STRC-Related Autosomal Recessive Hearing Loss
Synonym: STRC-Related Sensorineural Hearing Loss
Shelby Redfield, MS, CGC and A Eliot Shearer, MD, PhD.
Author Information and AffiliationsInitial Posting: December 14, 2023.
Estimated reading time: 24 minutes
Summary
Clinical characteristics.
STRC-related autosomal recessive hearing loss (STRC-HL) comprises both nonsyndromic sensorineural hearing loss and sensorineural hearing loss with decreased fertility in males who have biallelic contiguous gene deletions involving STRC and CATSPER2. The hearing loss is mild to moderate, congenital, bilateral, and symmetric. Mean pure tone hearing loss averages 40-50 decibels (dB) at the time of diagnosis; hearing loss is not severe to profound in children or young adults. Of note, while many newborns with STRC-HL will be identified by newborn hearing screening (NBHS), some newborns with STRC-HL will not because some screening methods may not detect milder hearing loss.
Males with biallelic contiguous gene deletions involving STRC and CATSPER2 are at risk for CATSPER2-related male infertility due to morphologic sperm abnormalities that affect sperm motility. In contrast, females with contiguous gene deletions do not have related fertility issues.
Diagnosis/testing.
The diagnosis of STRC-HL is established in a proband with suggestive findings who has ONE of the following identified by molecular genetic testing: (1) biallelic STRC pathogenic variants; (2) one STRC pathogenic variant and one contiguous gene deletion involving STRC and CATSPER2; or (3) biallelic contiguous gene deletions involving STRC and CATSPER2.
Management.
Treatment of manifestations: Multidisciplinary supportive treatment for hearing loss that includes an otolaryngologist with expertise in the management of early childhood otologic disorders, an audiologist experienced in the assessment of hearing loss in children, a speech-language pathologist, a clinical geneticist, a genetic counselor, and a pediatrician is recommended. Hearing aids (i.e., sound amplification), customized by an audiologist to the degree and frequency of hearing loss, may be recommended for individuals who have mild-to-moderate hearing loss.
When males with biallelic contiguous gene deletions involving STRC and CATSPER2 reach reproductive age, consultation with a reproductive specialist/endocrinologist for consideration of fertility-related evaluations is appropriate.
Surveillance: To monitor the degree of hearing loss, the individual's response to use of hearing aids, and development of speech and language, the following are recommended: (1) annual examination by an otolaryngologist familiar with genetic hearing loss to evaluate overall ear health; (2) repeat audiometry to identify any change in hearing, typically (a) every three months between birth and age two years, (b) every six months between ages two and five years, and (c) annually in children age five years and older if hearing is stable and there are no other otologic concerns; and (3) evaluation of speech/language/communication needs as recommended by a speech-language pathologist.
Agents/circumstances to avoid: Prolonged noise exposure exceeding 85 dB, including loud noise exposure from headphones and earbuds. Note that a headphone safety feature built into most smartphones can be set to limit the noise level.
Evaluation of relatives at risk: It is appropriate to clarify the genetic status of sibs of a proband with STRC-HL; early identification of infants and children with hearing loss allows appropriate support and management to be provided to the child and family.
Genetic counseling.
STRC-HL is inherited in an autosomal recessive manner. The parents of an individual with STRC-HL are typically heterozygous for a genetic alteration involving STRC (i.e., a STRC pathogenic variant or a contiguous gene deletion involving STRC and CATSPER2). If both parents are known to be heterozygous for a genetic alteration involving STRC, each sib of the proband has at conception a 25% chance of having STRC-HL, a 50% chance of being a carrier and not having STRC-HL, and a 25% chance of not being a carrier and not having STRC-HL. Males with biallelic contiguous gene deletions involving STRC and CATSPER2 are at risk of decreased fertility due to abnormal sperm motility; thus, when they reach reproductive age they may benefit from fertility counseling and discussion of assistive reproductive technology options. Once the genetic alterations involving STRC have been identified in a family member with STRC-HL, prenatal and preimplantation genetic testing are possible.
GeneReview Scope
GeneReview Scope: STRC-Related Autosomal Recessive Hearing Loss
View in own window
| Phenotype | Genotype |
|---|
| Nonsyndromic sensorineural hearing loss 1 | Biallelic STRC pathogenic variants |
| One STRC pathogenic variant & one contiguous gene deletion involving STRC & CATSPER2 |
| Sensorineural hearing loss w/decreased fertility in males | Biallelic contiguous gene deletions involving STRC & CATSPER2 |
Diagnosis
Suggestive Findings
The diagnosis of STRC-related autosomal recessive hearing loss (STRC-HL) should be considered in two scenarios: an abnormal newborn hearing screening (NBHS) result and a symptomatic individual with hearing loss.
Scenario 1: Abnormal Newborn Hearing Screening (NBHS) Result
Universal newborn hearing screening (NBHS) uses physiologic screening, either otoacoustic emissions (OAEs), which measure the response of the cochlea to auditory stimuli, or automated auditory brain stem response (AABR) testing, which measures physiologic response of the auditory nerve, brain stem, and brain to varying auditory stimuli. NBHS, required by law or rule in all 50 states in the United States, is performed on >98% of children in the US typically within days after birth (see www.cdc.gov). Note that NBHS, which is designed to detect moderate-to-profound hearing loss, may miss infants with mild hearing loss depending on the screening protocol used.
On receipt of an abnormal NBHS result, the following medical interventions will begin:
Scenario 2: Symptomatic Individual
STRC-HL should be suspected in a proband with the following clinical findings and family history.
Clinical Findings
Congenital, generally non-progressive sensorineural hearing impairment
that is mild to moderate as measured by ABR testing or pure tone audiometry. The audiograms of individuals with STRC-HL often have a gently downsloping configuration, with hearing typically less affected in the low frequencies compared with the high frequencies.
Hearing is measured in decibels (dB). The threshold or 0 dB mark for each frequency refers to the level at which young adults with normal hearing perceive a tone burst 50% of the time. Hearing is considered normal if an individual's thresholds are within ~10 dB of normal thresholds. Severity of hearing loss is graded as shown in Table 1.
Table 1.
Severity of Hearing Loss in Decibels (dB)
View in own window
| Severity | Hearing Threshold in dB |
|---|
| Slight | 12-25 dB |
| Mild | 26-40 dB |
| Moderate | 41-60 dB |
| Moderately severe | 61-70 dB |
| Severe | 71-90 dB |
| Profound | >90 dB |
No related systemic findings identified by medical history, physical examination, or imaging of the inner ear and temporal bones (if such imaging is performed).
Family History
Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
Establishing the Diagnosis
The diagnosis of STRC-HL is established in a proband with suggestive findings who has ONE of the following identified by molecular genetic testing (see Table 2):
Biallelic STRC pathogenic (or likely pathogenic) variants
OR
One STRC pathogenic variant (or likely pathogenic variant) and one contiguous gene deletion involving STRC and CATSPER2
OR
Biallelic contiguous gene deletions involving STRC and CATSPER2
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic STRC variants of uncertain significance (or of one known STRC pathogenic variant and one STRC variant of uncertain significance) does not establish or rule out the diagnosis.
Approaches to molecular genetic testing include use of a hearing loss multigene panel that includes methods to detect copy number variants (CNVs) or comprehensive genomic testing.
Note: Single-gene testing (sequence analysis of STRC, followed by gene-targeted deletion/duplication analysis) is NOT recommended.
A
multigene hearing loss panel
that includes methods to detect CNVs and
STRC and other genes of interest (see
Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. This may be necessary given the high genomic complexity of the
STRC-CATSPER2 region, which includes pseudogenes with high homology due to segmental duplication.
For an introduction to multigene panels click
here. More detailed information for clinicians ordering genetic tests can be found
here.
Comprehensive genomic testing does not require the clinician to determine which gene(s) is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. To date, a significant proportion of STRC pathogenic variants are deletions within the coding region which are variably detected by exome sequencing depending on the analysis tools used. Genome sequencing generally provides more sensitivity for detection of STRC deletions.
For an introduction to comprehensive genomic testing click
here. More detailed information for clinicians ordering genomic testing can be found
here.
Table 2.
Molecular Genetic Testing Used in STRC-Related Autosomal Recessive Hearing Loss
View in own window
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method | Percent of Individuals w/STRC-HL in Whom Method(s) Establishes Molecular Diagnosis 3 |
|---|
|
STRC
| Sequence analysis 4 | ~20% 5, 6 | ~30% (biallelic STRC pathogenic variants) |
| CNV analysis 7 | ~80% 8 | ~40% (biallelic contiguous gene deletions involving STRC & CATSPER2) 9 |
| Both sequence & CNV analysis | ~30% (compound heterozygosity for one STRC pathogenic variant & one contiguous gene deletion involving STRC & CATSPER2) |
CNV = copy number variant; STRC-HL = STRC-related autosomal recessive hearing loss
- 1.
- 2.
- 3.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
- 6.
Supplementing standard next-generation sequencing (NGS) methods with long-range PCR-based sequencing or NGS assays increases the yield of pathogenic STRC sequencing variants by eliminating pseudogene contamination.
- 7.
Most reported STRC deletions/duplications are large and detectable by chromosomal microarray analysis (CMA). CMA uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including STRC) that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the 15q15.3 region. CMA designs in current clinical use targets the 15q15.3 region. Smaller deletions/duplications involving single or multiple exons within the gene (which are less frequently seen than contiguous gene copy number abnormalities) are also detectable using quantitative PCR or multiplex ligation-dependent probe amplification (MLPA). MLPA is an effective method to also eliminate pseudogene contamination and is frequently used to evaluate STRC CNVs. Exome and genome sequencing with CNV detection may be able to detect deletions/duplications.
- 8.
- 9.
Based on published reports to date, biallelic contiguous gene deletions involving STRC and CATSPER2 are estimated to be the most prevalent genotype in individuals with STRC-HL [Nishio & Usami 2022].
Clinical Characteristics
Clinical Description
STRC-related autosomal recessive hearing loss (STRC-HL) comprises both nonsyndromic sensorineural hearing loss and sensorineural hearing loss with decreased fertility in males when associated with biallelic contiguous gene deletions involving STRC and CATSPER2.
Decreased Male Fertility
Males with biallelic contiguous gene deletions involving STRC and CATSPER2 are at risk for CATSPER2-related male infertility associated with morphologic sperm abnormalities that affect sperm motility.
Females with contiguous gene deletions involving STRC and CATSPER2 have no related fertility issues.
Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified that distinguish between the hearing loss associated in persons with the following two genotypes:
Biallelic intragenic STRC pathogenic variants (including whole-gene deletions without deletion of contiguous genes)
Compound heterozygosity for one intragenic STRC pathogenic variant (including a whole-gene deletion without a contiguous gene deletion) and one STRC contiguous gene deletion
Males with biallelic contiguous gene deletions involving STRC and CATSPER2 are at risk of decreased fertility due to abnormal sperm motility.
Nomenclature
Nonsyndromic hearing impairment may be referred to by the gene involved (e.g., STRC-related autosomal recessive hearing loss) or by the genetic locus (e.g., DFNB16).
Nonsyndromic deafness loci are designated DFN (for DeaFNess) and further classified by mode of inheritance (DFNA: autosomal dominant; DFNB: autosomal recessive; DFNX: X-linked) and a number indicating the order of gene mapping and/or discovery. The term DFNB16 is used consistently in the literature to refer to STRC-HL but, as a term, does not encompass the decreased male fertility associated with biallelic contiguous gene deletions involving STRC and CATSPER2.
Prevalence
Prevalence of STRC-HL.
STRC-HL, the second most common cause of hereditary sensorineural hearing loss after GJB2-related autosomal recessive nonsyndromic hearing loss, accounts for close to ~15% of all diagnoses of hereditary hearing loss and 30% of all diagnoses of mild-to-moderate sensorineural hearing loss [Shearer et al 2014, Sloan-Heggen et al 2016, Perry et al 2023].
In a large meta-analysis, the overall prevalence of STRC-HL in individuals who did not have GJB2-related autosomal recessive nonsyndromic hearing loss was 4.08%, and the proportion of STRC pathogenic variants in the mild-to-moderate hearing loss group was 14.36% [Han et al 2021]. A study analyzing a large cohort of Japanese individuals with hearing loss found the prevalence of STRC-HL to be 4.27% in individuals with mild-to-moderate hearing loss [Nishio & Usami 2022].
Carrier frequency for STRC pathogenic variants or STRC-CATSPER2 contiguous gene deletions. One study that analyzed exome data alongside phenotypic information from a large, ethnically and racially diverse cohort of normal-hearing children estimated the carrier frequency to be 1.8% [Shubina-Oleinik et al 2021]. In another meta-analysis of individuals with normal hearing the estimated carrier frequency was 1.36% [Han et al 2021].
Based on published data to date, an estimated 27,000 individuals in the United States have biallelic STRC pathogenic genetic alterations.
Differential Diagnosis
Autosomal recessive nonsyndromic hearing loss (AR NSHL). As of this writing, more than 75 genes have been associated with AR NSHL. Biallelic genetic alterations involving STRC are the most common cause of mild-to-moderate sensorineural hearing loss and the second most common cause of autosomal recessive hearing loss overall [Sloan-Heggen et al 2016]. See Genetic Hearing Loss Overview.
Table 4 lists selected genes of interest in the differential diagnosis of STRC-related autosomal recessive hearing loss; for a current, comprehensive list of all identified autosomal recessive nonsyndromic hearing loss genes, see Hereditary Hearing Loss Homepage.
Table 4.
Selected Genes of Interest in the Differential Diagnosis of Nonsyndromic Mild-to-Moderate STRC-Related Autosomal Recessive Hearing Loss
View in own window
| Gene(s) | Disorder | MOI | Comment |
|---|
|
GJB2
|
GJB2-related AR NSHL
| AR |
|
ADGRV1
USH2A
WHRN
|
Usher syndrome type II
| AR | Usher syndrome overall (i.e., Usher syndrome types I, II, & III) is the most common type of AR syndromic HL & is a nonsyndromic HL mimic (HL is congenital w/later onset of retinitis pigmentosa in adolescence or early adulthood). Usher syndrome type II is assoc w/congenital, bilateral sensorineural HL that is mild to moderate in the low frequencies & severe to profound in the high frequencies.
|
|
OTOA
| Nonsyndromic hearing loss (OMIM 607039) | AR |
|
OTOG
OTOGL
| Nonsyndromic hearing loss (OMIM 614944) | AR |
|
AD = autosomal dominant; AR = autosomal recessive; NSHL = nonsyndromic hearing loss; HL = hearing loss; MOI = mode of inheritance; XL = X-linked
Decreased fertility. See OMIM Phenotypic Series: Spermatogenic failure for genes associated with male infertility.
Management
Evaluations Following Initial Diagnosis
To establish the extent of involvement and needs of an individual diagnosed with STRC-related autosomal recessive hearing loss (STRC-HL), the following evaluations are recommended:
Complete assessment of auditory acuity using age-appropriate tests such as auditory brain stem response (ABR) testing, auditory steady-state response (ASSR) testing, and pure tone audiometry
Evaluation by an otolaryngologist to assess ear health (e.g., middle ear status, cerumen management), dizziness and vertigo (which could be an indication of benign paroxysmal positional vertigo [BPPV]), medical appropriateness of amplification/hearing aids, need for hearing support in a school setting, and overall well-being
Evaluation by a speech-language pathologist for assessment of communication needs (through early intervention, in a school setting, or privately)
Complete ophthalmologic examination to assess visual acuity. Although STRC-HL is not associated with ophthalmologic findings, ophthalmologic examination is performed because children with hearing loss rely heavily on their vision; thus, it is imperative that reduced vision of whatever cause be promptly identified and addressed.
Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of STRC-HL in order to facilitate medical and personal decision making. Counseling on risk for decreased fertility in males with biallelic contiguous gene deletions involving STRC and CATSPER2 should also be shared, when appropriate.
Assess need for family support and resources including community or online
resources such as
Parent to Parent and social work involvement for parental support.
Treatment of Manifestations
Multidisciplinary supportive treatment. Multidisciplinary supportive treatment for hearing loss that includes an otolaryngologist with expertise in the management of early childhood otologic disorders, an audiologist experienced in the assessment of hearing loss in children, a speech-language pathologist, a clinical geneticist, a genetic counselor, and a pediatrician is recommended.
Hearing aids (i.e., sound amplification), customized by an audiologist to the degree and frequency of hearing loss, are often recommended in individuals with mild-to-moderate hearing loss.
See Genetic Hearing Loss Overview for discussion of other management issues.
Decreased male fertility. Males with biallelic contiguous gene deletions involving STRC and CATSPER2 are at risk for abnormal sperm motility. When reproductive age is reached, consultation with a reproductive specialist/endocrinologist for consideration of fertility-related evaluations is appropriate.
Surveillance
To monitor the degree of hearing loss, the individual's response to use of hearing aids, and development of speech and language, the following evaluations are recommended:
Annual examination by an otolaryngologist familiar with genetic hearing loss to assure that no other reversible factors may be contributing to hearing loss, such as otitis media or cerumen impaction. This visit also ensures health of the ears in the presence of hearing aids.
Repeat audiometry to identify any change in hearing. In general, audiologic evaluation is recommended every three months between birth and age two years and every six months between the ages of two and five years. Hearing tests can occur annually for children age five years and older if hearing is stable and there are no additional otologic concerns. Audiologic scheduling and follow up will be determined by the individual's managing audiologist.
Evaluation of speech and language and/or communication as recommended by a speech-language pathologist
Agents/Circumstances to Avoid
Noise exposure is a well-recognized environmental cause of hearing loss. Since this risk can be minimized by avoidance, persons with documented hearing loss should be counseled appropriately and repeated overexposure to loud noises should be avoided. There is no established "safe" noise level; however, the United States Occupational Safety and Health Administration (OSHA) and National Institute for Occupational Safety and Health (NIOSH) have identified a permissible noise exposure limit of 85 decibels (dB) over an eight-hour work day.
One of the primary sources of loud noise exposure in our environment is sound from headphones and earbuds. An 85-dB limit on earbuds and headphones may provide a reasonable way to reduce loud noise exposure. The headphone safety feature built into most smartphones can be set to limit noise level.
Headphone/earbud safety features can be found in the phone settings menu:
In iPhones, under Settings > Sounds & Haptics > Headphone Safety
In Android phones, under Settings > Sounds & Vibrations > Volume > Media Volume Limit
Also see these general resources on noise reduction:
Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of sibs of a proband with STRC-HL if:
A newborn sib has an abnormal result on universal newborn hearing screening (NBHS);
A newborn sib has a normal result on NBHS (as NBHS may miss newborns with milder hearing loss); or
A sib did not undergo NBHS and/or NBHS results are unknown.
Early identification of infants and children with hearing loss allows appropriate support and management to be provided to the child and family.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Using a mouse model with a targeted deletion of STRC and a resulting 60-dB sensorineural hearing loss, Shubina-Oleinik et al [2021] used a dual adeno-associated viral vector approach to deliver a full-length copy of STRC to the outer hair cells of the cochlea that restored – in 50% of mice – auditory function by a significant margin. Although this study indicates STRC may be a promising target for gene therapy, to date there are no human clinical trials for this disorder.
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Mode of Inheritance
STRC-related autosomal recessive hearing loss (STRC-HL) is inherited in an autosomal recessive manner.
Risk to Family Members
Parents of a proband
The parents of an individual with STRC-HL are presumed to be heterozygous for a genetic alteration involving STRC (i.e., an STRC pathogenic variant or a contiguous gene deletion involving STRC and CATSPER2).
Molecular genetic testing capable of detecting the genetic alterations identified in the proband is recommended for the parents to confirm that both parents are heterozygous for a genetic alteration involving STRC and to allow reliable recurrence assessment.
If a genetic alteration is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the genetic alterations identified in the proband occurred as a
de novo event in the proband or as a postzygotic
de novo event in a mosaic parent [
Jónsson et al 2017]. Preliminary data suggest that a significant proportion
STRC copy number alterations are
de novo [
Klimara et al 2022].
If the proband appears to have homozygous genetic alterations (i.e., the same two genetic alterations), additional possibilities to consider include:
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the genetic alteration that resulted in homozygosity for the pathogenic variant in the proband.
Individuals who are heterozygous for a genetic alteration involving STRC do not have an increased chance of STRC-HL.
Sibs of a proband
If both parents are known to be heterozygous for a genetic alteration involving STRC, each sib of the proband has at conception a 25% chance of having STRC-HL, a 50% chance of being a carrier and not having STRC-HL, and a 25% chance of not being a carrier and not having STRC-HL.
STRC-HL is typically congenital and in the mild-to-moderate range of severity with minimal or no progression for both probands and sibs, regardless of the familial genetic alterations. There can be slight differences in clinical presentations between sibs.
Individuals who are heterozygous for a genetic alteration involving STRC do not have an increased chance of STRC-HL.
Offspring of a proband. Unless the proband's reproductive partner also has STRC-HL or is a carrier of a genetic alteration involving STRC, offspring will be obligate heterozygotes (i.e., carriers of a genetic alteration involving STRC).
Other family members. Each sib of the proband's parents has a 50% chance of being a carrier of a genetic alteration involving STRC.
Carrier detection. Carrier testing for relatives requires prior identification of the genetic alterations involving STRC in the family.
Prenatal Testing and Preimplantation Genetic Testing
Once the genetic alterations involving STRC have been identified in a family member with STRC-HL, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella
support organizations and/or registries for the benefit of individuals with this disorder
and their families. GeneReviews is not responsible for the information provided by other
organizations. For information on selection criteria, click here.
Alexander Graham Bell Association for the Deaf and Hard of Hearing
Phone: 866-337-5220 (toll-free); 202-337-5221 (TTY)
Fax: 202-337-8314
Email: info@agbell.org
American Society for Deaf Children
Phone: 800-942-2732 (ASDC)
Email: info@deafchildren.org
American Speech-Language-Hearing Association (ASHA)
Phone: 800-638-8255; 301-296-5650 (TTY)
Fax: 301-296-8580
BabyHearing.org
This site, developed with support from the National Institute on Deafness and Other Communication Disorders, provides information about newborn hearing screening and hearing loss.
Hands & Voices
Medical Home Portal
MedlinePlus
National Association of the Deaf
Phone: 301-587-1788 (Purple/ZVRS); 301-328-1443 (Sorenson); 301-338-6380 (Convo)
Fax: 301-587-1791
Email: nad.info@nad.org
Newborn Screening in Your State
Health Resources & Services Administration
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Table A.
STRC-Related Autosomal Recessive Hearing Loss: Genes and Databases
View in own window
Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Molecular Pathogenesis
The delicate molecular machinery of the cochlea that permits hearing in humans involves hundreds of genes. STRC encodes stereocilin, an extracellular structural protein that is expressed on outer hair cells (OHCs) in the organ of Corti of the cochlea. Stereocilin connects adjacent stereocilia and links hair cell bundles to the tectorial membrane, enabling sound dampening, amplification of soft sounds, and frequency tuning. For proper auditory function, a physical connection must be maintained between these bundles of stereocilia and the overlying tectorial membrane. The OHCs and tectorial membrane (which work to detect pitch, discriminate frequency, and dampen sound) are nonfunctioning in STRC-HL and result in loss of proper auditory function. Because the inner hair cells (IHCs) (which are responsible for the mechanotransduction of sound) are still viable, loss of stereocilin function does not lead to severe-to-profound hearing loss.
Mechanism of disease causation. Loss of function
STRC-specific laboratory technical considerations.
STRC is part of a large tandem duplication that gave rise to a pseudogene (STRCP1) that shares 98.9% overall homology with STRC and more than 99% sequence homology with the coding region of STRC [Francey et al 2012]. As such, accurate gene sequencing and detection of single nucleotide variants present a diagnostic challenge. Sensitivity for variant detection is improved with long-range PCR and genome sequencing techniques. Given these challenges, some clinical molecular diagnostic laboratories do not offer direct sequencing of STRC.
In addition, the STRC locus lies within a tandem duplication with a predisposition for nonallelic homologous recombination and is therefore associated with a high frequency of 15q15.3 contiguous gene deletions involving CATSPER2, necessitating accurate methods for detection of copy number variants (CNVs). Methods such as multiplex ligation-dependent amplification (MLPA), array comparative genomic hybridization (CGH), or single-nucleotide polymorphism (SNP) arrays should be considered by clinical molecular diagnostic laboratories testing for STRC-HL. CNV analysis methods as part of exome or genome sequencing may also be used. Genome sequencing has been shown to be sensitive for detection of deletions involving 15q15.3 [Abbasi et al 2022].
Chapter Notes
Author Notes
Translational Hearing Genomics Lab
A Eliot Shearer, MD, PhD (ude.dravrah.snerdlihc@reraehs.toile), is actively involved in clinical research regarding individuals with STRC-related autosomal recessive hearing loss (STRC-HL). He would be happy to communicate with persons who have any questions regarding diagnosis of STRC-HL or other considerations.
Dr Shearer is also interested in hearing from clinicians treating families affected by hereditary hearing loss in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.
Contact Dr Shearer to inquire about review of STRC variants of uncertain significance.
References
Literature Cited
Abbasi
W, French
CE, Rockowitz
S, Kenna
MA, Eliot Shearer
A. Evaluation of copy number variants for genetic hearing loss: a review of current approaches and recent findings.
Hum Genet.
2022;141:387-400.
[
PubMed: 34811589]
Achard
S, Campion
M, Parodi
M, MacAskill
M, Hochet
B, Simon
F, Rouillon
I, Jonard
L, Serey-Gaut
M, Denoyelle
F, Loundon
N, Marlin
S. Recurrent benign paroxysmal positional vertigo in DFNB16 patients with biallelic STRC gene deletions.
Otol. Neurotol.
2023a;44:e241-5.
[
PubMed: 36764706]
Achard
S, Simon
F, Denoyelle
F, Marlin
S. Recurrent benign paroxysmal positional vertigo in two DFNB16 siblings: A CARE case report.
Eur Ann Otorhinolaryngol Head Neck Dis.
2023b;140:127-9.
[
PubMed: 36526540]
Amr
SS, Murphy
E, Duffy
E, Niazi
R, Balciuniene
J, Luo
M, Rehm
HL, Abou Tayoun
AN. Allele-specific droplet digital PCR combined with a next-generation sequencing-based algorithm for diagnostic copy number analysis in genes with high homology: proof of concept using stereocilin.
Clin Chem.
2018;64:705-14.
[
PubMed: 29339441]
Back
D, Shehata-Dieler
W, Vona
B, Hofrichter
MAH, Schroeder
J, Haaf
T, Rahne
T, Hagen
R, Schraven
SP. Phenotypic characterization of DFNB16-associated hearing loss.
Otol. Neurotol.
2019;40:e48-55.
[
PubMed: 30531641]
Čada
Z, Brožková
DS, Balatková
Z, Plevová
P, Rašková
D, Laštůvková
J, Černý
R, Bandúrová
V, Koucký
V, Hrubá
S, Komarc
M, Jenčík
J, Marková
SP, Plzák
J, Kluh
J, Seeman
P. Moderate sensorineural hearing loss is typical for DFNB16 caused by various types of mutations affecting the STRC gene.
European archives of oto-rhino-laryngology.
2019;276:3353-8.
[
PubMed: 31552524]
Francey
LJ, Conlin
LK, Kadesch
HE, Clark
D, Berrodin
D, Sun
Y, Glessner
J, Hakonarson
H, Jalas
C, Landau
C, Spinner
NB, Kenna
M, Sagi
M, Rehm
HL, Krantz
ID. Genome-wide SNP genotyping identifies the stereocilin (STRC) gene as a major contributor to pediatric bilateral sensorineural hearing impairment.
Am J Med Genet A.
2012;158A:298-308.
[
PMC free article: PMC3264741] [
PubMed: 22147502]
Frykholm
C, Klar
J, Tomanovic
T, Ameur
A, Dahl
N. Stereocilin gene variants associated with episodic vertigo: expansion of the DFNB16 phenotype.
Eur J Hum Genet.
2018;26:1871-4.
[
PMC free article: PMC6244415] [
PubMed: 30250054]
Jónsson
H, Sulem
P, Kehr
B, Kristmundsdottir
S, Zink
F, Hjartarson
E, Hardarson
MT, Hjorleifsson
KE, Eggertsson
HP, Gudjonsson
SA, Ward
LD, Arnadottir
GA, Helgason
EA, Helgason
H, Gylfason
A, Jonasdottir
A, Jonasdottir
A, Rafnar
T, Frigge
M, Stacey
SN, Th Magnusson
O, Thorsteinsdottir
U, Masson
G, Kong
A, Halldorsson
BV, Helgason
A, Gudbjartsson
DF, Stefansson
K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.
Nature.
2017;549:519-22.
[
PubMed: 28959963]
Klimara
MJ, Nishimura
C, Wang
D, Kolbe
DL, Schaefer
AM, Walls
WD, Frees
KL, Smith
RJH, Azaiez
H. De novo variants are a common cause of genetic hearing loss.
Genet Med.
2022;24:2555-67
[
PMC free article: PMC9729384] [
PubMed: 36194208]
Mandelker
D, Amr
SS, Pugh
T, Gowrisankar
S, Shakbatyan
R, Duffy
E, Bowser
M, Harrion
B, Lafferty
K, Mahanta
L, Rehm
HL, Funke
BH. Comprehensive diagnostic testing for stereocilin an approach for analyzing medically important genes with high homology.
J Mol Diagn.
2014;16:639-47.
[
PubMed: 25157971]
Perry
J, Redfield
S, Oza
A, Rouse
S, Stewart
C, Khela
H, Srinivasan
T, Albano
V, Shearer
E, Kenna
M. Exome sequencing expands the genetic diagnostic spectrum for pediatric hearing loss.
Laryngoscope.
2023;133:2417-24.
[
PubMed: 36515421]
Richards
S, Aziz
N, Bale
S, Bick
D, Das
S, Gastier-Foster
J, Grody
WW, Hegde
M, Lyon
E, Spector
E, Voelkerding
K, Rehm
HL, et al.
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
Genet Med.
2015;17:405-24.
[
PMC free article: PMC4544753] [
PubMed: 25741868]
Shearer
AE, Kolbe
DL, Azaiez
H, Sloan
CM, Frees
KL, Weaver
AE, Clark
ET, Nishimura
CJ, Black-Ziegelbein
EA, Smith
RJ. Copy number variants are a common cause of non-syndromic hearing loss.
Genome Med.
2014;6:37.
[
PMC free article: PMC4067994] [
PubMed: 24963352]
Shubina-Oleinik
O, Nist-Lund
C, French
C, Rockowitz
S, Shearer
AE, Holt
JR. Duel-vector gene therapy restores cochlear amplification and auditory sensitivity in a mouse model of DFNB16 hearing loss.
Sci Adv.
2021;7:eabi7629.
[
PMC free article: PMC8673757] [
PubMed: 34910522]
Simi
A, Perry
J, Schindler
E, Oza
A, Luo
M, Hartman Tm Krantz
ID, Germiller
JA, Kawai
K, Kenna
M. Audiologic phenotype and progression in pediatric STRC-related autosomal recessive hearing loss.
Laryngoscope.
2021;131:E2897-E2903.
[
PubMed: 34111299]
Sloan-Heggen
CM, Bierer
AO, Shearer
AE, Kolbe
DL, Nishimura
CJ, Frees
KL, Ephraim
SS, Shibata
SB, Booth
KT, Campbell
CA, Ranum
PT, Weaver
AE, Black-Ziegelbein
EA, Wang
D, Azaiez
H, Smith
RJ. Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss.
Hum Genet.
2016;135:441–50.
[
PMC free article: PMC4796320] [
PubMed: 26969326]
Stenson
PD, Mort
M, Ball
EV, Chapman
M, Evans
K, Azevedo
L, Hayden
M, Heywood
S, Millar
DS, Phillips
AD, Cooper
DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.
Hum Genet.
2020;139:1197-207.
[
PMC free article: PMC7497289] [
PubMed: 32596782]
Yokota
Y, Moteki
H, Nishio
SY, Yamaguchi
T, Wakui
K, Ohyama
K, Miyazaki
H, Matsuoka
R, Abe
S, Kunakawa
K, Takahashi
M, Sakaguchi
H, Uehara
N, Ishino
T, Kosho
T, Fukushima
Y, Usami
SI. Frequency and clinical features of hearing loss caused by
STRC deletions.
Sci Rep.
2019;9:4408.
[
PMC free article: PMC6416315] [
PubMed: 30867468]
