**6. Syndromic genetic deafness**

More than 400 syndromes have been described in OMIM. Here, genetic aspects of common syndromes which are associted with HL are briefly explained.

**Usher Syndrome:** Usher syndrome, named after Charles Usher (1914) a British ophthalmologist, is the most prevalent cause of autosomal recessive HL, accounting for nearly 3-5 per 100,000 in the general population and 1-10% among profoundly deaf children [Boughman et al., 1983]. Several clinical subtypes have been distinguished based on its characterized features i. e. severity of the HL and the onset of retinitis pigmentosa [Yan & Liu, 2010]. Type 1 patients have profound HL, vestibular dysfunction and the onset of retinitis pigmentosa in childhood [Hope et al., 1997]. The type 2 patients have normal vestibular response, mild to moderate HL and RP begins in the second decade of life [Hope et al., 1997]. Progressive HL and variable vestibular response characterize type 3 patients and the onset of retinitis pigmentosa is variable as well [Smith et al., 1995]. Usher syndrome has a heterogeneous causality (Table 6); to date, 12 different loci and 10 genes have been reported (http://hereditaryhearingloss.org/). One of these identified genes, *MYO7A*, encoding myosin 7A, is a unique molecular motor for hair cells [Weil et al., 1995]. Cadherin 23, an adhesion molecule, coded by *CDH23* gene may have an important role in crosslinking of stereocilia [Bolz et al., 2001; Bork et al., 2001].


Table 6. Reported genes for Usher syndrome.

**Pendred syndrome:** Pendred syndrome, named after Vaughan Pendred (1896) a British physician, is the most common syndromic form of HL and associated with abnormal iodine metabolism (goiter). It is an autosomal recessive disorder which accounts for 4-10% of deaf cases [Fraser 1965]. The defective organic binding of iodine in the thyroid gland may distinguished by a positive potassium perchlorate discharge test; however the test is not specific and its sensitivity is unclear. HL is usually bilateral, severe to profound and may be present at birth, and sloping in the higher frequencies [Kopp et al., 2008]. The casual gene is *SLC26A4* (PDS) on chromosome 7q31 encoding a protein named pendrin (Figure 3). It regulates transportation of iodine and chloride/ bicarbonate ions in the inner ear, thyroid, and kidney. Mutations of this gene can cause NSHL DFNB4 and enlarged vestibular aqueduct syndrome as well [Everett et al., 1997].

More than 400 syndromes have been described in OMIM. Here, genetic aspects of common

**Usher Syndrome:** Usher syndrome, named after Charles Usher (1914) a British ophthalmologist, is the most prevalent cause of autosomal recessive HL, accounting for nearly 3-5 per 100,000 in the general population and 1-10% among profoundly deaf children [Boughman et al., 1983]. Several clinical subtypes have been distinguished based on its characterized features i. e. severity of the HL and the onset of retinitis pigmentosa [Yan & Liu, 2010]. Type 1 patients have profound HL, vestibular dysfunction and the onset of retinitis pigmentosa in childhood [Hope et al., 1997]. The type 2 patients have normal vestibular response, mild to moderate HL and RP begins in the second decade of life [Hope et al., 1997]. Progressive HL and variable vestibular response characterize type 3 patients and the onset of retinitis pigmentosa is variable as well [Smith et al., 1995]. Usher syndrome has a heterogeneous causality (Table 6); to date, 12 different loci and 10 genes have been reported (http://hereditaryhearingloss.org/). One of these identified genes, *MYO7A*, encoding myosin 7A, is a unique molecular motor for hair cells [Weil et al., 1995]. Cadherin 23, an adhesion molecule, coded by *CDH23* gene may have an important role in crosslinking

**6. Syndromic genetic deafness** 

of stereocilia [Bolz et al., 2001; Bork et al., 2001].

Table 6. Reported genes for Usher syndrome.

aqueduct syndrome as well [Everett et al., 1997].

Locus Gene Ref.

USH1B (11q13.5) *MYO7A* Weil et al.,1995 *USH1C* (11p15.1) *USH1C* Smith et al., 1992 USH1D (10q22.1) *CDH23* Bork et al., 2001 USH1F (10q21-22) *PCDH15* Ahmed et al., 2001 USH1G (17q24-25) *SANS* Mustapha et al., 2002 *USH2A* (1q41) *USH2A* Kimberling et al., 1990 USH2C (5q14.3-q21.3) *VLGR1* Weston et al., 2004 USH2D (9q32) *WHRN* Ebermann et al., 2007 USH3 (3q21-q25) *USH3A* Joensuu et al., 2001 10q24.31 *PDZD7* Ebermann et al., 2010

**Pendred syndrome:** Pendred syndrome, named after Vaughan Pendred (1896) a British physician, is the most common syndromic form of HL and associated with abnormal iodine metabolism (goiter). It is an autosomal recessive disorder which accounts for 4-10% of deaf cases [Fraser 1965]. The defective organic binding of iodine in the thyroid gland may distinguished by a positive potassium perchlorate discharge test; however the test is not specific and its sensitivity is unclear. HL is usually bilateral, severe to profound and may be present at birth, and sloping in the higher frequencies [Kopp et al., 2008]. The casual gene is *SLC26A4* (PDS) on chromosome 7q31 encoding a protein named pendrin (Figure 3). It regulates transportation of iodine and chloride/ bicarbonate ions in the inner ear, thyroid, and kidney. Mutations of this gene can cause NSHL DFNB4 and enlarged vestibular

syndromes which are associted with HL are briefly explained.

Fig. 3. Hypothetic structure and domains of Pendrin protein. The most common mutations (L236P, IVS8+1G>A, T416P, and H723R) accounting for approximately 60% of the total PS genetic load are shown. TM1-TM12 denotes transmembrane domains, EC1-6 denotes extracellular domains, IC denotes cytoplasmic domain, NT denotes amino (NH2) terminus and CT denotes carboxyl (COOH) terminus.

**Alport syndrome:** Alport syndrome, a hereditary disorder of basement membranes, is characterized by renal abnormalities including glomerulonephritis, hematuria ("red diaper") and renal failure, and ocular problems as well as progressive sensorineural HL [Wester et al., 1995]. Mutations in various genes encoding type 4 collagen (COL4A3, COL4A4 and COL4A5) have been reported to cause Alport syndrome [Lemmink et al., 1994; Hudson et al., 2003]; nearly 85% of the cases are due to COL4A5 mutations [Hudson et al., 2003]. These collagens are components of the basilar membranes, the spiral ligament and stria vascularis. X-linked pattern of inheritance is observed in the majority (80 %); the remaining shows autosomal recessive [Lemmink et al., 1994] and autosomal dominant [van der Loop et al., 2000], inheritance patterns. It is estimated that 10% to 15% of X-linked patients represent de novo mutations in *COL4A5* [Gubler et al., 2007]. Since uremia leads to death in males prior to 30 years of age, it is essential to diagnose it early in men. Symptoms are usually more severe than women. The progressive sensorineural HL usually begins in the adolescent years [Wester et al., 1995]. The mechanism of HL has not been explained exactly yet, although the basement membrane damages are suggested to affect adhesion of the cells of the organ of Corti and basilar membrane leading to HL [Merchant et al., 2004].

**Waardenburg syndrome**: Waardenburg disease, named after Petrus Johannes Waardenburg (1886-1979), accounts for 1-3% of congenital HL [Read & Newton, 1997]. In addition, the disease shows other clinical features. Four types of syndrome can be distinguished on the basis of accompanying abnormalities [Read & Newton, 1997]: In type 1, patients show dystopia canthorum, iris heterochromy, brilliant blue eyes, broad nasal root, premature

Genetics of Hearing Loss 229

The main problem in the diagnosis of disorders such as deafness is its heterogenicity.

e. Providing appropriate genetic counseling before marriage, especially when they have

Genetic evaluation should be considered for children with newly diagnosed loss of hearing especially if no specific cause is determined. For example, there is no need for genetic evaluation of the family of a child with HL due to meningitis; although, they may need assurance of not transmitting the disease to the next generation. Genetic evaluation includes

1. Reviewing the complete history of prenatal, neonatal and medical history of growth and

Based on previous studies, deaf people have positive assortive marriage; it is estimated that 90% of deaf individuals marry deaf. Depending on the pattern of inheritance they might have a deaf child. For example if both parental recessive alleles are similar, there is 100% chance of having a deaf child; and if one of the parents carry a dominant form of HL and the other carry the recessive form of HL the chance would be 50% for the dominant gene.

Early diagnosis of HL is important in gaining speech progression and social skills of the children which would lead to better life of these individuals and would later help them in cochlea implant. Hereditary or genetic understanding of the causes of HL is important. The benefits of this understanding and knowledge, not only allows physicians to help the families of at risk but also may help in treatment and control of HL. Sometimes it is possible to prevent hearing loss from worsening. HL may be one of the clinical signs of a syndrome and if the genetic cause of HL is determined it may help to predict and treat other clinical

HL is the most common sensory defect affecting human beings. It is categorized on the basis of several criteria. Genetic factors can be traced in half of the cases. Nonsyndromic HL can follow any of the Mendelian inheritance patterns, but the majority are ARNSHL. Approximately fifty genes have been reported to be involved in HL, and based on an estimation nearly 200 to 250 genes may cause HL. Genetic understanding of the causes of HL and finding the molecular mechanism of hearing process are valuable for genetic counseling, prevention and development of new therapeutic approaches. Many studies have been published about finding new genes causing prelingual nonsyndromic HL. Presbycusis is very common among eldely people and research on this phenotype needs more attention.

Genetic study of HL has considerable benefits for patients which are as follows:

a. Identifying the medical and non medical decisions e.g cochlear implant

heterogeneous conditions that carry different mutated genes.

2. Complete physical examination of patients and other family members

3. Evaluating the genetics, molecular and cellular diagnosis

**7. Genetic evaluation** 

several steps:

development

complications [Extivill et al., 1998].

**8. Conclusion** 

b. Carrier testing and prenatal diagnosis

c. Prediction for the progressive state of the disease d. Eliminating unnecessary tests and investigations

graying of hair, white forelock, and vestibular dysfunction. Type 2 patients have similar phenotype but not dystopia canthorum. In type 3 (so called Klein-Waardenburg syndrome) [Klein, 1983], upper extremity abnormalities other Type 1 clinical features and dystopia canthorum and are observed. In type 4 (so called Shah-Waardenburg syndrome) [Shah et al., 1981] patients demonstrate all findings shown in Type 2 with the addition of pigmentation abnormalities and Hirschsprung's disease. Sensorineural hearing loss is observed in 60 % and 90 % of type 1 and type 2 patients, respectively [Newton, 1990].

Types 1 and 3 of Waardenburg syndrome occur due to mutations in the *PAX3* gene encoding a DNA-binding protein essential for determining the fate of neural crest cells [Baldwin et al., 1994]. Type 2 is due to mutations in MITF gene [Tassabehji et al., 1994]. Mutations in three genes, *EDN3*, *SOX10* and *EDNRB* genes, can lead to Type 4 [Edery et al., 1996; Hofstra et al., 1996; Pingault et al., 1998]. *SOX10* mutations, account for approximately half of type 4 patients and are likely responsible for about 15% of Type 2 as well [Bondurand et al., 2007]. *In vitro* studies have shown that *EDN3* plays as a stimulation factor of proliferation and melanogenesis of neural crest cells. *EDNRB* is suggested to have an important role in the development of epidermal melanocytes and enteric neurons. *SOX10* is a DNA-binding transcription factor and involved in promoting cell survival prior to lineage commitment [Kapur, 1999]. There is a wide range of variation in HL phenotype so that some patients may not exhibit HL.

**Branchio-oto-renal syndrome:** Branchio-oto-renal syndrome (BOR) is an autosomal dominant disorder, accounting for 2% of profoundly deaf children and is characterized by branchial derived anomalies, otologic anomalies (Mondini's dysplasia and stapes fixation) and renal malformation. HL may affect 70-93% of the BOR patients but there is a high variability in age of onset and severity [Chen et al., 1995]. HL can be sensorineural, conductive or mixed, stable or progressive and mild or profound. Mutations in *EYA1* gene have been identified to cause BOR syndrome (BOR1) [Abdelhak et al., 1997]. It has been shown that this gene has a role in development of the inner ear and kidney [Abdelhak et al., 1997]. Studies of transgenic mice have indicated that EYA1 homozygous knockouts have not developed ears and kidneys. In addition to *EYA1*, mutations in two genes named SIX1 and SIX5 have been reported to cause BOR3 and BOR2, respectively [Ruf et al., 2004; Hoskins et al., 2007].

**Stickler Syndrome:** Stickler Syndrome (STL), named after Stickler (1965), follows an autosomal dominant pattern of inheritance and is characterized by progressive sensorineural HL, cleft palate, abnormal development of the epiphysis, vertebral abnormalities and osteoarthritis. On the basis of clinical features, four types of STL exist. Type 1 patients have typical features of the disease including progressive myopia leading to retinal detachment, midface hypoplasia, cleft palate, variable sensorineural HL and vitreoretinal degeneration. Mutations in *COL2A1* gene encoding a fibrillar collage type 2 subunitA1 can cause the classic phenotype [Ahmad et al., 1991]. There is no retinal detachment in Type 2 andthe phenotype is caused by *COL11A1* gene mutations [Richards et al., 1996]. Facial abnormalities seen in Type 1 are not observed in Type 3. Mutations of *COL11A2* lead to STL Type 3 [Vikkula et al., 1995]. Recently, mutations in *COL9A1* have been identified to cause an autosomal recessive form of STL, Type 4 [Van Camp et al., 2006].

graying of hair, white forelock, and vestibular dysfunction. Type 2 patients have similar phenotype but not dystopia canthorum. In type 3 (so called Klein-Waardenburg syndrome) [Klein, 1983], upper extremity abnormalities other Type 1 clinical features and dystopia canthorum and are observed. In type 4 (so called Shah-Waardenburg syndrome) [Shah et al., 1981] patients demonstrate all findings shown in Type 2 with the addition of pigmentation abnormalities and Hirschsprung's disease. Sensorineural hearing loss is observed in 60 % and 90 % of type 1 and type 2 patients, respectively [Newton, 1990].

Types 1 and 3 of Waardenburg syndrome occur due to mutations in the *PAX3* gene encoding a DNA-binding protein essential for determining the fate of neural crest cells [Baldwin et al., 1994]. Type 2 is due to mutations in MITF gene [Tassabehji et al., 1994]. Mutations in three genes, *EDN3*, *SOX10* and *EDNRB* genes, can lead to Type 4 [Edery et al., 1996; Hofstra et al., 1996; Pingault et al., 1998]. *SOX10* mutations, account for approximately half of type 4 patients and are likely responsible for about 15% of Type 2 as well [Bondurand et al., 2007]. *In vitro* studies have shown that *EDN3* plays as a stimulation factor of proliferation and melanogenesis of neural crest cells. *EDNRB* is suggested to have an important role in the development of epidermal melanocytes and enteric neurons. *SOX10* is a DNA-binding transcription factor and involved in promoting cell survival prior to lineage commitment [Kapur, 1999]. There is a wide range of variation in HL phenotype so that

**Branchio-oto-renal syndrome:** Branchio-oto-renal syndrome (BOR) is an autosomal dominant disorder, accounting for 2% of profoundly deaf children and is characterized by branchial derived anomalies, otologic anomalies (Mondini's dysplasia and stapes fixation) and renal malformation. HL may affect 70-93% of the BOR patients but there is a high variability in age of onset and severity [Chen et al., 1995]. HL can be sensorineural, conductive or mixed, stable or progressive and mild or profound. Mutations in *EYA1* gene have been identified to cause BOR syndrome (BOR1) [Abdelhak et al., 1997]. It has been shown that this gene has a role in development of the inner ear and kidney [Abdelhak et al., 1997]. Studies of transgenic mice have indicated that EYA1 homozygous knockouts have not developed ears and kidneys. In addition to *EYA1*, mutations in two genes named SIX1 and SIX5 have been reported to cause BOR3 and BOR2, respectively [Ruf et al., 2004;

**Stickler Syndrome:** Stickler Syndrome (STL), named after Stickler (1965), follows an autosomal dominant pattern of inheritance and is characterized by progressive sensorineural HL, cleft palate, abnormal development of the epiphysis, vertebral abnormalities and osteoarthritis. On the basis of clinical features, four types of STL exist. Type 1 patients have typical features of the disease including progressive myopia leading to retinal detachment, midface hypoplasia, cleft palate, variable sensorineural HL and vitreoretinal degeneration. Mutations in *COL2A1* gene encoding a fibrillar collage type 2 subunitA1 can cause the classic phenotype [Ahmad et al., 1991]. There is no retinal detachment in Type 2 andthe phenotype is caused by *COL11A1* gene mutations [Richards et al., 1996]. Facial abnormalities seen in Type 1 are not observed in Type 3. Mutations of *COL11A2* lead to STL Type 3 [Vikkula et al., 1995]. Recently, mutations in *COL9A1* have been identified to cause an autosomal recessive form of STL, Type 4 [Van Camp et al.,

some patients may not exhibit HL.

Hoskins et al., 2007].

2006].
