Genetic Basis of Hearing Loss

Introduction

Many factors can lead to hearing loss. Babies with hearing loss are genetically predisposed to 50 to 60 percent of cases. A variety of environmental factors might also result in hearing loss. At least 25 percent of infant hearing loss is brought on by "environmental" factors such as maternal infections during pregnancy and postpartum problems. Sometimes, hearing loss is brought on by both heredity and environment. For instance, some medications have the potential to result in hearing loss, but only in those with specific genetic abnormalities. The instructions that guide cells in people's bodies on how to develop and function are found in genes. For instance, a person's eye color is determined by genetic instructions. Numerous genes affect hearing. A gene may occasionally not develop as planned. It is known as a mutation. Depending on the mutation, some run in families, and some do not. It is referred to as "familial" when more than one member of a family suffers from hearing loss. It, therefore, runs in the family.

What Is Hearing Loss?

The impairment of auditory function caused by hearing loss can have serious long-term effects on a person's ability to communicate socially and linguistically. It can develop post-lingually (after speech and language development) or pre-lingually (before speech and language development). Hearing loss may be divided into two categories: sensorineural hearing loss (SNHL), which is brought on by malfunction of the inner ear or auditory nerve, and conductive hearing loss (CHL), which is brought on by a decrease in sound transmission via the external or middle ear to the inner ear. There are conductive and sensorineural components to mixed hearing loss. Inherited (e.g., hereditary) and acquired (e.g., noise-induced) types of sensorineural hearing loss can be distinguished. The genetic processes, diagnosis, and therapy of hereditary SNHL will be the main topics of this paper.

What Are the Genetic Hearing Loss Causes?

Hearing loss is a sign of an underlying pathogenic change to the auditory system rather than a diagnosis. Eighty percent of prelingual hearing loss is related to genetic factors, and a significant portion of people with adult-onset hearing loss also have a genetic component. Finding the genetic cause of hearing loss gives people and their families knowledge about the prognosis (e.g., whether hearing loss is static or progressive), whether hearing loss is nonsyndromic or syndromic (i.e., associated with other medical issues), the availability of disease-specific therapies, the possibility of recurrence, and habilitation options and other forms of supportive care.

• Nonsyndromic hearing loss is not linked to external ear abnormalities that can be seen or to other medical conditions, although it can be linked to middle ear and/or inner ear issues.

• Any combination of external ear abnormalities, disease problems affecting other organs or organ systems, or both is connected with syndromic hearing loss.

• Hearing loss that is not syndromic In the early presenting phase, when other organ system involvement may not be obvious on medical history and/or physical examination, syndromic hearing loss "mimics" nonsyndromic hearing loss. It should be noted that 20 % of children who initially have hearing loss as their only clinical symptom (i.e., who appear to have nonsyndromic hearing loss) will later be identified as having syndromic hearing loss.

1. Nonsyndromic Hearing Loss: There are more than 125 genes linked to nonsyndromic hearing loss. Prelingual hereditary hearing loss is nonsyndromic in around 70 % of cases. The majority of people (80 %) with non-syndromic hereditary hearing loss have biallelic pathogenic mutations that are inherited in an autosomal recessive manner. Additionally, autosomal dominant inheritance accounts for 19% of non-syndromic hearing loss inheritance, whereas X-linked or mitochondrial heredity accounts for 1 % of cases. Although similar data for postlingual nonsyndromic genetic hearing loss are not yet available, autosomal dominant inheritance is most frequently observed.

2. Recessive Autosomal Lack of Symptoms in Hearing: Autosomal recessive nonsyndromic hearing loss has been linked to more than 70 genes. Prelingual and severe to profound hearing loss are the norms for autosomal recessive nonsyndromic hearing loss.

1. BDP1: HL can be progressive & postlingual.

2. CDH23: Assoc w/phenotypic spectrum incl AR nonsyndromic HL & AR syndromic HL.

3. EPS8L2: HL can be progressive & postlingual.

4. GJB2: A most common cause of severe-to-profound AR nonsyndromic HL in Asian & White populations.

5. LOXHD1: HL can be progressive & postlingual.

6. MYO7A: HL can be progressive & postlingual. Assoc w/phenotypic spectrum incl AR & AD non-syndromic HL & AR syndromic HL (See Usher syndrome type I.)

7. PCDH15: Assoc w/phenotypic spectrum incl AR nonsyndromic HL & AR syndromic HL (See Usher syndrome type I.)

8. SLC26A4: HL can be pre- or postlingual, asymmetric, & progressive.

9. STRC: Biallelic STRC pathogenic variants are the most common cause of mild-to-moderate AR HL and the 2nd most common cause of AR HL overall.

10. TECTA & TMC1: Assoc w/phenotypic spectrum incl AR & AD nonsyndromic HL.

11. TMPRSS3: HL can be progressive & postlingual.

12. USH1C: Assoc w/phenotypic spectrum incl AR nonsyndromic HL & AR syndromic HL (See Usher syndrome type I.)

13. WHRN: Assoc w/phenotypic spectrum incl AR nonsyndromic HL & AR syndromic HL (See Usher syndrome type II.)

3. Autosomal Dominant Nonsyndromic Hearing Loss: With autosomal dominant nonsyndromic hearing loss, 50 genes have been linked. Autosomal dominant nonsyndromic hearing loss is often high frequency, postlingual, and progressive.

1. COL11A2 & DIAPH1: HL is low-frequency or mid-frequency.

2. GJB2: HL is prelingual. Assoc w/phenotypic spectrum incl AR (GJB2-DFNB) 1 & AD (GJB2-DFNA) 1 nonsyndromic HL.

3. MYO7A: Assoc w/phenotypic spectrum incl AD & AR nonsyndromic HL & AR syndromic HL (See Usher syndrome type I.)

4. TECTA: HL is prelingual. Assoc w/phenotypic spectrum incl AR & AD nonsyndromic HL.

5. TMC1: Assoc w/phenotypic spectrum incl AR & AD nonsyndromic HL.

6. WFS1: HL is low-frequency or mid-frequency.

4. X-Linked Nonsyndromic Hearing Loss: X-linked nonsyndromic prelingual or postlingual hearing loss is connected to five genes: AIFM1, COL4A6, POU3F4, PRPS1, and SMPX.

1. AIFM1: Assoc w/phenotypic spectrum incl XL nonsyndromic auditory neuropathy & XL syndromic auditory neuropathy w/other assoc neuropathies such as ataxia & Cowchock syndrome (X-linked recessive Charcot-Marie-Tooth disease type 4)

2. POU3F4: Assoc w/mixed conductive-sensorineural HL. Conductive hearing loss in this disorder is caused by stapedial fixation (see Agents/Circumstances to Avoid).

3. PRPS1: Assoc w/phenotypic spectrum incl XL nonsyndromic HL (PRPS1-DFNX) 1 & XL syndromic HL (phosphoribosylpyrophosphate synthetase (PRS) superactivity & PRS deficiency).

5. Mitochondrial DNA (mtDNA) Hearing Loss: Hearing loss linked to mitochondrial DNA is passed down maternally. The majority of multisystem illnesses and syndromic multisystem disorders are involved in mtDNA hearing loss. There are exceptions, such as the genes MT-RNR1 and MT-TS1, where hearing loss is nonsyndromic and most likely results from greater susceptibility to the cellular harm produced by aminoglycoside antibiotics and other ototoxic medications.

6. Syndromic Hearing Loss: A constellation of additional clinical abnormalities and organ system involvement are linked to syndrome hearing loss. Over 400 disorders have been linked to hearing loss. To rule out a syndromic illness, a comprehensive study should be prompted by the diagnosis of hearing impairment in a kid. Depending on the illness, the degree of hearing loss might range from modest impairment to catastrophic loss. Syndromic hearing loss can be inherited in an autosomal recessive, autosomal dominant, X-linked, or mitochondrial manner, much as non-syndromic deafness.

7. Autosomal Recessive Syndromic Hearing Loss:

1. Pendred Syndrome: It accounts for 10 % of all instances of hereditary hearing loss and is the most common cause of syndromic hearing loss.

2. Usher Syndromes: They accounts for 50 % of all instances of deafness-blindness, are the most prevalent syndromes affecting both hearing and vision and a common cause of autosomal recessive syndromic hearing loss. Usher syndrome has three subtypes: USH1, USH2, and USH3. Each has retinitis pigmentosa, hearing loss, and vestibular impairment to varied degrees.

3. Jervell and Lange-Nielsen Syndrome: SNHL and extended QTc intervals (>500 ms) are features of Jervell and Lange-Nielsen syndrome (JLNS).

4. Romano-Ward Syndrome: Romano-Ward syndrome, a related condition, does not have SNHL. The genes KCNQ1 and KCNE1, which encode potassium channel subunits in cardiac and auditory tissue, are the genetic causes of JLNS. An EKG should also be performed for children who have been diagnosed with sensorineural hearing loss to check for extended QTC intervals.

5. Miller Syndrome: At 1 per 1,000,000 live births, Miller syndrome is extremely uncommon. It is characterized by limb malformations, conductive hearing loss brought on by middle ear abnormalities, and craniofacial defects.

6. Nager Syndrome: Sensorineural hearing loss, abnormal ears, and facial and limb deformities are all parts of the Nager syndrome.

8. Autosomal Dominant Syndromic Hearing Loss:

1. Branchio-oto-renal Syndrome: About two percent of children with substantial hearing loss have the branchio-oto-renal (BOR) syndrome, which is characterized by a constellation of otologic, renal, and branchial arch abnormalities.

2. Waardenburg Syndrome: It has a frequency of 1 in 40,000 live births, and is characterized by SNHL and aberrant eye, skin, and hair coloring. Both iris heterochromia and the traditional "white forelock" are possible in patients.

3. Goldenhar Syndrome: Although it seldom occurs, autosomal dominant inheritance makes for the majority of the inheritance patterns for Goldenhar syndrome (hemifacial microsomia).

4. CHARGE Syndrome: It is characterized by coloboma, hearing abnormalities, atresia choanalis, stunted development, genitourinary deformities, and ear defects. It occurs in 1 in 8,500 to 10,000 live births.

5. Stickler Syndrome: It affects 1 in 7,500 to 9,000 live births, and is most frequently brought on by mutations in the COL2A gene, which is in charge of producing type II collagen. Flattened facial features, myopia, cleft palate, macroglossia, arthritis, scoliosis, and mitral valve prolapse are some of its characteristics.

6. Treacher Collins Syndrome: It has deformities of the face, eyes, and ears and has a frequency of 1 per 50,000 live births. Conduction hearing loss or high-frequency sensorineural hearing loss affects 40 to 50 percent of youngsters.

7. Apert Syndrome: The symptoms of Apert syndrome include craniosynostosis, frontal bossing, syndactyly, and visual and hearing impairment. It affects 1 in 65,000 to 88,000 live births. Ossicular chain fixation or middle ear effusions can cause patients to experience bilateral conductive hearing loss. Cochlear dysplasia can result in sensory hearing loss.

How Are they Evaluated?

• Hearing Screening for Newborns: The Universal Newborn Hearing Screening Program (UNHS) has greatly aided in the identification of children with hearing loss and lowered the average age of diagnosis from 24 to 30 months to two to three months. Children who fail the otoacoustic emissions (OAE) test during the screening will have to do it again in a few weeks. To validate the hearing loss, auditory brainstem evoked (ABR) testing is necessary if the kid keeps failing the hearing tests. Evoked otoacoustic emissions and auditory brainstem response tests have significantly increased the number of kids who have been diagnosed with hearing loss and decreased the number of babies who were mistakenly diagnosed with hearing loss.

• Genetic Testing: Genetic factors account for 50 % of all juvenile hearing loss and 66% of prelingual hearing loss. Only hearing loss above 35 dB may be detected by current hearing screening programs. Because routine screening misses children with moderate SNHL, genetic screening can assist. The three following questions should be addressed by clinicians: Is there an environmental cause? Does a pattern of symptoms and clinical traits that would point to a syndrome? Is there a family history of hearing loss with comparable onset and type patterns?

• Computed Tomography (CT): CT scans can be performed to look for any structural abnormalities that may be the cause of hearing loss in the temporal bones, mastoid, otic capsule, and middle ear. Mondini dysplasia, which is the hypoplasia of the cochlear basal turn and results in progressive SNHL, is one of the most frequent CT findings in SNHL. It is necessary to perform genetic testing for Pendred syndrome in patients of dilated vestibular aqueducts.

• Nuclear Magnetic Resonance Imaging (MRI): High resolution can find malformations of the cerebellopontine angle, internal auditory canal, and membranous labyrinth. The pars inferior is impacted by Scheibe dysplasia or cochleosaccular dysplasia. High-frequency hearing loss results from Alexander malformation, which damages the cochlear duct and basal turn of the cochlea. Cochlear nerve dysplasia or aplasia, which might be the cause of sensorineural hearing loss, can be found using MR imaging.

What Are the Treatments?

Electronic devices and conventional hearing aids increase the sound of the ears. Patients with mild to severe sensorineural hearing loss who have outstanding to exceptional speech recognition and hearing clarity typically benefit from them. In the ear (ITE), Behind the ear (BTE), and Canal types (either in the canal (ITC) or fully in the canal (CIC)) are the three different varieties of hearing aids. The majority of kids are fitted with BTE hearing aids, which makes them easier to use over time since they can easily be modified to fit a growing kid while still utilizing the same housing. The benefit of being less noticeable comes with non-BTE hearing aids.

Candidates for cochlear implantation are people with severe to profound hearing loss who receive little to no gain with hearing aids. A cochlear implant is an electronically implanted medical device that stimulates the auditory nerve's afferent fibers with electrical current in tandem with an external sound processor. With training and experience, they can give access to a larger frequency range and enhance speech interpretation, even if they do not completely replace acoustic hearing.

It has been demonstrated that cochlear implants considerably improve speech and language development in newborns who are deaf, with earlier implantation resulting in a larger vocabulary. For post-lingual deafness and those with early-identified deafness (younger than the age of two years), early cochlear implant intervention yields the greatest cochlear implant results. For babies who match the requirements and are as young as nine months old, the FDA has officially approved cochlear implantation. CHARGE syndrome, Jervell and Lange-Neilsen syndrome, Waardenburg syndrome, Usher syndrome, and Pendred syndrome have all been proven to benefit from cochlear implantation.

Conclusion

The impairment of auditory function caused by hearing loss can have serious long-term effects on a person's ability to communicate socially and linguistically. It can develop post-lingually (after speech and language development) or pre-lingually (before speech and language development). Social development may be significantly impacted by genetic hearing loss. They can be inherited through a variety of methods and manifest either prelingually or postlingually. This disorder has to be quickly detected and treated to prevent its long-term effects. The interprofessional team's involvement in diagnosing and treating individuals with genetic hearing loss is highlighted in this exercise, which also examines genetic hearing loss diagnosis and therapy.