolism with anosmia and early-onset retinitis pigmentosa being two universal findings. Other variable clinical features include neuropathy, ataxia, progressive severe HL, ichthyosis, cardiac, and skeletal (metacarpals/ metatarsals shortening) involvement. Increased serum concentration of phytanic acid establishes the diagnosis. The symptoms present an insidious onset usually during the late first through third decades of life. Causative recessive variants are found in the *PHYH* and *PEX*7 genes. In the medical care, diet modifications aimed at reduction of chlorophyll from the diet (exclusion of

found.

As it was previously stated, HL is a genetically heterogenous disease; nevertheless, there are some common, characteristic features, which may be a valuable asset in the process of dissecting the genetic reason of HL. Examples of pedigrees, characteristic audiometric features, and additional remarks for some common HL genes are shown in **Table 2**.

Despite quite a large number of genes causative for HL, the first step in the diagnostic approach should be the analysis of the DFNB1 locus, as the testing is inexpensive and fast [28]. Apart from obvious clinical indications, such as IP3 malformation for the *POU*3*F*4 gene analysis, the remaining cases should be rather streamed to wide, multigenic analysis.
