Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released 1.0.1
• GENE/GENE PANEL: CIB2, CABP2, CDH23, CLDN14, ESPN, ESRRB, GIPC3, GJB2, GRXCR1, ILDR1, LHFPL5, LRTOMT, MARVELD2, MYO15A, MYO3A, MYO6, OTOA, OTOG, OTOGL, PDZD7, POU3F4, PTPRQ, RDX, S1PR2, STRC, TECTA, TMC1, TMIE, TPRN, TRIOBP, PJVK
• Condition: Prelingual non-syndromic hearing loss and deafness
• Mode(s) of Inheritance: Unknown

Actionability Assertion

• CIB2 ⇔ 0016297 (deafness, autosomal recessive 48; dfnb48): Strong Actionability
• CABP2 ⇔ 0016297 (deafness, autosomal recessive 93; dfnb93): Strong Actionability
• CDH23 ⇔ 0016297 (deafness, autosomal recessive 12; dfnb12): Strong Actionability
• CLDN14 ⇔ 0016297 (deafness, autosomal recessive 29; dfnb29): Strong Actionability
• ESPN ⇔ 0016297 (deafness, autosomal recessive 36, with or without vestibular involvement; dfnb36): Strong Actionability
• ESRRB ⇔ 0016297 (deafness, autosomal recessive 35; dfnb35): Strong Actionability
• GIPC3 ⇔ 0016297 (deafness, autosomal recessive 15; dfnb15): Strong Actionability
• GJB2 ⇔ 0016297 (deafness, autosomal recessive 1a; dfnb1a): Strong Actionability
• GRXCR1 ⇔ 0016297 (deafness, autosomal recessive 25; dfnb25): Strong Actionability
• ILDR1 ⇔ 0016297 (deafness, autosomal recessive 42; dfnb42): Strong Actionability
• LHFPL5 ⇔ 0016297 (deafness, autosomal recessive 67; dfnb67): Strong Actionability
• LRTOMT ⇔ 0016297 (deafness, autosomal recessive 63; dfnb63): Strong Actionability
• MARVELD2 ⇔ 0016297 (deafness, autosomal recessive 49; dfnb49): Strong Actionability
• MYO15A ⇔ 0016297 (deafness, autosomal recessive 3; dfnb3): Strong Actionability
• MYO3A ⇔ 0016297 (deafness, autosomal recessive 30; dfnb30): Strong Actionability
• MYO6 ⇔ 0016297 (deafness, autosomal dominant 22; dfna22): Strong Actionability
• OTOA ⇔ 0016297 (deafness, autosomal recessive 22; dfnb22): Strong Actionability
• OTOG ⇔ 0016297 (deafness, autosomal recessive 18b; dfnb18b): Strong Actionability
• OTOGL ⇔ 0016297 (deafness, autosomal recessive 84b; dfnb84b): Strong Actionability
• PDZD7 ⇔ 0016297 (deafness, autosomal recessive 57; dfnb57): Strong Actionability
• POU3F4 ⇔ 0016297 (deafness, x-linked 2; dfnx2): Strong Actionability
• PTPRQ ⇔ 0016297 (deafness, autosomal recessive 84a; dfnb84a): Strong Actionability
• RDX ⇔ 0016297 (deafness, autosomal recessive 24; dfnb24): Strong Actionability
• S1PR2 ⇔ 0016297 (deafness, autosomal recessive 68; dfnb68): Strong Actionability
• STRC ⇔ 0016297 (deafness, autosomal recessive 16; dfnb16): Strong Actionability
• TECTA ⇔ 0016297 (deafness, autosomal dominant 12; dfna12): Strong Actionability
• TECTA ⇔ 0016297 (deafness, autosomal recessive 21; dfnb21): Strong Actionability
• TMC1 ⇔ 0016297 (deafness, autosomal recessive 7; dfnb7): Strong Actionability
• TMIE ⇔ 0016297 (deafness, autosomal recessive 6; dfnb6): Strong Actionability
• TPRN ⇔ 0016297 (deafness, autosomal recessive 79; dfnb79): Strong Actionability
• TRIOBP ⇔ 0016297 (deafness, autosomal recessive 28; dfnb28): Strong Actionability
• PJVK ⇔ 0016297 (deafness, autosomal recessive 59; dfnb59): Strong Actionability

Actionability Rationale

Although the consensus assertion was consistent with the assertion computed according to the rubric, there was discussion around ambiguity for likelihood and effectiveness outside of GJB2.

Final Consensus Scores

Gene Condition Pairs: CIB2 ⇔ 0016297 (OMIM:609439) CABP2 ⇔ 0016297 (OMIM:614899) CDH23 ⇔ 0016297 (OMIM:601386) CLDN14 ⇔ 0016297 (OMIM:614035) ESPN ⇔ 0016297 (OMIM:609006) ESRRB ⇔ 0016297 (OMIM:608565) GIPC3 ⇔ 0016297 (OMIM:601869) GJB2 ⇔ 0016297 (OMIM:220290) GRXCR1 ⇔ 0016297 (OMIM:613285) ILDR1 ⇔ 0016297 (OMIM:609646) LHFPL5 ⇔ 0016297 (OMIM:610265) LRTOMT ⇔ 0016297 (OMIM:611451) MARVELD2 ⇔ 0016297 (OMIM:610153) MYO15A ⇔ 0016297 (OMIM:600316) MYO3A ⇔ 0016297 (OMIM:607101) MYO6 ⇔ 0016297 (OMIM:606346) OTOA ⇔ 0016297 (OMIM:607039) OTOG ⇔ 0016297 (OMIM:614945) OTOGL ⇔ 0016297 (OMIM:614944) PDZD7 ⇔ 0016297 (OMIM:618003) POU3F4 ⇔ 0016297 (OMIM:304400) PTPRQ ⇔ 0016297 (OMIM:613391) RDX ⇔ 0016297 (OMIM:611022) S1PR2 ⇔ 0016297 (OMIM:610419) STRC ⇔ 0016297 (OMIM:603720) TECTA ⇔ 0016297 (OMIM:601543) TECTA ⇔ 0016297 (OMIM:603629) TMC1 ⇔ 0016297 (OMIM:600974) TMIE ⇔ 0016297 (OMIM:600971) TPRN ⇔ 0016297 (OMIM:613307) TRIOBP ⇔ 0016297 (OMIM:609823) PJVK ⇔ 0016297 (OMIM:610220)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Communication deficit / Referral to multidisciplinary care team, as available, to facilitate communication development and discussion of other interventions (such as hearing aids, cochlear implants)	1	3N	3B	3	10NB

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Hearing loss is the most common sensory deficit in humans, affecting up to 1 in 500 newborns. About 1.2 in every 1,000 children is severely or profoundly deaf at 3 years old. This rises to 2 to 3.65 in every 1,000 children by school age. In developed countries approximately 80% of congenital hearing loss is due to genetic causes and the remainder to environmental (acquired) causes. Approximately 80% of prelingual deafness is genetic, most often autosomal recessive and non-syndromic. [1, 2, 3, 4, 5, 6, 7, 8, 9, 10]

Clinical Features

This report is focused on the topic of non-syndromic genetic hearing loss with prelingual onset. Types of hearing loss include conductive, sensorineural, mixed, or hearing impairment due to central auditory dysfunction. Conductive hearing loss results from abnormalities of the external ear and/or the ossicles of the middle ear. Sensorineural hearing loss results from malfunction of inner ear structures (i.e., cochlea or auditory nerve), while mixed hearing loss is a combination of conductive and sensorineural hearing loss. Central auditory dysfunction results from damage or dysfunction at the level of the eighth cranial nerve, auditory brain stem, or cerebral cortex. Each type of hearing loss can vary by laterality and symmetry. Non-syndromic hearing impairment has no associated abnormalities of the external ear or any related medical problems, however, it can be associated with abnormalities of the middle ear and/or inner ear. Uniquely, POU3F4-related hearing loss is characterized by a pathognomonic temporal bone deformity. Prelingual hearing loss is present before language develops. All congenital hearing loss is prelingual, but not all prelingual hearing loss is congenital. Hearing is measured in decibels (dB) and the severity of hearing loss is graded by hearing threshold in dB from mild to profound.
GJB2-associated non-syndromic hearing loss is sensorineural, usually present at birth, typically bilateral and nonprogressive, and can range from mild to profound in severity. Vestibular function is normal; affected infants and young children do not experience balance problems and learn to sit and walk at age-appropriate times. Except for the hearing impairment, affected individuals are healthy; life span is normal.
Syndromic forms of hearing loss (such as Pendred syndrome), mitochondrial associated predisposition to aminoglycoside ototoxicity, and genes related to hearing loss with additional phenotypes that include other medical problems (such as OTOF-related hearing loss) are not included in this report. [1, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]

Natural History

Deafness is not typically associated with increased mortality. For children, deafness may have significant consequences for linguistic, cognitive, emotional, educational, and social development. Children with hearing loss may be at risk of language deprivation and have difficulty learning grammar, word order, idiomatic expressions, and other forms of verbal communication. Delayed language and speech, low educational attainment, increased behavior problems, decreased psychosocial well-being, and poor adaptive skills are all associated with hearing loss in children. Educational intervention is insufficient to completely remediate these deficiencies. Thus, early identification and timely intervention is essential for optimal cognitive development in children with prelingual deafness. Historically, children who are deaf or hard of hearing were not identified until two-to-three years of age, and those with hearing thresholds between ~25 and 40 dB hearing level were often undetected until school age.
Members of the Deaf community in the United States are deaf and use American Sign Language (ASL). As in other cultures, members are characterized by unique social and societal attributes. Members of the Deaf community (i.e., the Deaf) do not consider themselves to be hearing "impaired," nor do they feel that they have a hearing "loss." Rather, they consider themselves Deaf. Their deafness is not considered to be a pathology or disease to be treated or cured. "Hard of hearing" is more functional than audiologic. This term is used by the Deaf to signify that a person has some usable hearing – anything from mild to severe hearing loss.
"Hearing impairment" and "hearing loss" is terminology from a medical perspective that is often utilized in guidelines. Therefore, this report will use the terms as used in the guidelines. [3, 5, 6, 7, 8, 9, 11, 46]

2. How effective are interventions for preventing harm?

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making following a diagnosis of this condition: https://www.acmg.net/PDFLibrary/Hearing-Loss-ACT-Sheet.pdf

Referral to a multidisciplinary care center, when available, is recommended. A team approach that includes otolaryngologists, clinical geneticists, genetic counselors, audiologists, speech and ASL therapists, early hearing intervention and family support specialists (which may include other individuals who are deaf or hard of hearing or other parents of deaf or hard-of-hearing children), and other appropriate specialists offer optimal opportunity to provide ongoing management and support of deaf and hard-of-hearing individuals and their families as their needs change over time. (Tier 2) [7, 8, 12, 47]

Early intervention (EI) should begin as soon as possible after confirming hearing loss, regardless of age of identification or the type of hearing loss. When possible, it is recommended that intervention begin within the first year, optimally by the age of 6 months. EI comprises evaluation for amplification or sensory devices, surgical and medical evaluation, communication assessment and therapy, and access to education and support resources. The purpose of early intervention is to meet the individualized needs of the child and family, including acquisition of communication competence, social skills, emotional well-being and positive self-esteem. All children who are deaf from birth to age 3 years of age and their families should have EI providers who have the qualifications, knowledge, and skills (e.g. educational strategies for infants/toddlers who are deaf), to optimize the child's development and child/family well-being. (Tier 2) [3, 7, 11, 12]

Shorter duration of hearing loss was associated with better outcomes, as it meant upon detection of hearing loss children and families could be provided with intervention services. Eleven research studies reported on the influence of duration of hearing loss on outcomes for children with hearing loss. A wide range of speech and language measures were captured using different methodologies. Almost all studies included children who used cochlear implants. Children who had a shorter duration of hearing loss tended to do better in terms of speech and language measures compared to their peers with a longer duration of hearing loss. The impact of duration of hearing loss on other outcomes such as reading ability and play were poorly represented in the literature. The evidence indicates that a composite of interrelated constructs of a habilitation methodology contribute to optimal outcomes for children with hearing loss. (Tier 1) [9]

If the family chooses, fitting of hearing aid amplification no later than four months of age (or as soon as there is confirmation that the child is deaf or hard of hearing) is optimal, if not medically contraindicated (e.g., draining ear, local skin or ear canal condition, absent auditory nerves). The purpose of hearing aid amplification in infants who are deaf or hard of hearing is to facilitate timely and optimal auditory development as a precursor to development of spoken language. (Tier 2) [7, 11]

Age at fitting of hearing aids may influence outcomes for children who have hearing loss. Timely access to audition is likely to support the development of speech and language skills. Age at fitting of hearing aids interacts with other variables (such as age at diagnosis and commencement of intervention programs). This finding highlights the complex inter-relationship between variables and their influence on outcomes. (Tier 1) [9]

If the family’s goals for their child include development of spoken language, cochlear implants are the mainstay of treatment for most children with severe to profound hearing loss. Cochlear implants should only be considered after an assessment by a multidisciplinary team. As part of the assessment, children should also have had a valid trial of an acoustic hearing aid for at least 3 months (unless contraindicated or inappropriate). If there is failure to make expected progress with appropriately fitted amplification in those with severe to profound hearing loss, cochlear implants are indicated. Timing of the intervention remains critical, with better outcomes achieved for those receiving an implant by two years of age. Outcomes following cochlear implantation can be impacted by a number of variables that include: age at implantation, progression of hearing loss, duration of device use, cochlear morphology and cranial nerve VIII integrity, electrode placement, high qualify mapping of speech processor, parental educational level, and involvement in family centered, intensive-auditory based intervention. In general, device failure rates after successful implantation are low (less than 5% over 15 years). (Tier 2) [3, 6, 7, 11]

A child’s age at the time of cochlear implantation does influence outcomes for children who have hearing loss. The younger a child is when they receive a cochlear implant, the better the outcomes. However, there is no consensus regarding a minimum age or an optimum age for implantation. Success following implantation is dependent upon high quality intervention services. (Tier 1) [9]

There is recent research focused on cochlear implant performance based on causative gene. Most reports related to GJB2 pathogenic variants were retrospective analyses of cochlear implant patients. These studies indicate good or identical implant performance to those in other groups. In general, patients without GJB2 pathogenic variants consist of those with inner ear malformations, cochlear nerve deficiency and associated developmental disorders, thus limiting the outcomes for these groups. One report mentioned cochlear implant and electric acoustic stimulation (EAS) outcomes in patients with CDH23 pathogenic variants. Patients with biallelic CDH23 mutations showed good EAS performance. (Tier 5) [48]

Surveillance

Regular surveillance of hearing status is recommended for all children with hearing levels that fall outside the range of normal in one or both ears. Regular assessment of progress of communication development (receptive and expressive language, speech, and auditory skills) through appropriate protocols is recommended every 6 months in the infant/toddler period and every 12 months thereafter. (Tier 2) [7, 12]

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. (Tier 4) [5]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Unknown
The inheritance pattern among the disorders with prelingual non-syndromic hearing loss is up to 80% autosomal recessive, 20% autosomal dominant, and 1%-1.5% x-linked or other. [1, 2, 4, 5, 7, 8, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]

Prevalence of Genetic Variants

Non-syndromic hereditary hearing loss is characterized by extreme genetic heterogeneity: to date, more than 6,000 causative variants have been identified in more than 110 genes. (Tier 3) [7, 8]

The most common cause autosomal recessive non-syndromic hearing loss in a variety of populations is a pathogenic variant in GJB2. It accounts for approximately 50% of congenital severe-to-profound autosomal recessive non-syndromic hearing loss in the United States, France, Britain, and New Zealand/Australia. The contribution of pathogenic variants in GJB2 to deafness varies considerably by ethnicity and ranges from 15-40% of all deaf individuals in a variety of populations. The most common cause of mild-to-moderate autosomal recessive hearing loss is pathogenic variants in STRC; of note, there is ethnic-based variability. One gene, GJB2, accounts for the largest proportion of autosomal recessive early childhood hearing loss in many populations (Tier 3) [1, 5, 7, 8]

A meta-analysis of 179 studies, encompassing 43,530 hearing-loss probands and 7,518 individuals with biallelic GJB2-associated hearing loss, found a worldwide GJB2-associated hearing loss prevalence of 17.3%. GJB2 pathogenic variant prevalence was the highest in Europe (27.1%) and the lowest in sub-Saharan Africa (5.6%), but generally high throughout the world. (Tier 1) [2]

Penetrance

Certain pathogenic variants in GJB2 (167delT, 35delG and 235delC) associated with autosomal recessive non-syndromic prelingual sensorineural hearing loss are thought to have complete penetrance with variable expressivity. Two other variants in GJB2 (M34T and V34I) are associated with incomplete penetrance and variable expressivity. (Tier 3) [49]

Numerous studies have shown that it is possible to predict phenotype based on genotype in GJB2 associated hearing loss. A large cross-sectional analysis of GJB2 genotype and audiometric data from 1,531 persons from 16 different countries with autosomal recessive mild-to-profound non-syndromic deafness identified 83 different variants, 47 were predicted non-truncating (e.g., missense variants) and 36 were predicted truncating (e.g., premature stop codons). The authors defined three genotype classes: biallelic truncating (T/T) variants, biallelic non-truncating (NT/NT) variants, and compound heterozygous truncating/non-truncating (T/NT) variants. The degree of hearing impairment observed in the T/T variants group (77.3% of all) was 64% profound, 25% severe, 10% moderate and 1% mild. The NT/NT variants group (6.2% of all) was 13% profound, 8% severe, 26% moderate, and 53% mild. The T/NT variants group (16.5% of all) was 25% profound, 11% severe, 28% moderate, and 36% mild. The degree of hearing impairment associated with biallelic truncating variants was significantly more severe than the hearing impairment associated with biallelic non-truncating variants (P.0001). (Tier 3) [1]

Relative Risk

Information on relative risk was not available for the Pediatric context.

Expressivity

Intrafamilial variability in the degree of deafness is seen in GJB2-associated hearing loss. (Tier 4) [1]

GJB2-associated hearing loss has a high degree of variability of the audiologic phenotype. The severity of hearing loss is known to range from profound deafness at birth to mild, progressive hearing loss presenting in late childhood, and is highly dependent on genotype. (Tier 1) [2]

4. What is the Nature of the Intervention?

Nature of Intervention

Services for people who are deaf aim to improve their quality of life by maximizing their ability to communicate, using the means most appropriate for the person and their environment, and to enable the person to move safely within their environment. General risks and complications of CI surgery include risk of meningitis, infection, facial nerve paralysis, cerebrospinal fluid leak, electrode migration and anesthesia risk; however, the overall risks of complications of screening and treatment are estimated to be small (less than 1%). POU3F4-related hearing loss has a temporal bone deformity that results in perilymphatic fluid “gusher” during stapes surgery. [3, 6, 7, 11, 45]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

If 1 to 2 infants out of every 1000 are identified as deaf or hard of hearing at birth, it is estimated that another 1 to 2 per 1000 will later be identified with permanent hearing loss. This may reflect delayed-onset hearing loss as well as missed conductive, sensory, or neural hearing loss at the time of newborn hearing screen. Reports have described children with GJB2 pathogenic variants who pass the newborn hearing screen and have somewhat later-onset hearing loss. (Tier 3) [1, 7, 8]

Syndromic hearing loss can masquerade as non-syndromic hearing loss until secondary signs and symptoms present. (Tier 4) [5]

Date of Search: 03.31.2020 (updated 10.29.2020)

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